JPS63270047A - Artificial blood vessel - Google Patents

Abstract

PURPOSE:To enhance the adhesion strength of an artificial blood vessel to tissue to obtain durability, by setting the outermost layer of the artificial blood vessel to a specific thickness. CONSTITUTION:In an artificial blood vessel wherein all of vessel walls 1-3 are porous and the outermost layer 1 has an open cell structure, the thickness of the outermost layer 1 is set to 10mum and adjusted to 2/3 or less the vessel walls 1-3. For example, when the thickness of all of the vessel walls 1-3 of the artificial blood vessel having an inner diameter of 4mm is 0.4mm, the thickness of the outermost layer 1 is pref. 20-200mum and the optimum thickness thereof is 30-100mum. The outermost layer 1 is formed so as to have such an open cell structure that pores having a spherical shape, an oval shape or/and a deformed shape thereof whose average diameter is 10-150mum are arranged in the closest packing state and opened to the outer surface thereof so as to provide an average diameter of 10-150mum and adjacent voids communicate with each other through pores having a diameter of at least 5mum or more. As the constitutent material of the artificial blood vessel whose outermost layer 1 has this structure, polyether type polyurethane or polyurethane urea is pref.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an artificial blood vessel having an outermost layer with high tissue healing power.

[Prior art] Conventionally, artificial blood vessels have been made from polyethylene terephthalate, which is spun into a tube-like form by knitting and weaving polyester polymer fibers. This prevents the phenomenon of bending due to

Polytetra7ethylene is formed into a tube shape and then stretched to form fibrils (fine fibrous structure). When these are used as blood vessel substitutes, since the structure of the tube wall is porous, there is an advantage that cells can infiltrate and grow in the gaps and become living organisms.

However, in artificial blood vessels using the above materials,
Since the tissue cohesion force in the outermost layer and the cross section of the tube wall is weak, much of the bonding force between the biological blood vessel and the transplanted artificial blood vessel depends on the tension of the suture used to anastomose the two. For this reason, blood vessels, especially arteries, may be stimulated by repeated loads of blood pressure, slowing the healing of the living vessel stump and promoting the growth of panus (excessive granulation tissue) into the lumen. In addition to causing occlusion, it can also cause an aneurysm to form at the anastomotic site over a long period of time.

[Problems to be solved by the invention] As mentioned above, conventional artificial blood vessels have weak tissue healing power, cannot maintain patency and durability over a long period of time, and have an inner diameter of 6 pus or less. However, it could not be practically used, especially as a blood vessel with a diameter of 4 cm or less.

Therefore, an object of the present invention is to provide an artificial blood vessel whose outermost layer has a strong tissue cohesive force, thereby increasing long-term patency and durability.

[Means and effects for solving the problem] The inventor
First, we focused on the point that in order to increase the tissue cohesiveness of the outermost layer of an artificial blood vessel, it is necessary to enhance the anchoring effect of the surrounding connective tissue in the outermost layer through the growth of active cells.

As a result, it was found that simply making the outermost layer a porous structure was insufficient.

In other words, even if the outermost layer has a porous structure, if the thickness is too small, the tissue binding force will be weak and it will easily peel off due to external forces acting on the blood vessel.On the other hand, if the outermost layer is too thick, the strength of the artificial blood vessel as a whole will be affected. This is because there may be a tendency for the surface area to decrease or become flattened over time.

Therefore, as a result of studies based on these findings, it was discovered that by making the outermost layer have a thickness within a certain range, it is possible to create an artificial blood vessel with high tissue bonding strength, thereby completing the present invention. reached.

The present invention provides an artificial blood vessel in which the entire vessel wall is porous and has an outermost layer with an open pore structure, wherein the outermost layer has a thickness of 10 μm.
The present invention relates to an artificial blood vessel characterized in that the thickness is less than % of the thickness of the vessel wall.

The artificial blood vessel of the present invention has a porous structure due to integral molding. In particular, the outermost layer is a part that participates in bonding with connective tissue and influences tissue healing power.

This outermost layer needs to have a thickness of lθμ or more and less than % of the thickness of the tube wall. It is preferable that the inner diameter is 4i+, for example,
When the thickness of the entire wall of an artificial blood vessel of n is 0.4■,
The thickness of the outermost layer is preferably in the range of 20 to 200 tiles, more preferably 30 to 100 JAW.

In addition, this outermost layer has a spherical shape with an average diameter of 10 to 150%,
Oval-shaped and/or modified-shaped pores are arranged in a close-packed manner, and the outer surface of the tube wall has a density of 10 to 150μ.
The openings have an average diameter of
- It has an open hole structure that communicates with a hole having a diameter of more than -.

The average diameter of the above-mentioned pores and openings is preferably in the range of 10 to 150μ; below this, there is little cell invasion and sufficient connective tissue healing is not observed, especially when adjacent pores communicate with each other. If the diameter of the hole is less than 5 mm, no invasive growth of cells will be observed.

On the other hand, when the average diameter exceeds 150 mm, the cohesive force between the surrounding connective tissue and the artificial blood vessel decreases rapidly.

The main reason for this is thought to be that the anchoring effect decreases due to a decrease in connective tissue adhesion per unit area on the blood vessel surface.

Here, the average diameter of holes, openings, etc. is a magnification of 10
Measure the maximum diameter of each hole, each shoulder, etc. in a field of view of 1 or 2 mm obtained by randomly taking photographs with a scanning electron microscope at 00x magnification, and calculate the average value of the same operation performed 10 times. say.

As described above, the open pore structure of this outermost 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 outer surface of the tube wall.

Therefore, if the outermost layer has an open-pore structure with the above-mentioned thickness, it will ensure the fusion of the connective tissue on the outer surface of the artificial blood vessel after implantation, and prevent complications caused by the repeated stress of long-term blood pressure on the sutures at the anastomotic part. It becomes possible to prevent

A very high value of ~0.99 can facilitate invasive growth of connective tissue.

The material for constructing the artificial blood vessel of the present invention having such a structure as the outermost layer is a substance 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 durability. Polymers that do not cause inflammation in surrounding tissues even when implanted are preferred; examples of such polymers include polyvinyl halides, polystyrene and its derivatives, polyolefin polymers, polyester condensates, cellulose polymers, and polyurethanes. Examples include polyamide-based polymers, polysulfone-based resins, and polyamide-based polymers. Of course, copolymers or mixtures containing these materials may also be used; 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,
Includes hard and soft segments that contain fluorine. Polyether-type polyurethane or polyurethane urea is preferable to polyester-type because it is less susceptible to biodegradation.

The polyether constituting the polyether segment such as the polyurethane is most preferably polytetramethylene oxide, but other polyalkylene oxides (however, alkylene has 2 and/or 3 carbon atoms) are also preferred.
Specific examples of such polyalkylene oxides include polyethylene oxide, polypropylene oxide, ethylene oxide-propylene-silica copolymers, and block copolymers. Further, a polyurethane having both wood-philicity 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 of 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 3,000, preferably 450 to 2.500, more preferably 500 to 2.5
00, and the best polyether segments have a molecular weight of 800 to 2.500, especially 1.3.
00 to 2.000 polytetramethylene oxide chains. The molecular weight of this polyether soft segment is 3.
If it exceeds 000, 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 reacting the above-mentioned polyether with hydroxyl groups at both terminals with diisocyanates used in known polyurethane synthesis, such as 4,41-diphenylmethane diisocyanate, toluidine diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, and hexamethylene diisocyanate. A prepolymer of terminal isocyanate is made by using the process, and this is mixed with diamines such as ethylene diamine, propylene diamine, tetramethylene diamine, etc.
It may be synthesized using a conventional method of chain extension with a diol such as ethylene glycol, 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 components of the constituent materials represents "weight %", and the attached drawing is a sketch of a micrograph at 600 times magnification of a tube wall cross section.

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 incyanate groups at both ends. Next, the prepolymer was reacted with butanediol to form polyurethane (average molecular i1.2X10'
) was obtained. The obtained polyurethane was reprecipitated three times in a tetrahydrofuran-ethanol mixed solvent,
The purified polyurethane was then dissolved in a mixed solvent of 60% dimethylamide and 40% tetrahydrofuran to prepare a solution having a polyurethane concentration of 17%. A chromium-plated stainless steel plate with an outer diameter of 4 mm and an average surface roughness of 0 and 3 pI was placed in the solution obtained in this way from an orifice with a diameter of 6 m + s and placed concentrically with the orifice. The forest was pushed out at a constant speed. By this operation, a uniform amount of the fake 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. 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 was the artificial blood vessel of the present invention, which had an inner diameter of 4 mm, an outer diameter of 5 am, and a tube wall thickness of 0.6 mm, and the entire tube wall was porous as shown in the drawing.

The outermost layer l located on the outside of this artificial blood vessel has a thickness of 80 mm.
The porosity of the door was 97%.

Moreover, the minute pores in this layer l have an average diameter of 15 mm on the outer surface of the tube wall.
It was opened at ~70° and partitioned with ta fiber-like or thin plate-like polyurethane. Inspection of the cross section by RI1 confirmed that these pores communicated with each other through holes having a diameter of 5 mm or more, and that the outermost layer 1 had an open pore structure.

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

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

Furthermore, the inner side of this intermediate layer 2 has an average diameter of 200 to 300.
There was an innermost layer 3 consisting of a huge group of vacancies.

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 that is at least 1 greater than the thickness of the tube wall, and that each pore extends throughout the entire layer in the radial direction, with the wall membrane of the pores on the blood contacting surface side. It is preferable that it is 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. 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 lumen of this blood vessel was filled with fresh blood and an internal pressure of 450 mmHH was applied for 48 hours, but no plasma passed through and the vessel wall was impermeable. The blood used in this experiment was washed with physiological saline and then fixed with geltaraldehyde as a specimen, and its cross section was observed with a metallurgical microscope. As a result, blood has penetrated into the huge pores in the innermost layer 3,
It was confirmed that it did not enter the obturator foramen present 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 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 outer surface was covered with connective tissue with a thickness of about 1.5 mm, and it was completely fused with the artificial blood vessel and could not be peeled off. The inner surface of the anastomosis part is smoothly connected to the biological blood vessel, and the inner surface of the anastomosis part is smoothly connected to the biological blood vessel, and the inner surface of the anastomosis part is smoothly connected to the biological blood vessel.
A thin intima of 21 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 61 cm or less.

Example 2 A polyurethane porous tube having an inner diameter of 511I6 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~
120-, the porosity due to pores was 96-98%. Further, the pores have an average diameter of 30 to 100 mm on the outer surface of the wall surface.
It was open. According to the observation of the cross section, fibrous polyurethane having a thickness of 2 to 10 μm was entangled in this layer, and an open pore structure was formed in which adjacent pores communicated with the phase W.

Inside this layer, there is an intermediate layer with a thickness of about 80 mm and containing a large number of 1 to 3 independent obturator pores, and further inside this layer has an average diameter of 300 to 500 mm. There was an innermost layer with huge pores.

This blood vessel was bypass-grafted between the carotid artery and vein of an 8CIltl-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 the bleeding stopped completely after 10 seconds, demonstrating excellent hemostasis.

After this, continue to puncture this blood vessel 5 times daily.
Although it continued for several months, no hematoma or hematoma occurred, and 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. There was also no panus or thrombus present on the inner surface.

[Effects of the Invention] The artificial blood vessel of the present invention has the outermost layer having a thickness of 10 layers or more and less than the thickness b of the tube wall, so that the tissue healing power of the artificial blood vessel is increased. The artificial blood vessel can be made durable over a long period of time. Moreover, its high tissue healing power suppresses the occurrence of aneurysm at the anastomotic site, and
It not only has excellent long-term patency and durability as an artificial blood vessel for blood vessels smaller than 1 mm, especially arteries smaller than 411I11, but also can be used as a blood access for hemodialysis without hematoma or plasmama, and can stop bleeding after puncture. This is an artificial blood vessel with excellent performance.

[Brief explanation of the drawing]

The accompanying drawing is a sketch of a micrograph of a cross section of a tube wall.

Claims (1)

[Scope of Claims] 1. In an artificial blood vessel in which the entire tube wall is porous and has an outermost layer with an open pore structure, the outermost layer has a thickness of 10 μm or more and is equal to the thickness of the tube wall. An artificial blood vessel characterized by being 2/3 or less. 2. The artificial blood vessel according to claim 1, wherein the tube wall is made of polyurethane. 3. The artificial blood vessel according to claim 1, wherein the tube wall is made of polyurethane urea. 4. The open pore structure of the outermost layer has an average diameter of 10 to 150
μm spherical, oval, or/and modified shapes thereof, with holes opening to the outer surface of the tube wall with an average diameter of 10 to 150 μm, and adjacent holes having a diameter of at least 5 μm communicating with each other. The artificial blood vessel according to any one of claims 1 to 3, which comprises a hole.