JP2587066B2 - Artificial blood vessel - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an artificial blood vessel having excellent patency, particularly an artificial blood vessel having a small or medium diameter.

(Problems to be Solved by the Related Art and the Invention) Conventionally, replacement or bypass surgery using an artificial medical tube has been performed as an exterminating operation for securing the functions of the affected ureter, trachea, esophagus and blood vessels. I have.

As the artificial blood vessel, a pleated tube made of a knitted or woven polyester fiber, a tube made of polyfluoroethylene, and then drawn to have a fine fibrous structure are used.

When these artificial blood vessels are applied as blood vessels having an inner diameter of 10 mm or more, relatively good patency results are obtained, but they are still insufficient. In addition, the patency of a blood vessel having an inner diameter of 7 mm or less, particularly 6 mm or less, is extremely poor, and the porous polyethylene fluoride is used only for limited applications.

In particular, artificial blood vessels that can be applied to peripheral arteries with an inner diameter of 3 to 4 mm have been widely desired by clinicians, including applications to coronary artery bypass surgery. Recently, many small and medium-sized blood vessels have been studied. However, there is no usable one yet.

In the artificial blood vessel in which the polyester fiber is woven, a thrombus layer having a thickness of 1 mm occurs in the lumen immediately after transplantation,
If this material is applied to small and medium diameter blood vessels, the lumen will be blocked by a thrombus within a short time. Therefore, it is essential that the material itself has an antithrombotic property that is not blocked by the initial thrombus.

On the other hand, a number of artificial blood vessels with different cross-sections and inner surface structures were prototyped using several types of polyether polyurethane or polyurethane urea with different antithrombotic properties, and transplantation experiments with dogs showed that the cause of the occlusion was all anastomotic Is known to be a panus.

This pasta is a granulation that grows from the cross section of the living organ wall at the part where the living organ is cut and the end face and the tube are anastomosed, and flows through the inside by the granulation growing to the lumen side. The flow of blood or the like is disrupted. In particular, in the artificial blood vessel, the portion flowing from the living blood vessel side to the artificial blood vessel side, that is, when the panus grows at the central side anastomosis, immediately after that, a stagnant portion of blood occurs, the thrombus gradually grows, The effective cross-sectional area is reduced, the blood velocity is reduced, and eventually the prosthesis is blocked by a thrombus. The generation of this panus is essentially unavoidable because it is a self-repairing function of the cut tissue, and the problem is that the panus grows in the anastomosis with the artificial blood vessel toward the center of the cross section of the lumen. It is.

Such a phenomenon does not occur in, for example, an artificial blood vessel made of a coarse mesh polyester cloth. However, when this coarse-meshed polyester cloth is applied to an artificial blood vessel having a small inner diameter, a thrombus as large as 1 mm or more is formed on the entire surface of the lumen in a short time as described above. And thrombus growth is promoted, eventually leading to occlusion.

In recent years, basic studies on antithrombotic properties have been advanced, and materials capable of remarkably suppressing thrombus formation in a flow at a certain shear rate or higher have been developed.

Therefore, it is thought that patency for one to two years can be guaranteed if a tube having a certain degree of irregularity on the inner surface is manufactured from such a material and implanted. However, in practice, small and medium diameter artificial blood vessels have not been successful.

The reason for this is that panus is excessively formed in the anastomosis toward the center of the cross section of the lumen, and in the case of an artificial blood vessel, a stagnant portion of the blood flow behind the artificial blood vessel and a thrombus is formed. is there.

That is, if the problem of the anastomosis part is solved, an artificial blood vessel that is currently eagerly desired by a clinician can be used.

Therefore, an object of the present invention is to solve the above problems and to provide an artificial blood vessel having excellent patency, particularly an artificial blood vessel for hemodialysis.

(Means for Solving the Problems) The artificial blood vessel of the present invention forms a polymer compound solution layer on the inner surface of the lumen near the end, adheres the powder thereto, and then coagulates the polymer compound solution. And then a large number of holes having an opening diameter and depth of 20 to 10 μm formed by removing the powder.

As a constituent material of the artificial blood vessel of the present invention, a material having excellent compatibility with blood and living tissue, that is, having no acute or chronic toxicity, pyrogenicity, or hemolytic property, and having a long-term effect on surrounding tissues after transplantation. Use a polymer compound that does not cause inflammation.

Examples of such a high molecular compound (high molecular elastomer) include polyvinyl halide, polystyrene and derivatives thereof, polyolefin polymers, polyester polymers, cellulose polymers, polyurethane polymers,
Examples thereof include a polysulfone-based polymer, a polyamide-based polymer, and the like, and a copolymer or a mixture containing these components may be used.

Among these, polyurethane-based polymers are preferred from the viewpoint of mechanical properties, stability in vivo, and antithrombotic properties.

Examples of such a polyurethane-based polymer include polyurethane, polyurethane urea, and a mixture of these with a silicone polymer. Examples of the polyurethane-based polymer include segmented polyurethane or polyurethane urea, those containing polydimethylsiloxane in the main chain, and those containing fluorine in the hard and / or soft segments. Of the polyurethanes or polyurethane ureas, the polyether type is more preferable than the polyester type because it is less susceptible to biodegradation.

As the polyether constituting the polyether segment of polyurethane or polyurethane urea, polytetramethylene oxide is most preferable, but other polyalkylene oxides having 2 to 3 carbon atoms of alkylene may be used. Such polyalkylene oxides include, for example, polyethylene oxide or polypropylene oxide or ethylene oxide-propylene oxide copolymers or block polymers. Further, a polyurethane having both hydrophilicity and mechanical properties including a polytetramethylene oxide segment and a polyalkylene oxide segment having 2 to 3 carbon atoms of alkylene in the same main chain may be used.

The molecular weight of the polyether constituting the soft segment is usually in the range of 400 to 3000, preferably 450 to 2500, more preferably 500 to 2500, but the most excellent polyether segment has a molecular weight of 800 to 2500, particularly 1300 to 2000. Is a polytetramethylene oxide chain. If the molecular weight of the polyether soft segment exceeds 3,000, the mechanical properties of the artificial blood vessel obtained will be poor, and if it is less than 400, the artificial blood vessel will be too hard to use as an artificial blood vessel.

Polyurethane is produced by reacting the above-mentioned polyethers having hydroxyl groups at both ends with diisocyanates used in known polyurethane synthesis such as 4,4'-diphenylmethane diisocyanate, toluidine diisocyanate, 4,4'-dicyclohexylmethane diisocyanate, and hexamethylene diisocyanate. The obtained prepolymer having an isocyanate group at the terminal can be produced by a conventional method in which a chain is extended with a diamine such as ethylenediamine, propylenediamine or tetramethylenediamine or a diol such as ethyleneglycol, propyleneglycol or butanediol.

Next, the method for producing an artificial blood vessel according to the present invention will be described with reference to an example.

First, a solution of a polymer compound to be a constituent material of a tube is prepared.

The solvent used here can be appropriately selected according to the polymer compound, but is preferably a water-soluble solvent from the viewpoint of preventing remaining in the product and the production cost. Examples of such a solvent include dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, dioxane, tetrahydrofuran,
Acetone and the like can be mentioned. Note that the solution of the polymer compound does not necessarily have to be in a good dissolved state. Therefore, a large amount of a swelling agent such as a poor solvent or urea can be mixed.

Next, by using this solution, a rigid core rod having a circular cross section is extruded from a circular orifice, so that a polymer compound solution is adhered to the entire peripheral surface of the core rod through a gap slit between the orifice and the core rod. As it is (wet solidification method)
Alternatively, after a drying step (dry coagulation method), the core rod is guided into a coagulation bath, and the attached polymer compound solution is coagulated. Next, the tube is obtained by sufficiently washing with water to remove the solvent, and then removing the core rod.

It is necessary that the rigid rod used as the core rod does not dissolve in the solution and does not easily change its shape until it is led to the coagulation bath. In addition, since corrosion resistance is required, for example, stainless steel or steel or brass subjected to chrome plating or Teflon processing is preferable. The end of the polyurethane tube obtained in this manner A polymer compound solution is injected into a nearby lumen surface to form a solution layer of the polymer compound on the lumen surface. Next, the powder is injected into the inner cavity surface near the end, that is, the portion where the hole is to be formed, and adheres to the surface of the solution layer. After attaching the powder,
Hold it for a while. Thereafter, the tube is dried or immersed and held in a coagulation bath to coagulate the polymer compound solution. Next, after separating and removing the powder, the artificial blood vessel having a large number of holes in the lumen surface near the end can be obtained by drying. In addition to the above method, for example, after turning a tube made of polyurethane from one end so that the lumen surface becomes the outer surface, a polymer compound solution is applied to the surface to form a portion where a hole is to be formed. Then, after performing the same processing such as coagulation and powder removal, the tube can be turned over again.

The polymer compound used in these methods may be any compound that can be used as a constituent material of an artificial blood vessel and may be any compound that is soluble in a solvent, for example, polyvinyl chloride, polymethyl methacrylate, and polyurethane. And polyurethane urea.

As the solvent, a good solvent is preferably used, and among them, those which are easy to handle and remove are preferable, and examples thereof include tetrahydrofuran, dioxane, acetone, dimethylformamide, and dimethylacetamide. As such a solvent, a poor solvent can be added and mixed as necessary.

The concentration of the polymer compound solution is not particularly limited as long as a solution layer can be formed, but is usually 5 to 35% by weight, preferably 5 to 25% by weight. If this concentration is too high, the strength of the resulting artificial blood vessel will increase, but the rate of penetration of the polymer compound solution into the attached powder will be too slow, which is not preferred. On the other hand, if the concentration is too low, a thick artificial blood vessel can be obtained, but the strength is undesirably low.

The powder needs to be insoluble in the polymer compound solution and capable of being separated and removed from the polymer compound in a subsequent step. The powder is appropriately selected in consideration of the porosity of the artificial blood vessel to be obtained, the pore size (pore diameter), and the shape. For example, in order to increase the porosity, a material having the same regular shape and easy to pack is used. This is because in the case of the closest packing, the smaller the gap, the higher the porosity of the obtained material.

As powder, water-soluble organic or inorganic salts, for example,
Sodium chloride, potassium chloride, calcium chloride, sodium sulfate, sodium carbonate, sodium acetate and the like; water-soluble starch; casein and the like can be used as the powder. Among these, the water-soluble starch is preferable because it is spherical, and it is preferable to use it after sieving to obtain a porous material having a desired pore size. As the powder, a powder having a lower melting point than the polymer compound used to the extent that it can be removed by heating, or a powder having a significantly different chemical reactivity from a polymer compound that can be removed by hydrolysis can be used. .

The method for attaching the powder to the solution layer is not particularly limited, but it is preferable to attach the powder so that the powder has a uniform thickness.

After adhering the powder, hold it for a predetermined time,
The polymer compound solution is caused to enter the powder by capillary action. Therefore, the amount of powder to be attached (the thickness of the powder layer)
Is determined in relation to the amount of the polymer solution to be penetrated.

The holding time in this case varies depending on factors such as the viscosity of the polymer compound solution, the ease with which the powder leaks, and the state of packing of the powder, but is usually from several seconds to several minutes.

Thereafter, the tube to which the powder is attached is dried or dipped in a coagulation bath and held.

As the coagulation bath used here, a solvent that is poorly soluble or insoluble in the polymer compound and the powder is used, but other than these, there is a sufficient difference in the dissolution rate or a coagulation of the solution proceeds sufficiently quickly. Should be fine.

The retention period in the coagulation bath varies depending on the type of the polymer compound used and the solvent used as the coagulation bath.
24 hours.

The method of removing the powder from the polymer compound varies depending on the properties of the powder used. For example, when a water-soluble starch is used as the powder, a method of immersing the powder in hot water at 50 ° C. or higher for a certain period of time or decomposing with amylase or dilute hydrochloric acid can be applied.

Thus, each hole formed by attaching the powder and removing the powder after coagulation may or may not be in communication, but is in communication with the outer surface of the tube. Absent. The diameter and depth of the opening are 20 to 100.
μm, preferably 20-80 μm. When the diameter and the depth of the opening are less than 20 μm, there is no effect of suppressing the growth of the panus in the anastomotic portion, and when it exceeds 100 μm, a large amount of thrombus is generated in the anastomotic portion. Further, it is preferable that a large number of such holes are present uniformly, and it is preferable that there are at least 100 or more, preferably 200 or more per 1 cm ² . 1 hole
If the number is less than 00, the effect of suppressing the growth of the panus in the center direction of the lumen cross section is low. It should be noted that, among the formed holes, those whose diameter and depth are out of the above ranges may be inadvertently present. When a hole is formed near the end, it is preferable that the distance be 5 to 10 mm from the end of the tube. If the distance from the end is less than 5 mm, the effect on suppressing granulation is insufficient, and if it exceeds 10 mm, for example, adhesion or change of a flowing substance is likely to occur.

The artificial blood vessel obtained in this way is heated at a temperature lower than the softening point of the constituent material and higher than the glass transition point while a mold having an appropriate size is inserted into the end, thereby obtaining the diameter of the end. Only can be extended. This makes it possible to prepare for a decrease in the lumen cross-sectional area due to granulation tissue generated near the end. In this case, the diameter near the end is
It is preferable that the inner diameter is larger by about 1 mm than the diameter of the part that is not expanded. If the inside diameter is too large, it may cause turbulence of blood, and a large amount of thrombus may be formed immediately after transplantation.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples. In the following, “%” is all “% by weight”.

Reference Example 1 Polytetramethylene glycol having a molecular weight of 1300 and having hydroxyl groups at both ends was reacted with 4,4'-diphenylmethane diisocyanate to obtain a prepolymer of isocyanates at both ends, and chain-extended with butanediol to synthesize polyurethane. . The synthesized polyurethane was repeatedly precipitated three times with a tetrahydrofuran-ethanol solvent and purified. This purified polyurethane was dissolved in dimethylacetamide to give a 20% solution.

From a circular orifice with a diameter of 6 mm, from an annular uniform gap between a stainless steel rod with an outer diameter of 4 mm set to be concentric with this orifice and the orifice,
The rod was extruded while adhering the polyurethane solution to the entire peripheral surface of the rod, introduced into water at 25 ° C., and rapidly solidified from the outside. After being immersed in water for 48 hours to sufficiently remove the solvent, the rod was pulled out and dried.

The obtained polyurethane tube was white and transparent, had a porous wall film, and pores of 5 to 15 μm were observed on the surface. The outer diameter of the tube was about 6 mm, the inner diameter was about 4 mm, and the wall film thickness was about 1 mm.

The tube was cut into a length of 5 cm, and a needle having an outer diameter of 0.3 mm was repeatedly punctured in a range of 5 mm in length from both ends. The puncture hole was smaller than the needle diameter used and was 20-30 μm due to the elasticity of the polyurethane.

The artificial blood vessel thus obtained was transplanted into the abdominal aorta of a dog. As a result, blood flow was good even after 2 months, and no excessive formation of granulation was observed in the anastomotic area even when angiography was performed. After the lapse of six months, the transplanted artificial blood vessel was observed after sacrifice and death. The cells used for suturing showed a somewhat thick cell growth on the suture, but the cells continued to run smoothly. No granulation growth was observed in the direction of the center.

Reference Example 2 From both cross sections of the same polyurethane tube as Reference Example 1
The area of 10 mm is adjusted to the dimethylacetamide 5 of polyurethane.
5 seconds after immersion in 50% solution, immediately 50%
In warm water to remove the solvent.

A rough porous inner surface having irregular irregularities of 20 to 80 μm was formed in the portion subjected to such treatment. The tube was replaced and implanted in a part of the abdominal aorta of two dogs.

As a result of excision after 4 months, a range of about 5 mm from the interface from the suture to the living blood vessel was covered with a transparent tissue having a thickness of 0.1 to 0.2 mm. After 8 months, the blood flow was still good, and the thickness of the specimen near the anastomosis was about 0.
A granulation tissue of 3 mm was observed, but was tightly fused to the inner surface of the tube wall.

Comparative Example 1 Polyurethane was produced by the method of Reference Example 1, and a tube was wet-molded. However, they were sterilized as they were without puncturing the vicinity of both ends and transplanted into the abdominal aorta of a dog.

Three months later, I was able to touch the pulse pressure from the surface of my body, but when I performed angiography and observed it, the anastomosis with the living blood vessels revealed that the granulation extended about 1 mm into the lumen and was in the shadow of the granulation. Had a red thrombus. After six months, blood flow stopped.

Comparative Example 2 Polyurethane was produced by the method of Reference Example 1, and a tube was wet-molded.

Next, after crushing the salt, sieving it to a particle size of 100
~ 200μm, 1g of 10% of polyurethane
It was added to 2 ml of the dimethylacetamide solution and mixed well. Then, a portion of 7 mm from both ends of the tube was immersed in this solution, and then the attached salt was dissolved, and 100 to 2
A tube having many 00 μm holes was obtained.

When this tube was transplanted into the abdominal aorta of a dog,
Blood stopped in a month. A large amount of red thrombus was formed at the end of the extracted sample.

Example 1 A polyurethane tube having a length of 5 cm and an inner diameter of 0.5 cm obtained by the method of Reference Example 1 was coated with a molecular weight of 150,00
A 20% solution of dimethylacetamide in polyether polyurethane of 0 is injected with a syringe-like injection device and the thickness is 50-80.
A polyether polyurethane solution layer of μm was formed. Next, using the same apparatus, a water-soluble starch having a maximum diameter of 100 μm was attached to the surface of the solution layer at a portion 10 mm from both ends of the tube. Then, it was left as it was for 1 minute.
Next, the tube was immersed in water at 25 ° C. and held for 12 hours to coagulate the polyether polyurethane. Thereafter, the tube was kept in hot water at 50 ° C. for 5 hours to remove water-soluble starch, and air-dried.

In this way, an artificial blood vessel having a large number of holes in the luminal surface at both ends was obtained. The diameter of the opening of the hole was 30 to 100 μm, the depth was 40 to 90 μm, and the number thereof was 5 × 10 ³ / cm ² .

When this artificial blood vessel was used and transplanted into the abdominal aorta of a dog in the same manner as in Reference Example 1, excellent results were obtained.

Example 2 A polyurethane tube having a length of 10 cm and an inner diameter of 5.5 mm obtained by the method of Reference Example 1 was turned over from one end, and the end was immersed in the polyether polyurethane solution of Example 1. Thereafter, a water-soluble starch was attached to a portion 1 cm from both ends of the tube so as to have a thickness of 2 mm, and was then held for 1 minute. Thereafter, the same treatment as in Example 1 was performed, and then the tube was turned over again to obtain an artificial blood vessel having a large number of holes in the lumen surface at both ends. The diameter of the opening of the hole is 30 to 60 μm and the depth is 40 to 50 μm, and the number is 10
^{It was 4} pieces / cm ² . When this artificial blood vessel was used and transplanted into the abdominal aorta of a dog in the same manner as in Reference Example 1, excellent results were obtained.

Example 3 A stainless steel conical mold was pushed into both ends of a tube having a large number of holes in the lumen surface near both ends manufactured in Example 2, and heat treatment was performed at 100 ° C. for 20 minutes. Expanded into a trumpet shape. At this time, the inner diameter at both ends increased by about 25% to the original diameter to about 5 mm.

This tube was replaced with a part of the abdominal aorta of a dog as an artificial blood vessel and transplanted.

As a result of observation of the specimen taken 6 months later, a granulation tissue with a thickness of about 0.3 to 0.4 mm was found near the anastomosis, but both ends of the artificial blood vessel were firmly fused to the expanded part in advance. The lumen had a smooth surface.

(Effect of the Invention) When the artificial blood vessel of the present invention is anastomosed with a living organ, since the granulation tissue does not grow toward the center of the cross section of the lumen at the anastomosis part, the patency of the anastomosis part is maintained for a long time. Can be maintained.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Masahiro Moriwaki 5996-1 Shinyoshida-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Ube Industries, Ltd. Chiba Research Institute Yokohama Branch Office (56) References JP-A-60-182959 (JP, A) JP-A-60-194956 (JP, A) JP-A-63-222758 (JP, A) JP-A-56-75151 (JP, A)

Claims (7)

(57) [Claims] 1. A solution layer of a polymer compound is formed on the inner surface of a lumen near the end of a tube, powder is adhered to the solution layer, the polymer compound solution is solidified, and then the powder is removed. The diameter and depth of the opening is 20-100 μm
An artificial blood vessel having a large number of holes. 2. The artificial blood vessel according to claim 1, wherein an inner diameter near the end of the tube is larger than an inner diameter of the other portion. 3. A tube extrudes a core rod having a circular cross section from a circular orifice, thereby causing a solution of a high molecular compound to adhere to the entire peripheral surface of the core rod through a gap slit between the orifice and the core rod. The artificial blood vessel according to claim 1, wherein the artificial blood vessel is a tube obtained by coagulating the solution. 4. The artificial blood vessel according to claim 1, wherein the powder is a water-soluble salt, water-soluble starch or casein. 5. The artificial blood vessel according to claim 1, wherein the tube is made of a polymer elastomer. 6. The method according to claim 5, wherein the high molecular elastomer is polyurethane and / or polyurethane urea.
Item 2. The artificial blood vessel according to item 1. 7. The artificial blood vessel according to claim 1, wherein the artificial blood vessel is a hemodialysis artificial blood vessel.