JPH04300559A - Composite artificial blood vessel - Google Patents

Abstract

PURPOSE:To provide the artificial blood vessel to be used as a substitute for a small- diameter blood vessel, such as coronary artery or peripheral blood vessel. CONSTITUTION:This artificial blood vessel is constituted by compounding a biotissue inductive material and an antithrombotic material with a porous tube consisting of a thermoplastic fluorine-containing elastomer without substantially contg. additives, except polymer components so as to cover the entire front surface of the pores of the porous tube to void closing the pores. This artificial blood vessel is formed by compounding the biotissue inductive material and the antithrombotic material with the thermoplastic fluorine-containing elastomer which has the compliance equal to the compliance of the bioblood vessel and is not deteriorated in the living body and, therefore, the excellent initial antithrombotic property after implantation is obtd. In addition, rapid internal membrane formation is induced, by which the antithrombotic property equal to the antithrombotic property of the bioblood vessel is imparted to this blood vessel. Since this blood vessel has the compliance equal to the compliance of the bioblood vessel, the hyperformation of the internal membrane in the anastomosia part does not arise even upon lapse of long period and the decomposition and deterioration do not arise. A good interstitial property is thus exhibited over a long period of time.

Description

[Detailed description of the invention]

0001

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

0002

BACKGROUND OF THE INVENTION Conventionally, polyester fiber knitted fabrics, woven fabrics, and stretched polytetrafluoroethylene tubes have been used as artificial blood vessels. These polymeric materials have an inner diameter of 4
Since it cannot be applied to small-diameter artificial blood vessels with a diameter of less than mm, in order to improve the tissue compatibility and antithrombotic properties of the artificial blood vessels, biological tissue-inducing substances such as collagen and antithrombotic substances such as heparin are added to the porous polymer material. An artificial blood vessel that is a composite of these has been proposed (Japanese Unexamined Patent Publication No. 46169/1983). However, although these artificial blood vessels that have been proposed in the past have excellent tissue compatibility and antithrombotic properties, they have poor suturing properties due to the high elastic modulus of the tube, and their compliance is significantly different from that of living blood vessels, making them difficult to implant in living organisms. It has been pointed out that after a long period of time, the anastomosis becomes occluded due to intimal hyperplasia.

0003

[Problems to be Solved by the Invention] As a means to solve this problem, porous polyurethane and aspirin-coated polyurethane have been developed.
Artificial blood vessels made of composite biomaterials such as polylactic acid have been proposed (Japanese Unexamined Patent Publication No. 2-54102, Wildefia et al., Surgery
y), 101(4), 459 (1987)). This artificial blood vessel has compliance close to that of biological blood vessels, so
It is said that hyperplasia of the intima at the anastomotic site does not occur even during long-term transplantation. However, polyurethane has the problem that it gradually decomposes when it stays in the body for a long time (Stokes et al.
System (Life Support System)
, 5, 25, (1987)) and cannot be applied to long-term transplantation.

[0004] Recently, an artificial blood vessel made of fluorine-containing thermoplastic rubber has been proposed (Utility Model Application Publication No. 63-77048).
Although the utility model specification mentions the characteristics of fluororubber, such as non-toxicity, resistance to deterioration, antithrombotic properties, good anastomotic properties, and shape retention, There is no description of the functions necessary for intimalization, that is, the physical structure, the combination of biological tissue-inducing substances and antithrombotic substances, and their effects.

[0005] As described above, no matter what conventional materials are used, they have excellent antithrombotic properties, intimal formation properties, and in vivo deterioration resistance.
Furthermore, it has not been possible to obtain an artificial blood vessel that satisfies all the required characteristics, such as not causing intimal hyperplasia at the anastomotic site during a long period of transplantation.

[0006]

[Means for Solving the Problems] The present inventor has provided a porous tube made of a thermoplastic fluorine-containing elastomer containing substantially no additives other than the polymer component, and in which the pores of the porous tube are not blocked. The inventors discovered that by combining a biological tissue-inducing substance and an antithrombotic substance so as to coat the surface of the pores, an artificial blood vessel that satisfies all of the above-mentioned necessary properties could be obtained, and the present invention was completed. Ta.

The artificial blood vessel of the present invention is a porous fluorine-containing elastomer tube in which a substance having a biological tissue-inducing effect and a substance having an antithrombotic effect are combined. The porous fluorine-containing elastomer tube has pores with a diameter of 1 to 500 μm that penetrate from the inner surface to the outer surface of the tube, and in order to prevent the pores from being blocked, the entire surface of the pores is designed to be inductive to living tissue. Substances and antithrombotic substances are combined. That is, the artificial blood vessel of the present invention has a porous structure coated with these substances. In the artificial blood vessel of the present invention, due to the action of the biological tissue-inducing substance,
After transplantation, living tissues and capillaries quickly invade the pores and an endometrium is formed. Until the intima is formed, antithrombotic properties are maintained by the action of the combined antithrombotic substances.

[0008] The present inventor has developed a porous fluorine-containing elastomer tube so that the pores of the porous tube are not clogged.
Moreover, in artificial blood vessels that are made by combining a biological tissue-inducing substance and an antithrombotic substance so that the entire surface of the pore is covered, as has been pointed out in the case of conventional composite artificial blood vessels, the intima may deteriorate at an early stage. Even if it is formed, it will not remain stable for a long period of time, and it will not cause narrowing or occlusion at the anastomotic site.
It was discovered that a stable endometrium can be maintained for a long period of time.

[0009] This is because the porous fluorine-containing elastomer tube used in the present invention has the same compliance as a living blood vessel, so it can repeatedly expand and contract like a living blood vessel due to pulsation caused by blood flow. Because of this, the tissue that has invaded the pore is placed in a physical environment equivalent to the tissue components on the biological blood vessel side, so the tissue has good connectivity with the biological blood vessel, and the tissue that has invaded and the intima remain stable for a long period of time. This is thought to be due to the presence of Furthermore, the artificial blood vessel of the present invention can repeatedly expand and contract like a biological blood vessel due to the pulsation associated with blood flow, so no step is created at the anastomosis, and occlusion at the anastomotic part is less likely to occur. In addition, fluorine-containing elastomers do not deteriorate or decompose even after a long period of time, as has been pointed out with polyurethane, so they can maintain their structure and physical properties after transplantation for a long period of time. , can function as a stable artificial blood vessel over a long period of time.

[0010] Therefore, the composite artificial blood vessel of the present invention is
This could not be achieved with any conventional material.
It is a comprehensively superior artificial blood vessel with excellent antithrombotic properties in the initial stage of transplantation, mid- to long-term intimal stability, and resistance to deterioration and decomposition.

Examples of the material for the porous fluorine-containing elastomer tube include fluorine-containing olefins and/or copolymers with olefins. Examples of the fluorine-containing olefin include tetrafluoroethylene, hexafluoropropylene, vinylidene fluoride, and perfluoroalkyl vinyl ether. Examples of non-fluorine-containing olefins include ethylene and propylene. A porous structure can be obtained by mixing a pore-forming agent with these copolymers and extracting the pore-forming agent after extrusion molding. As the pore-forming agent, inorganic salts such as common salt and calcium carbonate, inorganic polymer materials such as silica gel, polymer materials such as paraffin, and water-soluble polymer materials such as starch can be used.

[0012] The porous structure has a pore diameter of 1 to 500 μm,
Preferably, the holes extend through the wall from the inner surface to the outer surface. It is desirable that the porosity is between 50 and 90%, preferably between 70 and 90%. Further, the compliance of the tube is preferably similar to that of a biological blood vessel, and is between 0.1 and 0.8.

[0013] These porous fluorine-containing elastomer tubes can be composited by immersing them in a solution of a biological tissue-inducing substance or an antithrombotic substance, or by injecting the solution into the wall of the tube under pressure or vacuum. Artificial blood vessels can be created. The biological tissue-inducing substance and the antithrombotic substance may be composited individually, or they may be mixed in advance, or if necessary, mixed with a third polymeric material before being composited. However, as mentioned above, it is important to prevent the pores of the porous tube from being blocked and to coat the entire surface of the pores. If the pores are filled or a layer of composite material is formed only on the inner surface of the tube,
Since the elastic modulus of the composite material and the fluorine-containing elastomer tube are significantly different, the composite material may peel off due to handling during implantation or pulsation after implantation. therefore,
Even when a layer is formed on the inner surface of the tube as necessary, it is necessary to physically stabilize the forming layer by compounding the entire surface of the pore.

[0014] Among the substances compounded into the porous fluorine tube, substances having a biological tissue-inducing effect include cell adhesion proteins and growth factors such as endothelial cell growth factors and vascular growth factors. Among these, collagen, gelatin, albumin, and laminin are preferred. In any case, by combining these substances, the invasion of living tissue from the outer wall of the artificial blood vessel and the extension of endothelial cells from the living blood vessels on both sides of the artificial blood vessel are promoted.

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 anti-blood coagulation substances such as heparin, anti-platelet aggregation substances such as aspirin, prostaglandin E1 and prostaglandin I2, 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 the antithrombotic properties are imparted by endothelial cells that are formed later.

As mentioned earlier, this composite artificial blood vessel has excellent antithrombotic properties, intimal formation properties, and resistance to decomposition and deterioration in vivo, which could not be achieved using any conventional material, and is highly resistant to implantation. We discovered that this is an excellent vascular graft that does not cause intimal hyperplasia at the anastomotic site for a long period of time.

[0017]

EXAMPLES The present invention will be explained in detail below using specific examples, but the present invention is not limited to these specific examples.

Example 1 Fluorine-containing elastomer powder (110μ
m or less) to 300 ml of sodium chloride powder (100 μm or less).
(below) 700 ml was mixed, and the inner diameter was 1.5 by extraction molding.
A tube with an outer diameter of 2.5 mm was obtained. Sodium chloride was extracted from this tube with hot water to obtain a porous tube having through holes extending from the inner surface to the outer surface of the tube, a porosity of 70%, an average pore diameter of 70 μm, and a compliance of 0.3. 0.5% bovine tendon derived I from the inside of this tube
After injecting an aqueous solution of type collagen in a vacuum and crosslinking with glutaraldehyde, it was impregnated with a 10% aqueous heparin solution and dried in a vacuum. The combined amounts of collagen and heparin are 0.2 mg/cm and 1.6 mg/cm, respectively (300UNI
T/cm). When observed with a scanning electron microscope, collagen and heparin were found to be thinly composited over the entire pore surface, and the porous structure was maintained.

[0019] This composite artificial blood vessel was transplanted into the abdominal aorta of a rat. The inner endothelial coverage rate after 1 month was 90%, and the patency rate after 2 years was 95%, and no hyperplasia of the intima or disassembly or deterioration of the tube at the anastomotic site was observed.

Examples 2 to 3 Composite artificial blood vessels were prepared by the same method as in Example 1,
transplanted into rats. The results are shown in the table, and the endothelial coverage was good, and even after 2 years, there was no intimal hyperplasia or separation or deterioration of the tube at the anastomotic site, and the patency rate was good.

Comparative Example 1 A 10 cm fluorine-containing elastomer porous tube prepared in the same manner as in Example 1 was directly implanted into a rat. 1
The endothelial coverage rate after 1 month was low at 18%, and the patency rate after 2 years was also low at 55%.

Comparative Example 2 A stretched polytetrafluoroethylene tube with an average fiber length of 60 μm, a porosity of 70%, a compliance of 0.02, an inner diameter of 1.5 mm, and an outer diameter of 2.5 mm is 0.0 mm from the inside.
A 3% collagen aqueous solution was injected under vacuum, and after crosslinking with glutaraldehyde, it was impregnated with a 10% heparin aqueous solution and dried under vacuum. The combined amount of collagen and heparin is 0.2m
g/cm, 1.7mg/cm (320UNIT/cm)
Met. This composite artificial blood vessel with a length of 10 cm was transplanted to a rat. The endothelial coverage rate after 1 month was good at 85%, but after 2 years, intimal hyperplasia frequently occurred at the anastomotic site, and the patency rate was as low as 60%.

Comparative Example 3 Average pore diameter 50 μm, porosity 50%, inner diameter 1.5 mm,
Collagen and heparin were composited into a polyether-based polyurethane porous tube having an outer diameter of 2.5 mm in the same manner as in Example 1. Composite amount is 0.3mg/c each
m, 1.6 mg/cm (300 UNIT/cm). This composite artificial blood vessel with a length of 10 cm was transplanted to a rat. The endothelial coverage rate after 1 month was good at 80%, but after 2 years, a portion of the tube had degraded and deteriorated, and the patency rate was as low as 65%.

Comparative Example 4 An inner diameter of 1.5 mm and an outer diameter of 2 manufactured in the same manner as in Example 1.
．． A 0.5% collagen aqueous solution was vacuum injected from the inside of a porous fluorine-containing elastomer tube with a diameter of 5 mm, a porosity of 70%, and an average pore diameter of 70 μm, crosslinked with dialdehyde starch, and then vacuum dried. The amount of collagen complexed is 0.2
mg/cm. When observed with a scanning electron microscope, the porous structure of the tube was maintained. This composite artificial blood vessel was transplanted into a rat. The patency rate after one month was as low as 65%.

Comparative Example 5 An inner diameter of 1.5 mm and an outer diameter of 2 manufactured in the same manner as in Example 1.
．． Fill the lumen of a porous fluorine-containing elastomer tube with a diameter of 5 mm, a porosity of 70%, and an average pore diameter of 70 μm with a 0.5% collagen aqueous solution without applying pressure, plug both ends of the tube, and move it in the circumferential direction of the tube. Dry by rotating slowly. After crosslinking with glutaraldehyde, 10%
It was impregnated with an aqueous heparin solution and dried under vacuum. The combined amounts of collagen and heparin are 0.2 mg/cm and 1, respectively.
．． It was 7 mg/cm (310 UNIT/cm). When observed using a scanning electron microscope, collagen and heparin formed a wall-like layer with a thickness of 8 μm on the inner surface of the tube, and the inside of the pore was not composited. This composite artificial blood vessel 10
cm was implanted into the rat abdominal aorta. One month later, the patency rate was 55%, the inner surface endothelial coverage was 70%, and some collagen had peeled off. Two years later, the patency rate had decreased to 40%, and even in cases where the anastomosis was patent, the anastomosis was narrowed.

[0026]

[Effects of the Invention] As explained above, the composite artificial blood vessel according to the present invention has the same compliance as a biological blood vessel, and the pores of the porous tube are filled with a porous fluorine-containing elastomer tube that does not deteriorate in vivo. So that there is no
Moreover, it is a compound containing a biological tissue-inducing substance and an antithrombotic substance so as to cover the entire surface of the pore. This composite artificial blood vessel has excellent antithrombotic properties in the initial stage after transplantation, and by causing rapid intimal formation, it can provide antithrombotic properties equivalent to that of biological blood vessels, and even over a long period of time. Also, there is no hyperplasia of the intima at the anastomosis site, no decomposition and deterioration, and good patency over a long period of time.

[0027] Therefore, the composite artificial blood vessel according to the present invention satisfies all the required properties such as antithrombotic properties, tissue conductivity, flexibility, and resistance to decomposition and deterioration. could not. It is effective as a substitute blood vessel for small diameter blood vessels such as coronary arteries and peripheral blood vessels.

[0028]

[Table 1]

Claims (3)

[Claims] Claim 1: A porous tube made of a thermoplastic fluorine-containing elastomer containing substantially no additives other than polymer components, and a biological material so as to prevent the pores of the porous tube from being blocked and to cover the entire surface of the pores. An artificial blood vessel made by combining a tissue-inducing substance and an antithrombotic substance. [Claim 2] The porous tube has a pore diameter of 1 to 500 μm.
m, the pores penetrate from the inner wall to the outer surface, the porosity is between 50 and 90%, and the compliance of the tube is between 0.1 and 0.8.
The artificial blood vessel described. 3. The artificial blood vessel according to claim 1, wherein the biological tissue-inducing substance is at least one of collagen, gelatin, laminin, and albumin.