JPH0457345B2 - - Google Patents

Description

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

[Prior Art] Artificial blood vessels are required to have good penetrability of suture needles during anastomosis with biological blood vessels from the viewpoint of their use and surgical operation. In addition, blood access for hemodialysis, which is used to connect arteries and veins, requires frequent punctures, so it is difficult to withstand repeated punctures, and hematoma and seroma (plasmoma) occur due to bleeding after puncture. It is required that the tube wall be impermeable to blood to avoid blood loss.

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 of at least 0.0254 mm 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. . For this reason, even if this layer has a thickness of about 5 μm, for example, since it does not have pores, 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 seroma formation, 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 causes turbulence and partial stagnation of blood, leading to thrombus formation. Therefore, in addition to being 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 invention has investigated the structure of the wall of an artificial blood vessel. the result,
An artificial blood vessel that has an outermost layer that participates in fusion with connective tissue, an innermost layer made of large pores, and an intermediate layer with a specific structure solves the problems of conventional artificial blood vessels mentioned above. I found out that
The present invention has now been completed.

That is, the present invention provides an artificial blood vessel in which the tube wall is composed of an outermost layer having an open pore structure, an innermost layer consisting of a group of large pores, and one or more intermediate layers located between these layers. has a porous structure in which the intermediate layer is composed of mutually independent closed pores, and
The present invention relates to an artificial blood vessel characterized by being impermeable to blood.

This at least one intermediate layer consists of a large number of independent obturator pores of 0.01 μm or more, and the obturator pores are intended to enhance the penetrability of the needle of the artificial blood vessel and to adjust its physical properties, and the diameter thereof is preferably 0.1～
in the range of 100 μm, most preferably 1-3 μm
is within the range of

The diameter of the obturator pore is more than the above value (100μm 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, the diameter of the obturator foramen is less than the above value (0.01μ
m or less), this layer becomes dense and the tube wall becomes rigid.

Further, the thickness of the layer is preferably 5 to 500 μm,
The thickness is preferably in the range of 50 to 300 μm; 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 material for constructing the artificial blood vessel of the present invention having at least one intermediate layer having such a structure is a material that is highly compatible with blood and tissues, that is, it does not have acute or chronic toxicity, pyrogenicity, or hemolysis, and has long-term properties. Preferably, the polymer does not cause inflammation in the surrounding tissue even if it is implanted for 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, triidine 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 used to create a prepolymer of terminal isocyanates, such as diamines such as ethylene diamine, propylene diamine, and tetramethylene diamine, and ethylene glycol. It may be synthesized using a conventional method of chain extension with a diol such as , propylene glycol or butanediol.

[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 glycol 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 treated with dimethylamide.
A solution with a polyurethane concentration of 17% was prepared by dissolving it in a mixed solvent of 60% polyurethane and 40% tetrahydrofuran. Together with the solution obtained in this way, the surface roughness was 0.3μ on average from an orifice with an outer diameter of 4mm installed concentrically with the orifice.
A chrome-plated stainless steel rod of m was extruded at a constant speed. By such operation,
A uniform amount of polyurethane solution was applied to the entire circumferential surface of the orifice and the stainless steel rod through a gap of uniform distance between the orifice and the stainless steel rod. The extruded rod was immediately introduced into water at 35°C and rapidly solidified from the outside. Thereafter, the rod was kept in water to remove the solvent, then pulled out of the water, the rod was taken out, washed, and dried at about 40° C. to obtain a polyurethane tube.

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

The outermost layer 1 located on the outside of this artificial blood vessel had a thickness of 80 μm and a porosity of 97% due to pores.

Further, the minute pores in this layer 1 opened to the outer surface of the tube wall with an average diameter of 15 to 17 μm, and were partitioned by 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 5 μm or more, and it was confirmed that the outermost layer 1 had an open pore structure.

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

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

Furthermore, the inside of this intermediate layer 2 has an average diameter of 200~
There was an innermost layer 3 consisting of a group of gigantic pores of 300 μm.

Here, the innermost layer 3 is a portion that imparts flexibility to the tube wall, prevents kinking, and contributes to long-term patency.

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 blood contacting surface facing the pore wall membrane. It is preferable that the layers are formed continuously and thinly.

In this way, due to the presence of huge pore groups, the inner anastomosis is smoothly connected due to the flexibility of the blood contacting surface, causing partial blood stagnation that causes the formation of a large amount of thrombus. do not have. Therefore, the generation of panus from the biological blood vessel at the cut end surface of the material of the artificial blood vessel is suppressed, and patency is significantly improved.

Furthermore, since the contact area with the biological blood vessel at the cut end of the material of the artificial blood vessel is reduced, foreign body reaction stimulation is reduced, and healing of the biological blood vessel is promoted.

The inner wall 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 opaque and hypertransparent. 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, the blood is in the innermost layer 3
It was confirmed that the particles were penetrating into the large pores of the pores, but not into the obturator pores that existed in the outer intermediate layer.

A 5 cm piece of this artificial blood vessel was transplanted into the iliac artery of an adult mongrel 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 removed 12 months later, the outer surface was covered with connective tissue approximately 1.5 mm thick, and the fusion with the artificial blood vessel was complete and could not be removed. The inner surface of the anastomosis was smoothly connected to the living blood vessel, and the inner surface was completely covered with a thin intima with a thickness of 0.1 to 0.2 mm, 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 having 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 outermost layer located on the outside of this artificial blood vessel has a thickness of 80 to 120 μm, and the porosity due to pores is 96 to 98%.
It was hot. In addition, the pores have an average diameter on the outer surface of the wall surface.
The opening was 30 to 100 μm. Observation of the cross section revealed that within this layer, fibrous polyurethane with a thickness of 2 to 10 μm were intertwined, forming an open pore structure in which adjacent pores communicated with each other.

The inside of this layer has a thickness of about 80 μm, and there is a
There was an intermediate layer containing many independent closed pores of ~3 μm, and further inside this layer was an innermost layer with huge pores having an average diameter of 300-500 μm.

This blood vessel was bypass-grafted between the carotid artery and vein of an 8 cm mongrel adult 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 blood dialysis.

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.

[Effects of the Invention] The artificial blood vessel of the present invention has a porous structure in which at least one intermediate layer has closed pores, and is impermeable to blood, so that it is effective as a barrier against blood and cells. Furthermore, due to its porous structure, it has good penetrability with a suture needle and has excellent durability against repeated punctures. As a result, the cut end surface is not exposed at the anastomotic site with the biological blood vessel, so thrombus formation due to panus growth and blood turbulence is suppressed.
This artificial blood vessel has excellent long-term patency and durability.

[Brief explanation of the drawing]

The attached drawing is a sketch of a micrograph of a cross section of a tube wall. 1...outermost layer, 2...middle layer, 3...innermost layer.

Claims (1)

[Scope of Claims] 1. An artificial blood vessel consisting of multiple layers of polyurethane and/or polyurethane urea, the entire tube wall of which is porous, comprising an outermost layer with an open pore structure, an innermost layer consisting of a group of large pores, and an intermediate layer with a closed pore structure located between the layers, (1) the outermost layer has an open pore structure with 15 to
It has pores that open with an average diameter of 100 μm, and these adjacent pores communicate with each other. (3) the intermediate layer has a thickness of 5 to 500 μm,
A blood-impermeable artificial blood vessel characterized in that the obturator pore structure has mutually independent obturator pores having a diameter of 0.01 to 100 μm.