JPS602254A - Artificial blood vessel and production thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] More specifically, the present invention relates to an artificial blood vessel having physical properties similar to that of a living blood vessel and a method for manufacturing the same.

Since the study by Carrel et al. in 1912, many studies on artificial blood vessels have been conducted.

Currently, as artificial blood vessels for large-diameter arteries with an endoluminal system of about 6 mm or more, for example, Dobesky artificial blood vessels made of Dacron knitted fabric made by USCI, and VoreTex made of expanded polytetrafluoroethylene made by Boa Co., Ltd. are in clinical practice. It is used in However, the physical properties (particularly compliance) of these artificial blood vessels are significantly different from those of biological blood vessels, so they have the disadvantage that various types of stress are generated at the anastomotic site, making them susceptible to aneurysm and the like. In addition, the inner diameter of the pipe is approximately 611
Arterial vascular grafts with a small caliber of less than 100 mm are affected by differences in physical properties in addition to the inner diameter of the tube and small blood flow rate, while venous vascular grafts are affected by differences in physical properties in addition to the tendency for blood to coagulate. However, no one with sufficient patency for clinical use has been developed.

Further, an attempt to make the compliance of an artificial blood vessel similar to that of a biological blood vessel is disclosed in US Pat. No. 4,173,689. However, the problem remains that although the compliance of artificial blood vessels produced using this method is certainly greater, it is still smaller than that of biological blood vessels.

JP-A-57-150954 proposes a method of increasing compliance by combining a solid zone and a porous zone of elastomer. The method described in this publication is a solid zone - a zone containing salt.
This method involves creating a solid zone and then eluting the salt with water or the like, but it is unlikely that the salt will be eluted through the solid zone. In addition, it is difficult to elute the pore-forming agent that is independently wrapped in the polymer, and it is technically difficult to make the elastomer itself into a porous body with a size of 1 to 150 JAn using these methods. It is considered difficult to match the compliance of artificial blood vessels to that of living blood vessels.

In view of the drawbacks of the prior art, such as slanting, the present inventor aimed to improve the physical properties of the artificial blood vessel, especially the compliance, in order to obtain an excellent artificial blood vessel that can be applied to small-caliber arterial artificial blood vessels, venous artificial blood vessels, etc. As a result of intensive research on methods to make blood vessels resemble blood vessels, we have completed the present invention.

That is, the present invention provides a layer having a blood contact surface made of an elastic material with excellent antithrombotic properties (hereinafter referred to as layer A), and a support layer of one or more layers made of an elastic material (hereinafter referred to as layer B).
The present invention relates to an artificial blood vessel consisting of a layer (referred to as a layer), in which the darkness between All and B layers and the B layer and another B layer are partially bonded, and the remaining portion exists as a void, and a method for manufacturing the same.

In other words, in the present invention, by using an elastic material with excellent antithrombotic properties for the A layer of the artificial blood vessel, the antithrombotic properties of the blood contact surface can be improved. In addition, by partially bonding the A layer and the B layer and between the B layer and other B layers, and leaving the remaining part as a gap, the physical properties of the artificial blood vessel, especially the compliance, can be improved compared to the biological blood vessel. It can be made similar to that, and a remarkable effect can be obtained on the patency of the artificial blood vessel.

The elastic material with excellent antithrombotic properties constituting layer A used in the present invention is not particularly limited as long as it is an elastic material with excellent antithrombotic properties, but preferred specific examples include polyurethane, polyurethane urea, silicone rubber, Examples include polyurethane and blends of polyurethane urea and silicone polymers. Among the above-mentioned polyurethanes or polyurethane ureas, polyether type polyurethanes or polyurethane ureas are preferable to polyester types from the viewpoint of durability in vivo, and more preferable examples include segmented polyurethanes, segmented polyurethane ureas, and JP-A Examples include polyurethane and polyurethane urea containing polydimethylsiloxane in the main chain, which are disclosed in Japanese Patent Publication No. 57-211358. Particularly preferred are polydimethylsiloxanes having the formula: %Formula% (wherein R1-R6 are alkylene groups having 1 or more carbon atoms, preferably 2 to 6 fullkylene groups such as ethylene, propylene, butylene, hexamethylene; a, e are integers of 0 to 30; bSd is 0 or 1; o is an integer of 2 or more, preferably an integer of 5 to 15o1, particularly preferably 10 to 4o), and the polyether The part is-
(-CIH2-OH2-aH2-OH2-0-)-26
~30 Rethane or polyurethane urea.

When a material with excellent antithrombotic properties is used as the material constituting layer A, the antithrombotic properties of the blood contact surface are improved, and when an elastic material is used, physical properties similar to those of biological blood vessels, especially compliance, can be achieved. By using an elastic material with excellent antithrombotic properties, it is possible to obtain an AWI that combines the characteristics of both of the above.

The blood contact surface of layer A used in the present invention preferably does not have large pores or irregularities that would disrupt blood flow or damage blood components.

The blood contacting surface of layer A is basically composed of an elastic material with excellent antithrombotic properties, but in order to further improve the initial antithrombotic properties when implanted in a living body, blood contacting surfaces are The surface may be coated with albumin, chondroitin sulfate, heparinized material, or the like.

The thickness of layer A is preferably about 5 to 300 ρ, more preferably about 10 to 200 µ, and particularly preferably about 15 to 150 µ. When the thickness is less than about 5 IIm, the layer A is likely to be destroyed during use. Also, the thickness is about 300mm. If the strength exceeds 100%, the strength becomes too strong and properties such as compliance tend to no longer resemble those of biological blood vessels. Note that the layer A preferably has a sparse structure that reduces the strength per unit cross-sectional area. That is, as a specific embodiment, it is preferable that the A layer has minute holes inside. The pores preferably have a spherical shape, and although the size of the pores is not particularly limited, the diameter of the pores is preferably about 10 mm or less, particularly preferably about 1 mm or less.

The B layer used in the present invention is a layer that does not come into contact with blood and exists outside the A layer for the purpose of adjusting the strength, durability, compliance, thickness, etc. of the artificial blood vessel, and its thickness is preferably is about 5 to 500 terms, more preferably about 10
~300I1m1, particularly preferably about 20~200Rm
It is. If the thickness of the B layer is less than about 5ρ, the strength will be insufficient or it will tend to peel off, and if it exceeds about 500f, the strength will become strong and compliance similar to that of biological blood vessels will not be obtained. The structure of layer B preferably has a low density structure, and it is desirable to have minute holes substantially uniformly inside.

The diameter of the holes is not particularly limited, but is about 10ρ.
The following is preferable, and about 1ρ or less is more preferable. The number of layers of the B layer may be determined so that the compliance of the artificial blood vessel, the thickness of the tube, etc. are similar to those of a living blood vessel, and the number of layers may be one layer or multiple layers.

The elastic material constituting layer B is not particularly limited as long as it is an elastic material, but a preferred specific example is polyether-type polyurethane or polyurethane urea. The material constituting the B layer may be the same as the material constituting the A layer, as long as it is dissolved in the same solvent as the material constituting the A layer, and the B layer and the A layer are uniformly bonded. , may be different.

The artificial blood vessel of the present invention has a B layer outside the A layer, and the A and B layers and the B layer and other B layers are partially connected, and the remaining part is a void. It exists as. Preferably, said partial connections are substantially uniform throughout the artificial surface tube. The size of the void is preferably about 1 to 1000 in the circumferential direction.
．． 11111. More preferably about 3 to 500 parts, particularly preferably about 5 to 200 parts, preferably about 1 to 300 parts in the radial direction, even more preferably about 2 to 200 parts, particularly preferably about 3 to 100 parts! m, and in the axial direction preferably about 1 to 10,000 am, more preferably about 3 to 10,001! m1 is particularly preferably about 5 to 500
It is ρ.

The reason why the artificial blood vessel as described above is desirable is as follows. In other words, the inventors have found that when the thickness of an artificial blood vessel made of an elastic material is reduced, there is a point at which the physical properties, particularly the compliance, approximate those of a biological blood vessel at a certain thickness. However, this thickness differs greatly from that of biological blood vessels, making anastomosis difficult. Therefore, by stacking concentric cylindrical tubes that are thinner than an artificial blood vessel whose compliance is similar to that of a biological blood vessel, and partially connecting the cylinders while leaving other parts as voids, it is possible to This is because the thickness of the blood vessel and the tube are almost the same, making it easy to anastomose, and an artificial blood vessel having compliance similar to that of a living blood vessel can be obtained.

Between layers A and B, between layers B and B, inside layer A, inside layer B, or outside of Bll constituting the outermost layer, as necessary to reinforce the artificial blood vessel of the present invention. Reinforcements may also be incorporated. There are no particular limitations regarding the reinforcing material, but
A reticulated net made of an elastic material is preferred. In addition, in order to strengthen the bond between the artificial blood vessel and the tissue at the implantation site, a hole with a diameter and depth of about 1 to 300 ts, more preferably a hole with a diameter of about 2 to 100 ρ is formed on the outer surface of layer B, which constitutes the outermost layer. It may also have holes, particularly preferably holes of about 5 to 30 m.

Next, the artificial blood vessel of the present invention will be explained based on the drawings.

FIG. 1 is a schematic cross-sectional diagram of the artificial blood vessel p of the present invention,
FIG. 2 is a schematic longitudinal cross-sectional view of the artificial blood vessel of the present invention.

In Figures 1 and 2, (1) is the A layer, and there is a minute hole ('71) inside the A layer. There is a minute hole (8) inside the B layer.A bonding point (3) exists between the A layer and the B layer, and All and the B layer are bonded. There is also a connection point (5) between the layer and another B layer, and B
The layer and another B layer are combined. The bond points between each layer are such that the bond is substantially homogeneous. A
A void (4) exists between the layer B and a void (6) exists between the B layer and the B layer.

Since the artificial blood vessel of the present invention has the above-described structure, it has excellent antithrombotic properties, has physical properties, particularly compliance, similar to those of a biological blood vessel, and exhibits excellent patency when implanted in a living body.

In the artificial blood vessel of the present invention, after layer A is formed on the mandrel, a solution of the elastic material constituting layer B is coated on the mandrel, and then the mandrel is coated with a solution of the elastic material constituting layer B. Step 1 is to precipitate layer B by immersing it in a solvent (hereinafter referred to as poor solvent) that has good compatibility with the solvent (hereinafter referred to as good solvent) that does not dissolve the elastic material constituting layer A and layer B (hereinafter referred to as poor solvent). When manufacturing an artificial blood vessel by repeating the manufacturing process twice or more, the poor solvent is dotted on a layer made of an elastic material already formed on the mandrel (and) or the elastic material forming layer B is used. is produced by adjusting the time that the solution of elastomeric material remains on the layer of elastomer material already formed on the mandrel.

Next, the method for manufacturing an artificial blood vessel of the present invention will be explained by showing embodiments.

A layer A is formed on the mandrel to a substantially uniform thickness. Said A
Although the method for forming the layer is not particularly limited, the following two methods are preferred. One method is to immerse a mandrel in a solution of an elastic material with excellent antithrombotic properties constituting layer A, take it out, coat the mandrel with the solution to a substantially uniform thickness, and then dry it. In this method, a layer made of an elastic material with excellent antithrombotic properties is formed on the mandrel with a substantially uniform thickness, and this operation is repeated as necessary to obtain the layer with a desired thickness. The other method is to immerse a mandrel in a solution of an elastic material with excellent antithrombotic properties constituting layer A, take it out, and coat the mandrel with the solution to a substantially uniform thickness;
Next, the elastic material with excellent antithrombotic properties constituting All is immersed in a solvent (usually water is preferably used) that does not dissolve the elastic material and is miscible with the solvent of the solution to form layer A. This is a method in which an elastic material with excellent antithrombotic properties is deposited on the mandrel.

As the mandrel, a glass rod, a Teflon rod, a stainless steel rod, or the like with a smooth surface is suitable.

Next, the solution of the elastic material forming the B layer is coated onto the mandrel forming the A layer. This coating method is not particularly limited, but is preferably a so-called depping method in which the mandrel is immersed in the solution and then taken out. This mandrel is immersed in a poor solvent that has good compatibility with a good solvent that dissolves the elastic material constituting layer B (but does not dissolve the elastic material constituting layer A and B), and then The elastic material constituting the B layer is precipitated by replacing with the B layer to form the B layer.At this time, the poor solvent is dotted on the A layer formed on the mandrel and/or the B layer is formed. By adjusting the time that the solution of the elastic material stays on the A layer, the A layer and the B layer are partially bonded, and the remainder exists as a void.

Dotting the poor solvent on the A layer means that although the presence of the poor solvent cannot be confirmed macroscopically, the poor solvent is dotted on the All microscopically, and the preferred method is as follows. This is a method in which the mandrel on which layer A is formed is immersed in a poor solvent and then taken out, and the poor solvent adhering to the surface is partially removed using a filter paper or the like or by drying. Water is preferably used as the poor solvent.

The time that the solution of the elastic material forming the B layer stays on the A layer can be adjusted by adjusting the amount of poor solvent scattered on the A layer, the type of good solvent, and the amount of the elastic material solution forming the B layer. It is influenced by viscosity, material concentration, temperature, etc., and cannot be uniformly determined, but it is important to keep it as short as possible, preferably within 1 minute, more preferably within 30 seconds, and particularly preferably 15 seconds.
Within seconds.

The voids are formed for the following reasons. That is, by dotting a poor solvent on All or shortening the time that the solution of the elastic material constituting layer B stays on layer A, layer A is partially dissolved in a good solvent.
The remaining part exists in an undissolved state, and when the mandrel is immersed in a poor solvent in a sagging state and a B layer is formed by replacing a good solvent with a poor solvent, the dissolved part of the A layer becomes the B layer. The undissolved portion of layer A becomes a void. Therefore, as the residence time increases, the area where layer A is dissolved by the good solvent increases. In other words, the bonding area between layer A and Bm increases, the gap area decreases in proportion to this, and eventually layer A and layer B are bonded over substantially the entire surface, and no gap exists.

By the above-mentioned operation for forming layer B by replacing a good solvent with a poor solvent, the 8 layers themselves usually have minute pores inside, resulting in a sparse structure, and layer A also comes into contact with the solution of the elastic material constituting layer B. The side contains minute pores due to the substitution of good and poor solvents that have penetrated, resulting in a sparse structure.

The artificial blood vessel of the present invention is then produced by repeating the above operation for the desired number of B layers.

The artificial blood vessel of the present invention has a blood contact surface made of an elastic material with excellent antithrombotic properties. It has excellent thickness, strength, durability, and compliance similar to that of living blood vessels, the ends of the artificial blood vessel do not fray during suturing, and the penetrating ability of the suture needle is similar to that of living blood vessels.
No nodules occur. When the artificial blood vessel of the present invention, which has the above-mentioned advantages, is implanted in a living body, it has excellent antithrombotic properties, so there is little thrombus formation, and physical properties such as compliance are similar to biological blood vessels, so it can be used for a long time. Shows stable patency over a period of time.

Since the artificial blood vessel of the present invention has the above-mentioned characteristics, it can be used not only as an artificial blood vessel for large diameter arteries, an artificial blood vessel for small diameter arteries, and an artificial blood vessel for veins, but also as a batch for blood access and blood vessel repair. In particular, it can be suitably used as an artificial blood vessel for small diameter arteries.

Next, the artificial blood vessel of the present invention will be explained in more detail based on Examples.

Example 1 Polyether polyurethane containing polydimethylsiloxane in the main chain (Example 1 of Japanese Patent Application No. 72298/1983)
The polyurethane described in 1) was dissolved in N,N-dimethylacetamide at a polymer concentration of 12% (wt%, same hereinafter). The resulting solution had a viscosity of 300 centiboise (measured at 20°C using a B-type viscometer) and a temperature of 20°C. A glass rod with a diameter of 31 m with a smooth surface was immersed in the solution, then taken out, and the glass rod was coated with the polymer solution to a substantially uniform thickness. Deposit a polyurethane layer of uniform thickness, replace the water three times, and thoroughly remove the solvent.
A layer was formed.

Next, the glass rod is taken out of the water, the water present on the surface is removed using a filter paper, and the glass rod is immersed in the polymer solution, immediately taken out, and immersed in water to replace the solvent and water to precipitate the polymer. Ta. The time from immersing the glass rod in the polymer solution to immersing it in water was about 10 seconds.

The water was exchanged three times and the solvent was thoroughly removed to form Bll.

Next, the glass rod was taken out from the water, and after removing the water on the surface with a filter paper, the same operation as described above was repeated three times.

Thereafter, the solvent was thoroughly removed at 50° C. for one day while occasionally exchanging water. Both ends of the resulting molded body on the glass rod were cut with a knife, and the molded body was extracted from the glass rod to obtain an artificial blood vessel. The inner diameter of the obtained artificial blood vessel was 3!1 ID1, and the thickness of the tube was about 0.5 mm. A cross section of this artificial blood vessel in the radial direction was observed using a scanning electron microscope at a magnification of 110 times, and the results were photographed. A sketch of the photograph is shown in Figure 3.

When the ends of the resulting artificial blood vessel were sutured, the penetrating force of the suture needle was comparable to that of a living blood vessel, and the artificial blood vessel did not tear even when the suture was passed through and pulled at a point approximately 211,111 points from the end. The compliance of this artificial blood vessel was also large and similar to that of a dog's carotid artery. The length of the artificial blood vessel is 10 cm.
) was implanted into the carotid artery of a mongrel dog, and when it was removed 2 months later, it remained patent, indicating that it was an excellent artificial blood vessel.

Example 2 The polyurethane of Example 1 was dioxane/N.

The polymer was dissolved in a mixed solvent of 773 (by volume) N-dimethylacetamide at a concentration of 10%. The resulting solution had a viscosity of 200 centiboise (measured at 20°C using a B-type viscometer) and a temperature of 20°C. A glass rod with a diameter of 31,111 mm and a smooth surface was immersed in this solution and then taken out. After coating the glass rod with the polymer solution to a substantially uniform thickness, the solvent was completely removed with hot air. Next, add this glass rod to water! After crushing it, take it out, lightly remove the water on the surface with a filter paper, immerse this glass rod in the polymer solution, take it out immediately, and immerse it in water,
The polymer was precipitated by replacing the solvent with water. The time from immersing the glass rod in the polymer solution to immersing it in water was about 10 seconds. The water was exchanged 5 times to fully replace the solvent and water, forming 8 layers. Next, remove the glass rod from the water, remove the water on the surface with filter paper, and
The same operation as above was carried out until the outer diameter of the molded body on the mandrel was approximately 4.2n+
This was repeated until it reached +ll.

Thereafter, the mixture was kept at 50° C. for 24 hours to remove the solvent sufficiently by exchanging water occasionally, and then the molded body was extracted from the glass rod to obtain an artificial blood vessel. A radial cross section of this artificial blood vessel was observed using a scanning electron microscope at a magnification of 100 times, and the results were photographed. A sketch of the photograph is shown in Figure 4.

The obtained artificial blood vessel had an inner diameter of 3+nll1, a tube thickness of about o,
The compliance of emm is similar to that of a dog's carotid artery, and when the artificial blood vessel with a length of 1 ocw+ was implanted in a dog's carotid artery, there were no problems when suturing it, and it remained patent when removed after 2 months. , was found to be an excellent artificial blood vessel.

[Brief explanation of drawings]

Fig. 1 is a schematic cross-sectional view of the artificial blood vessel of the present invention, Fig. 2 is a schematic longitudinal cross-sectional view of the artificial blood vessel of the present invention, and Fig. 3 is an embodiment of the artificial blood vessel of the present invention with an inner diameter of 3 mn + A sketch of a scanning electron micrograph (110x magnification) of a radial cross-section of a vascular graft with a tube thickness of approximately 0.5 mm; FIG. FIG. 2 is a sketch of a scanning electron micrograph (100x magnification) of a radial cross section of a vascular graft with a thickness of approximately 0.611I11. <Main symbols of the drawing> (11: A layer + 21: 8th layer (3), (5): connection point), (6): void Figure 1, Country 2, Figure 3

Claims (1)

[Scope of Claims] 1. Consisting of a layer having a blood contacting surface made of an elastic material with excellent antithrombotic properties and a support layer of 1 ml or multiple layers made of an elastic material, the layer having a blood contacting surface and the support layer. An artificial blood vessel in which the supporting layer and the other supporting layer are partially bonded, and the remaining portion exists as a void. 2. After forming a layer having a blood contact surface made of an elastic material with excellent antithrombotic properties on the mandrel, coating the mandrel with a solution of the elastic material constituting the support layer, and then covering the mandrel with the support layer. immersed in a poor solvent that has good compatibility with the good solvent in which the elastic material constituting is dissolved and does not dissolve the elastic material constituting the layer having a blood contact surface and the support layer;
When producing an artificial blood vessel by repeating the operation of depositing the elastic material constituting the support layer once or twice, the poor solvent is dotted on the layer made of the elastic material already formed on the mandrel. and (or) adjusting the time that the solution of the elastic material constituting the support layer stays on the layer of the elastic material already formed on the mandrel. It consists of a layer having a blood contact surface made of an elastic material and one or more support layers made of an elastic material, and between the layer having the blood contact surface and the support layer and between the support layer and the other support layer. A manufacturing method for artificial blood vessels in which the darkness is partially joined and the remaining part exists as a void.