JPH0581258B2 - - Google Patents

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides an artificial material that has good penetrability with suture needles, etc., has durability against repeated punctures, and prevents blood from penetrating through the tube wall. Concerning blood vessels.

[Prior Art] Artificial blood vessels are required to have excellent long-term patency due to their use and good penetrability of suture needles during anastomosis with biological blood vessels from the viewpoint of surgical operations. On the other hand, blood access for hemodialysis, which is used to connect arteries and veins, requires frequent punctures, so it is difficult to withstand repeated punctures and to prevent hematoma and seroma (plasmoma) from occurring due to post-puncture bleeding. It is also required that the tube wall be impermeable to blood to prevent this from occurring.

Here, blood impermeability refers to
This means that blood cells and plasma do not pass through even if an internal pressure of 450 mmHg is applied.

As an artificial blood vessel that satisfies these requirements, JP-A-57
-There is one disclosed in Publication No. 150954. However, this artificial blood vessel has a homogeneous, dense layer that does not contain vacuoles with a diameter of at least 0.1 μm or more, which is obtained by applying a solution of a polymer compound to a rod-shaped mold, drying it, and then removing the solvent. ing. This causes the tube wall to become rigid, and for example, the thickness of this layer is approximately
Even in the case of 5 μm, it significantly obstructs the passage of a suture needle when connecting to a biological blood vessel, making surgical operations difficult. As a result, repeated punctures may make it difficult to stop bleeding, which may cause the formation of seroma, or the cut end surface of the living blood vessel may be exposed on the lumen side of the anastomosis with the living blood vessel, resulting in panus growth into the lumen. It may become the cause of. In addition, turbulence on the inner surface is caused by turbulent flow of blood,
causing partial stagnation and thrombus formation. Therefore, in addition to being made of an antithrombotic material, it is important that the tube wall does not have such a dense layer in order to suppress occlusion by the initial thrombus that forms on the inner surface after transplantation.

Moreover, the presence of such a dense layer is also undesirable for suppressing occlusion of the lumen, that is, kinking, caused by bending of the artificial blood vessel.

[Problems to be Solved by the Invention] As mentioned above, conventional artificial blood vessels have good suture needle penetration, are durable against repeated punctures, and have excellent blood impermeability, and are not suitable for practical use. There was nothing that could be offered.

The present invention was made against this background, and aims to provide an artificial blood vessel that solves the above problems and can be used for a long period of time.

[Means and Effects for Solving the Problems] In order to achieve the above object, the present inventors have studied the structure of the wall of an artificial blood vessel. As a result, in order to maintain long-term patency, the innermost layer on the inner surface side must have an open-pore structure that has high tissue healing power with the intimal tissue, etc. In order to prevent the death of the intimal tissue (closer to the outer surface) inside (deep part), to improve the penetrability of the suture needle, and to maintain blood impermeability, the intermediate layer adjacent to the innermost layer must be mutually bonded. The present inventors have discovered that an obturator pore structure consisting of independent obturator pores is essential for solving the problems of the conventional artificial blood vessels described above, and have completed the present invention.

That is, the present invention provides an artificial blood vessel consisting of multiple layers of polyurethane and/or polyurethane urea, the entire vessel wall of which is porous, at least an innermost layer with an open pore structure and an intermediate layer with a closed pore structure adjacent to the innermost layer. , the open pores and the closed pores are not in communication, and (1) the innermost layer has a thickness of 5 μm or more,
and the open pore structure is 2/3 or less of the thickness of the tube wall, and the open pore structure is spherical, oval, or/and a modified shape thereof with an average diameter of 5 to 150 μm, and has 5 to 100 pores on the inner surface of the tube wall.
It has pores that open with an average diameter of 150 μm,
The distance between these adjacent holes is at least 3 μm.
(2) The intermediate layer has a thickness of 5 to 500 μm, and the obturator structure has mutually independent obturator pores with a diameter of 0.01 to 100 μm. The artificial blood vessel is characterized in that at least the innermost layer of the vessel wall of the blood vessel and the artificial blood vessel described above contains short fibers made of synthetic resin.

The artificial blood vessel of the present invention has a porous structure throughout the tube wall consisting of multiple layers. In particular, the innermost layer is
It is a part that participates in bonding with intimal tissue and granulation tissue and influences tissue healing power.

This innermost layer must have an open pore structure consisting of open pores that communicate with each other, and have a thickness of 5 μm or more and 2/3 or less of the thickness of the tube wall. but,
For example, in order to withstand operations such as repeated punctures when used in blood vessels for hemodialysis, the thickness is preferably 20 μm or more. Here, for example, when an artificial blood vessel with an inner diameter of 4 mm has a total wall thickness of 0.4 mm, the thickness of the innermost layer is preferably in the range of 10 to 200 μm, more preferably 20 to 100 μm.

Moreover, this innermost layer has an average diameter of 5 to 150 μm.
spherical, egg-shaped or/and modified pores thereof are arranged in a close-packed manner, and open with an average diameter of 5 to 150 μm on the inner surface of the tube wall,
It has an open pore structure in which adjacent pores communicate with each other through holes having a diameter of at least 3 μm or more.

The average diameter of the pores and openings is 5 to 150 μm.
If it is less than this range, granulation tissue growing from the biological blood vessel at the anastomosis site cannot be suppressed.

On the other hand, if the average diameter exceeds 150 μm, the unevenness of the inner surface of the tube wall becomes large, resulting in the formation of a large amount of initial thrombus after transplantation, which is inconvenient and causes short-term occlusion. Moreover, since there is a proportional relationship between the thickness of the initial thrombus layer and the thickness of the neointima that forms over it over a long period of time, even if short-term occlusion does not occur, the inner diameter becomes thinner over a long period of time, and eventually occlusion occurs. I end up.

Here, the average diameter of holes, openings, etc. is the maximum diameter of each hole, opening, etc. within a field of view of 1.2 mm ² obtained by randomly photographing with a scanning electron microscope with a magnification of 1000 times. The average value obtained by measuring 10 times and performing the same operation 10 times.

From the above, the open pore structure of this innermost layer is substantially isotropic, and when this layer is cut at any position and in any direction, the cross section has an appearance similar to the inner surface of the tube wall.

Therefore, if the innermost layer has an open-pore structure as described above, the healing power with the intimal tissue after transplantation will be increased, suppressing panus growth and thickening of the intimal tissue, and preventing blood vessel occlusion for a long time. It is possible to prevent this from happening.

Furthermore, if the porosity (bulk specific gravity/specific gravity of raw material) of this layer is made extremely high at 0.90 to 0.99, it is possible to facilitate the intrusive growth of endometrial tissues and the like.

On the other hand, the intermediate layer of the obturator pore structure adjacent to the innermost layer consists of a large number of independent obturator pores of 0.01 μm or more. The diameter thereof is preferably in the range of 0.1 to 100 μm, most preferably in the range of 1 to 3 μm.

The diameter of the obturator foramen is more than the above value (100 μm or more)
This is because the pressure resistance of the tube wall decreases, and creep over time after implantation causes the inner diameter to increase and minute pinholes to occur. On the other hand, if the diameter of the obturator pore is less than the above value (0.01 μm or less), this layer becomes dense and the tube wall becomes rigid.

Further, the thickness of the layer is preferably 5 to 500 μm,
Particularly preferably, the thickness is in the range of 50 to 300 μm, and if the thickness is less than 5 μm, the pressure resistance decreases, and the blood impermeability aimed at by the present invention cannot be maintained due to the above-mentioned creep over time.

The constituent material of the artificial blood vessel of the present invention, which has at least the innermost layer and the intermediate layer described above, is a substance that has excellent compatibility with blood and tissues, that is, does not have acute or chronic toxicity, pyrogenicity, or hemolysis. Preferred are polymers that do not cause inflammation in surrounding tissues even when implanted over a long period of time. Examples of such polymers include polyvinyl halide, polystyrene and its derivatives, polyolefin polymers, polyester condensates, cellulose polymers, polyurethane polymers, polysulfone resins, polyamide polymers, etc. . Of course, a copolymer or a mixture containing these materials may also be used. Among these, polyurethane-based materials are preferred from the viewpoint of mechanical properties, in-vivo stability, and antithrombotic properties. Specific examples thereof include polyurethane, polyurethane urea, blends of these with silicone polymers, and those having an interpenetrating network structure. These also include segmented polyurethanes or polyurethane ureas, those containing polydimethylsiloxane in the main chain, and those containing fluorine in the hard and soft segments. Polyether-type polyurethane or polyurethane urea is preferable to polyester-type because it is less susceptible to biodegradation.

The polyether constituting the polyether segment of the polyurethane is most preferably polytetramethylene oxide, but other polyalkylene oxides (however, the number of carbon atoms in alkylene is 2
and/or 3) are also preferred. Specific examples of such polyalkylene oxides include polyethylene oxide, polypropylene oxide, ethylene oxide-propylene oxide copolymers, and block copolymers. Furthermore, a polyurethane having both hydrophilicity and mechanical properties, which contains a polytetramethylene oxide segment and a polyalkylene oxide (alkylene has 2 and/or 3 carbon atoms) in the same main chain, may be used. Since this polyurethane has outstanding antithrombotic properties and biocompatibility, it is more preferable as a constituent material for the artificial blood vessel of the present invention.

The molecular weight of the polyether forming these soft segments is usually in the range of 400 to 3000, preferably 450 to 2500, more preferably 500 to 2500, and the best polyether segments have a molecular weight of 800 to 2500. , especially molecular weight 1300~
2000 polytetramethylene oxide chains. The molecular weight of this polyether soft segment is 3000
If it exceeds 400, the mechanical properties of the polyurethane artificial blood vessel will be poor, and if it is less than 400, it will be too hard to be used even if it is molded as an artificial blood vessel.

Synthesis of polyurethane involves converting the above-mentioned polyether with hydroxyl groups at both terminals into 4,4'-diphenylmethane diisocyanate, toluidine diisocyanate,
4,4'-Dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, and other known diisocyanates used in polyurethane synthesis are reacted to create a terminal isocyanate prepolymer, which is then mixed with diamines such as ethylene diamine, propylene diamine, and tetramethylene diamine, ethylene glycol, It may be synthesized using a conventional method of chain extension with a diol such as propylene glycol or butanediol.

Further, as in the artificial blood vessel shown in Japanese Patent Application No. 60-133195, the entire artificial blood vessel or the innermost layer may be formed of polyurethane or polyurethane urea containing heparin, which is an anticoagulant. This is particularly effective in reducing the formation of initial thrombi in artificial blood vessels with an inner diameter of 4 mm or less, and therefore it is possible to reduce the thickness of the neointima after a long period of time.

Furthermore, when manufacturing the above-mentioned artificial blood vessel, for example, polyester, polypropylene,
Short fibers made of synthetic resin such as polyethylene, nylon, and Teflon may be mixed. This improves the strength of the artificial blood vessel, and is particularly effective in increasing the strength of the innermost layer, which participates in bonding with intimal tissues and the like.

[Examples] Hereinafter, the present invention will be described in more detail by presenting examples and using the accompanying drawings. In addition, all "%" used below regarding the component of a constituent material represents "weight%." The attached drawing is a sketch of a micrograph taken at 50x magnification of a cross section of the tube wall.

Example 1 Polytetramethylene gtycol having a molecular weight of 1500 and having hydroxyl groups at both ends was reacted with 4,4'-diphenylmethane diisocyanate to obtain a prepolymer having isocyanate groups at both ends. Next, the prepolymer was reacted with butanediol to obtain polyurethane (average molecular weight: 1.2×10 ⁴ ). The obtained polyurethane was purified by reprecipitation three times in a tetrahydrofuran-ethanol mixed solvent. Next, the purified polyurethane was dissolved in a mixed solvent of 60% dimethylacetamide and 40% tetrahydrofuran to produce a solution with a polyurethane concentration of 17%. In the solution thus obtained, a diameter of 6
A chromium-plated stainless steel rod with an outer diameter of 4 mm and an average surface roughness of 0.3 μm was extruded from a 2 mm orifice at a constant speed, and was placed concentrically with the orifice. By this operation, a uniform amount of polyurethane solution was deposited on the entire circumferential surface of the orifice and the stainless steel rod through a gap of a uniform distance between the rod and the orifice. The extruded rod was immediately introduced into water at 35°C and rapidly solidified from the outside. After that, the rod was kept in water to remove the solvent, then pulled out of the water, the rod was taken out, washed, dried at about 40℃, and the inner diameter was 3.9 mm.
A polyurethane porous tube with an outer diameter of 5.4 mm was obtained.

The polyurethane solution was uniformly applied to the inside of the tubular article. After leaving it for a certain period of time, a mixture of soluble starch (particle size 20 to 100 μmφ) and short polyester fibers with a length of about 0.5 mm was sprinkled on the inner surface, left for 1 minute, and the polyurethane solution was applied by capillary action. After filling the spaces between the starch powders, the starch was coagulated in water and the solvent was removed. After that, this tube was treated with hot water at 60℃ for 3 hours to dissolve and remove the starch.
After washing with water and drying, an artificial blood vessel having an innermost layer with an open pore structure and an intermediate layer with an adjacent closed pore structure was obtained.

The intermediate layer having a closed pore structure is formed by forming a polymer film using a wet method near a critical composition during the process in which the inner part of the first porous tube is redissolved in a polyurethane solution applied later and then resolidified. The obturator foramen is formed by a mechanism similar to that of
Furthermore, the drying operation removes a trace amount of residual solvent in the polyurethane and a trace amount of water that permeated into the polyurethane during the coagulation process, and the formation of cavities progresses to form an intermediate layer.

This was the artificial blood vessel of the present invention, which had an inner diameter of 4 mm, an outer diameter of 5 mm, and a tube wall thickness of 0.6 mm, and the entire tube wall was porous as shown in FIG.

The innermost layer 1 located inside this artificial blood vessel had a thickness of 80 μm and a porosity of 97% due to pores.

In addition, in this layer 1, short polyester fibers were randomly distributed, and minute holes with an average diameter of 15 to 70 μm were opened on the inner surface of the tube wall, and each opening was partitioned with fibrous or thin plate-like polyurethane. . Observation of the cross section revealed that these pores communicated with each other through holes having a diameter of 3 μm or more, and it was confirmed that the innermost layer 1 had an open pore structure.

Moreover, within this layer, all positions had the same structure.

Outside said layer 1 there was an intermediate layer 2 with a thickness of 5-10 μm and containing a large number of mutually independent spherical obturator pores with a diameter of about 1 μm.

Furthermore, the outside of this intermediate layer 2 has an average diameter of 200 mm.
There was an outermost layer 3 consisting of a group of huge pores of ~300 μm.

Here, the outermost layer 3 is a portion that imparts flexibility to the tube wall, prevents kinking, and contributes to bonding with connective tissue.

It is preferable that the pore group has a diameter of at least 1/5 or more of the tube wall thickness, and that each pore extends throughout the entire layer in the radial direction, with the pore wall film on the outer surface side. It is preferable that it is formed continuously and thinly.

As described above, by making the innermost layer have an open-pore structure, the tissue cohesion force on the inner surface is improved, and panus growth from the biological blood vessel on the stump surface of the artificial blood vessel or thickening of the intimal tissue on the inner surface of the artificial blood vessel is achieved. is inhibited, and vascular patency is significantly improved. Moreover, since the entire tube wall is porous, the area of contact with the living blood vessel at the cut end of the artificial blood vessel is reduced, so foreign body reaction stimulation is reduced, and healing of the living blood vessel is promoted.

In addition, by making the intermediate layer adjacent to the innermost layer have an obturator structure, the penetrability of the suture needle is improved, and the artificial blood vessel has durability against repeated punctures and has excellent blood impermeability. .

The lumen of this blood vessel was filled with bovine blood and an internal pressure of 450 mmHg was applied for 48 hours, but no plasma passed through it.
The tube wall was impermeable. The blood vessels used in this experiment were washed with physiological saline and fixed with glutaraldehyde as specimens, and the cross section was observed with a metallurgical microscope. As a result, it was confirmed that blood did not enter the obturator pores present in the intermediate layer, and that the intermediate layer was impermeable to blood.

A 5 cm portion of this artificial blood vessel was transplanted into the iliac artery of a remaining adult dog. The suturing operation was extremely easy, and there was no bleeding from the needle hole.

This blood vessel remained patent even after 8 months and was extremely excellent as a small-diameter artificial blood vessel.

When this blood vessel was extracted 12 months later, the inner surface of the anastomosis was smoothly connected to the living blood vessel.
A thin intima with a thickness of 0.1 to 0.2 mm completely covered the inner surface, and no panus or thrombus was observed.

Therefore, since it has excellent patency, unlike conventional artificial blood vessels, it can be used for blood vessels of 6 mm or less.

Example 2 A polyurethane porous tube with an inner diameter of 5 mm was prepared in the same manner as in Example 1.

The obtained artificial blood vessel had an inner diameter of 5 mm, a total wall thickness of 0.8 mm, and was porous.

The innermost layer of this artificial blood vessel has a thickness of 80 to 120 μm.
The porosity due to pores was 96-98%. In addition, the pores have an average diameter of 30 to 30 mm on the inner wall surface.
The opening was 100 μm. Observation of the cross section reveals that within this layer, fibrous polyurethane with a thickness of 2 to 10 μm are intertwined, and short polyester fibers are randomly distributed, forming an open pore structure in which adjacent pores communicate with each other. was.

This layer has a thickness of about 80 μm on the outside and 1 layer on the inside.
There was an intermediate layer containing many independent closed pores of ˜3 μm, and outside of this layer an outermost layer with large pores with an average diameter of 300-500 μm.

8 cm of this blood vessel was bypass-grafted between the carotid artery and vein of an adult mongrel dog and implanted subcutaneously.

After 3 weeks, an 18G needle was punctured from the outside, and it smoothly penetrated the wall of the artificial blood vessel. The needle was left in place for 4 hours and then removed, but bleeding stopped completely after 10 seconds, demonstrating excellent hemostasis.

After this, we continued to puncture this blood vessel five times a day for one month, but no hematoma or plasmama occurred.
It showed excellent performance as a blood access for hemodialysis.

Three months later, this blood vessel was extracted and its condition was observed. As a result, the external connective tissue was firmly fused to the artificial blood vessel. In addition, there was no panus or thrombus present on the inner surface.

In both of the above embodiments, the artificial blood vessel has a three-layer structure, which has an innermost layer with an open-pore structure on the inner surface side of the blood vessel, and an intermediate layer with an obturator structure adjacent to this innermost layer. However, as shown in Figure 2, in addition to the structure on the inner surface side, the outermost layer has an open-pore structure, and the intermediate layer adjacent to this layer has an obturator structure. Needless to say, it's fine.

[Effects of the Invention] The artificial blood vessel of the present invention has at least an innermost layer with an open hole structure and an intermediate layer with an obturator structure adjacent to this innermost layer, so it has excellent long-term patency and has low suture needle penetration. This artificial blood vessel has a great practical advantage of being highly durable, exhibiting excellent blood impermeability to repeated punctures, and excellent durability.

[Brief explanation of drawings]

The attached drawings are sketch diagrams of micrographs of a cross section of the wall of an artificial blood vessel showing an embodiment of the present invention.
The figure shows a sketch of the tube wall having a three-layer structure, and FIG. 2 shows a sketch of the tube wall having a five-layer structure. 1... Innermost layer, 2... Middle layer, 3... Outermost layer.

Claims (1)

[Scope of Claims] 1. An artificial blood vessel consisting of multiple layers of polyurethane and/or polyurethane urea, the entire vessel wall of which is porous, at least an innermost layer with an open-pore structure and an intermediate layer with a closed-pore structure adjacent to this innermost layer. and has
The open pores and the obturator pores are not in communication, and (1) the innermost layer has a thickness of 5 μm or more and 2/3 or less of the thickness of the tube wall, and the open pore structure is Spherical, oval, and/or modified shapes with an average diameter of 5 to 150 μm, and 5 to 150 μm to the inner surface of the tube wall.
It has open pores with an average diameter of m, and the distance between adjacent pores is at least 3 μm.
(2) the intermediate layer has a thickness of 5 to 500 μm,
An artificial blood vessel characterized in that the obturator pore structure has mutually independent obturator pores having a diameter of 0.01 to 100 μm. 2. An artificial blood vessel consisting of multiple layers of polyurethane and/or polyurethane urea, the entire vessel wall of which is porous, having at least an innermost layer with an open pore structure and an intermediate layer with an obturator structure adjacent to this innermost layer,
The open pores and the obturator pores are not in communication, and (1) the innermost layer has a thickness of 5 μm or more and 2/3 or less of the thickness of the tube wall, and the open pore structure is Spherical, oval, and/or modified shapes with an average diameter of 5 to 150 μm, and 5 to 150 μm to the inner surface of the tube wall.
It has open pores with an average diameter of m, and the distance between adjacent pores is at least 3 μm.
(2) the intermediate layer has a thickness of 5 to 500 μm,
An artificial blood vessel characterized in that the obturator pore structure has mutually independent obturator pores having a diameter of 0.01 to 100 μm, and (3) at least the innermost layer of the vessel wall contains short fibers made of synthetic resin.