JPH04300537A - Composite artificial blood vessel - Google Patents

Abstract

PURPOSE:To obtain the interstitial property good over a long period of time after implantation by compounding a biotissue inductive material and antithrombotic material into stretched polytetrafluoroethylene (PTFE) having a long fiber structure which is excellent in the infiltration property of the biotissue and an integral structure which is dynamically excellent. CONSTITUTION:A liquid oil lubricant is intimately mixed into the unsintered powder of the stretched PTFE and the mixture is extruded to a tube shape by a ram type extruder. The extruded tube is heated by continuously applying a temp. gradient between the inside and outside surfaces of the tube. The rearrangement of the fiber- knot structure arriving at the outside surface from the inside surface of the tube takes place and the tube is further stretched more than before the treatment, by which the long fibered parts and short fibered parts are obtd. The material having a biotissue induction effect and the antithrombotic material are applied respectively independently or after being mixed with another high-molecular material on the parts constituted of the long fibers. The parts constituted of the short fibers maintain the structure as the tube since the short fiber parts thereof continue like network from the inside surface to the outside surface of the tube wall in the circumferential direction of the tube, thereby imparting tear and tensile strength to the tube.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a small-diameter artificial blood vessel used as a substitute blood vessel for coronary arteries, peripheral blood vessels, and the like.

0002

[Prior Art] Conventionally, polyester fiber knitted or woven fabrics, stretched polytetrafluoroethylene (hereinafter referred to as PTF),
E) Tubes have been used as artificial blood vessels. Stretching P
TFE tubes can be used as artificial blood vessels in smaller diameter areas than polyester because the PTFE material itself has excellent antithrombotic properties, and the porous structure of fibers and knots obtained by stretching has excellent tissue compatibility. It has been put into practice.

However, even expanded PTFE cannot be said to have sufficient antithrombotic properties, and in particular, a sufficient patency rate has not been obtained for artificial blood vessels with an inner diameter of 6 mm or less. Therefore, conventional methods to solve these problems include (1) improving the antithrombotic properties of the material itself, and (2) imparting antithrombotic properties by guiding living tissue and causing intimal formation after implanting the artificial blood vessel. A method to do so is being considered. As for the former, the development of antithrombotic polymeric materials such as phase-separated structures and antithrombotic agent immobilization materials has been considered, but no material has been obtained that exhibits good antithrombotic properties for a long period of time after transplantation. In the latter case, in order to promote intima formation after transplantation, an artificial blood vessel has been proposed in which stretched PTFE is combined with adhesive proteins such as fibronectin and collagen, and heparin as necessary (Japanese Patent Application Laid-Open No. 1983-1999). 46169).

0004

[Problems to be Solved by the Invention] However, with conventional artificial blood vessels made of stretched PTFE tubes combined with collagen and heparin, the tissue penetration speed is still insufficient, it takes time for intimal formation, and the tissue that has invaded There were problems in that the stability of the intima was poor and the tissue became calcified or necrotic during the long term of transplantation, resulting in poor long-term patency. These problems are caused by the fact that the pore size of the porous structure is not large enough for the invasion of living tissues and capillaries, and the tissues cannot penetrate sufficiently. Therefore, in order to solve these problems, it is necessary to increase the pore diameter of the porous material and allow a large amount of living tissue to quickly enter the pores.

[0005] Expanded PTFE tubes have a fine fibrous structure consisting of very fine fibers and nodules interconnected by the fibers. Therefore, in order to increase the pore diameter, it is sufficient to increase the drawing ratio and lengthen the fibers. However, in stretched PTFE tubes, the fine fibers generated by stretching are strongly oriented in the stretching direction, so the tensile strength of the tube is high in the axial direction, but the strength in the circumferential direction of the tube is low, and it is easy to tear in the axial direction. It has the following drawbacks. For this reason, increasing the drawing ratio and lengthening the fibers will significantly reduce the mechanical properties of the tube, and the suture needle or suture thread may tear the tube when suturing it with a living body. It becomes impossible to maintain the lumen structure and cannot withstand use as an artificial blood vessel.

[0006] Possible means to solve this problem of deterioration in mechanical properties include increasing the wall thickness of the tube and reinforcing the outside of the tube with mesh or the like.
In the former case, there is a problem of a decrease in the ability to invade living tissue, and in the latter case, problems such as peeling of the reinforcing material occur. Therefore, even if these tubes are combined with biological tissue-inducing substances, it is impossible to fully exhibit their effects.

[0007]

[Means for Solving the Problems] The present invention provides a stretched PTFE tube with a monolithic structure that has a long fiber structure that is excellent in penetrating into living tissues and has excellent mechanical properties, and a living tissue-inducing substance and an antithrombotic substance. The purpose of the present invention is to provide a composite artificial blood vessel that has excellent initial antithrombotic properties and quickly forms a stable intima by combining a chemical substance and exhibits good patency over a long period of time.

[0008] The expanded PTFE tube to which the present invention is directed consists of two parts, a long fiber part and a short fiber part, from the inner surface to the outer surface. Preferably, the long fiber part has an average fiber length. is 60 μm or more, and the short fiber portion has an average fiber length of 20 μm or less, and has a structure that continues in the shape of a mesh in the circumferential direction of the tube and the thickness direction of the tube wall.

[0009] Such an expanded PTFE tube is basically manufactured by the method described in Japanese Patent Publication No. 13560/1983. First, a liquid lubricant is mixed with unsintered PTFE powder, and the mixture is extruded into a tube using a ram extruder. The liquid lubricant is removed from the tube, or the tube is stretched at least in the tube axis direction without being removed. Next, both ends of the tube are fixed so as not to shrink, and both the inner and outer surfaces of the tube are heated to a sintering temperature of 327° C. or higher. At that time, a continuous temperature gradient is applied between the inner and outer surfaces of the tube,
The temperature of the outer surface is set higher than the temperature of the inner surface by 50 to 300°C, preferably 100 to 250°C. As a result, the fiber-knot structure is rearranged from the inner surface to the outer surface of the tube, resulting in a portion where the fibers are further drawn and become long fibers than before the treatment, and a portion where the fibers are shorter than before the treatment. It is desirable to control the inner surface temperature to 500° C. or less so that the PTFE does not decompose.

[0010] Japanese Patent Publication No. 58-1656 and Japanese Unexamined Patent Publication No. 1982-1656
No. 5-76648 describes a method for producing stretched PTFE with excellent strength in the direction perpendicular to the stretching direction by further heating a portion of the stretched PTFE at a temperature of 327° C. or higher. However, as described in the same specification, in this method, only one side of the tube is heated to 327°C or higher, and the other side is heated to 327°C or higher.
℃ or below, the fiber-nodule structure does not rearrange from the inner surface to the outer surface of the tube as described above, and as described in the present invention, the tube is divided into long fiber portions and short fiber portions, Moreover, a structure in which the short fiber portions are continuous in a mesh-like manner in the circumferential direction and thickness direction of the tube cannot be obtained. In this way, by appropriately setting the temperature difference between the inner surface and the outer and outer surfaces at a temperature of 327°C or higher, the tube is made up of long fiber portions and short fiber portions, and the short fiber portions are distributed in the circumferential direction and thickness of the tube. Stretched PTF with a continuous mesh-like structure in the direction
An E-tube is obtained.

[0011] The expanded PTFE tube thus obtained is immersed in a solution of a biological tissue-inducing substance or an antithrombotic substance, or the solution is injected into the wall of the tube under pressure or vacuum. , a composite artificial blood vessel can be produced. The biological tissue-inducing substance and the antithrombotic substance may be combined individually or separately, or both may be mixed in advance, or if necessary, a third polymeric material may be mixed and then combined. .

[0012] In the composite artificial blood vessel according to the present invention, by compounding a biological tissue-inducing substance into the portion composed of long fibers with an average fiber length of 60 μm or more, a high A large amount of living tissue and capillaries invade from the outside of the artificial blood vessel wall at high speed. In this way, the tissue that invades in large quantities at an extremely high speed compared to conventional artificial blood vessels forms a stable intima over a long period of time.
Because it can be maintained, it shows good patency over a long period after transplantation. In order to cause such good organization, the average fiber length of the long fiber portion needs to be 60 μm or more, preferably 100 μm or more,
More preferably, the thickness is 150 μm or more.

[0013] The portion composed of short fibers having an average fiber length of 20 μm or less has a high density in the nodule portion, and therefore has excellent strength characteristics. This short fiber portion continues in a mesh pattern in the circumferential direction of the tube and from the inner surface to the outer surface of the tube wall.
It maintains the structure of the tube and provides the tube with tear strength and tensile strength necessary for suturing. In order to provide good strength, the average fiber length of the short fiber portion is 20 μm.
It is necessary that the following is true.

[0014] Among the substances compounded into this stretched PTFE tube, substances having a biological tissue-inducing effect include adhesive proteins and growth factors such as endothelial cell growth factor and vascular growth factor. Among these, collagen, gelatin, albumin, and laminin are preferred. By combining these substances into the expanded PTFE tube, a large amount of living tissue and capillaries can enter the tube more rapidly than with conventional materials, and a stable intima can be maintained over a long period of time. Can be done.

[0015] As for the method of forming a composite, it may be applied alone, it may be mixed with another polymer material and applied, or it may be fixed chemically as required. As for the composite structure, it is desirable that the composite be thinly composited throughout the entire wall thickness and within the pores so that the porous structure is maintained even after the composite is composited. Further, since the expanded EPTFE tube according to the present invention has a high stretching ratio and a large pore diameter, blood leakage occurs when it is implanted alone, but blood leakage can be prevented by combining proteins in this way.

Among the substances to be combined, the antithrombotic material is
After transplantation, until the inner surface of the artificial blood vessel is covered with endothelial cells having antithrombotic properties, the composite is used to impart antithrombotic properties to the artificial blood vessel. These substances include anticoagulants such as heparin, aspirin, prostaglandin E1, and prostaglandin I.
Examples include anti-platelet aggregation substances such as No. 2, and thrombolytic substances such as urokinase. These substances can be applied alone, mixed with another polymeric material, or fixed with covalent or ionic bonds as necessary, but in any case, the It is necessary to compound the amount necessary to keep the inner surface of the artificial blood vessel antithrombotic until antithrombotic properties are imparted by the intima formed later.

[0017]

[Examples] The present invention will be specifically explained below with reference to Examples, but the scope of the present invention is not limited thereby.

Example 1 27 parts by weight of a liquid lubricant was added to 100 parts by weight of PTFE powder Polyflon F-104 (manufactured by Daikin Industries, Ltd.) and mixed, and after pressurized preforming, an extruder was used to make the inner diameter 1.
．． It was extruded into a tube shape of 5 mm and outer diameter of 2.5 mm. After removing the liquid lubricant from this tube, remove the tube from
It was heated to 90°C and stretched 1000%. A stainless steel rod with an outer diameter of 1.5 mm was inserted into this stretched tube, and the outer surface side was heated at 650° C. and the inner surface side was heated at 450° C. for 35 seconds. As a result, a tube having physical properties shown in Table 1 below was obtained.

A 0.5% bovine tendon-derived type I collagen aqueous solution was vacuum injected from the inside of this tube, crosslinked with glutaraldehyde, and then impregnated with a 10% heparin aqueous solution.
Vacuum dried. The combined amounts of collagen and heparin are 0.3 mg/cm and 1.8 mg/cm (329 U
NIT/cm).

[0020] This composite artificial blood vessel was transplanted into the abdominal aorta of a rat. Two weeks later, the inside of the tube wall was filled with living tissue components such as fibroblasts. The endothelial coverage of the inner surface was as high as 92%, and the patency rate was 100%. Furthermore, even after one year had passed, the formed endothelium was stable and the patency rate was 95%.

Examples 2 to 4 Composite artificial blood vessels were prepared in the same manner as in Example 1, except that the composite substances shown in Table 1 were used, and transplanted into rats. The results are shown in Table 1, and after 2 weeks, tissue penetration into the pores was good, the inner surface coverage was high, and the patency rate was high. Furthermore, even after one year, the formed endothelium was stable and had a high patency rate.

Comparative Example 1 Average fiber length 30 μm, inner diameter 1.5 mm, outer diameter 2.5
A 0.5% bovine tendon-derived type I collagen aqueous solution was vacuum injected from the inside of a mm stretched PTFE tube, crosslinked with glutaraldehyde, impregnated with a 10% heparin aqueous solution, and vacuum dried. The combined amounts of collagen and heparin are 0.3 mg/cm and 1.7 mg/cm (311
UNIT/cm). This composite artificial blood vessel 10c
m was implanted in a loop shape into the rat abdominal aorta. After 2 weeks, there was not enough tissue within the pores, the inner surface endothelial coverage was 63%, and the patency rate was 90%. Furthermore, after one year had passed, the invading tissue had become calcified, and the endothelium had also partially peeled off, and the patency rate was 50%.

Comparative Example 2 Expanded PTFE produced by the same method as Example 1
The tube was directly implanted into a rat. There was severe blood leakage during transplantation, and two weeks later, the tissue was not sufficiently contained within the pore, and the inner surface endothelial coverage was 55% and the patency rate was 75%. After one year, the endothelial coverage was 100%, but the patency rate was 50%.

[0024]

[Table 1]

[0025]

As explained above, the composite artificial blood vessel according to the present invention has a long fiber structure that allows living tissue to penetrate quickly and in large quantities, and is made of a monolithic expanded PTFE tube with excellent mechanical properties. By combining a biological tissue-inducing substance and an antithrombotic substance, it has excellent antithrombotic properties in the initial stage of transplantation, and also shows good patency over a long period of time after transplantation by quickly forming a stable intima. . Therefore, the artificial blood vessel according to the present invention is effective as a substitute for small-diameter blood vessels such as coronary arteries and peripheral blood vessels, which could not be put to practical use using any conventional material.

[Brief explanation of drawings]

FIG. 1 is an internal view of the composite artificial blood vessel of the present invention.

FIG. 2 is an enlarged view of the inner surface of the composite artificial blood vessel of the present invention.

FIG. 3 is an axial cross-sectional view of the composite artificial blood vessel of the present invention.

Claims (3)

[Claims] 1. A polytetrafluoroethylene porous tube having a fine fibrous structure consisting of fibers and nodules interconnected by the fibers, the tube having long portions of fibers from the inner surface to the outer surface of the tube. A living tissue-inducing substance and an antithrombotic substance are added to the tube, which is composed of two short fiber parts, and the short fiber parts are continuous in the circumferential direction of the tube and from the inner surface to the outer surface of the tube. An artificial blood vessel made by combining the following. Claim 2: The average fiber length of the long fiber portion on the inner surface of the tube is 60 μm or more, and the average fiber length of the short fiber portion is 20 μm.
The artificial blood vessel according to claim 1, which has a diameter of less than m. 3. The artificial blood vessel according to claim 1, wherein the biological tissue-inducing substance is at least one of collagen, gelatin, albumin, and laminin.