JPH0379019B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to an artificial blood vessel, and more particularly, to an artificial blood vessel that can be used for a long period of time. [Prior art] Conventionally, artificial blood vessels have been made of polyethylene terephthalate, which is spun into a tube-like shape by knitting and weaving polyester polymer fibers, which are then given bellows-like pleats to achieve the kink phenomenon (bending). In addition, polytetrafluoroethylene has been formed into a tube shape and 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. (Problems to be solved by the invention) Artificial blood vessels made of conventional polyester fibers and artificial blood vessels made of stretched polytetrafluoroethylene
When transplanted into a living body, a coagulated layer is first formed on the inner surface that comes into contact with blood, and cells proliferate on this layer to form an endothelial membrane, which becomes an antithrombotic intima. In this way, an artificial blood vessel can only function as a biological substitute after the inner wall of the blood vessel becomes a living body, but the thickness of the blood clot layer that initially forms reaches 1 mm to 1.5 mm, and an endothelial membrane is formed. Thickening of this endothelial membrane can be seen over time even after treatment. Therefore, after transplantation as a blood vessel, stenosis of the internal caliber usually occurs. For those with an inner diameter of 10 mm to 6 mm, the inner diameter gradually narrows over time, and the patency rate after 3 years is 60 to 70%.
At present, artificial blood vessels with an inner diameter of 6 mm or less do not have long-term patency, and in particular, there are no artificial blood vessels with an inner diameter of 4 mm or less that can be put to practical use. Coronary artery bypass surgery, which is performed to save patients suffering from heart failure due to coronary artery stenosis, involves removing the own saphenous vein and using it exclusively, but some people use an appropriate saphenous vein. Veins may not be available. Fortunately, even if the patient's own saphenous vein is extracted and utilized and coronary artery bypass surgery is successfully performed, the patency rate is said to be 60-70% after 5 years, and 30-30%. 40% of people will have to undergo another surgery after 5 years. In this case, it is difficult to save the patient's life because there is no longer a saphenous vein available. In order to save these people, the inner diameter must be 4.
Artificial blood vessels with excellent patency of mm to 3 mm are needed, but despite over 10 years of strenuous development efforts by researchers around the world, there has been no successful development of a small-diameter artificial blood vessel that can be put to practical use. . The cause of this failure was occlusion of the transplanted artificial blood vessel. In order to obtain long-term patency in artificial blood vessels, it is necessary to use materials with inherently excellent antithrombotic properties. The basic performance required for artificial blood vessels is wide-ranging, but the most strongly desired ones at present are that they have sufficient mechanical properties for practical use, do not deteriorate in vivo, have good biocompatibility, and have antithrombotic properties. Excellent, no stenosis or occlusion, and easy handling.
In particular, it has good suturing properties, has easy healing properties, and does not change shape due to pulsating pressure during use. The present inventors have discovered that it does not deteriorate in vivo over a long period of time,
Moreover, detailed research has been conducted with the aim of developing artificial blood vessels with excellent antithrombotic properties. As a result, it was found that artificial blood vessels made of polyurethane and/or polyurethane urea essentially have less platelet adsorption, are extremely antithrombotic, and have promising performance as artificial blood vessels. However, despite this, the results of animal experiments indicate that these blood vessels cannot be used for a long period of time. As a result of intensive research to determine the cause, the inventors of the present invention found that
We found that the cause of vascular occlusion is mainly at the anastomosis with the host blood vessel. At the anastomotic site, host blood vessels undergo tissue growth with intense cell division as a healing response of the body, but polyurethane or polyurethane urea has a structure that is too dense and essentially lacks space to accommodate these growing cells. Abnormal granulation formations - called punnus - develop from the stumps of host blood vessels. At the anastomosis, even the slightest surface abnormality causes disturbances in the blood flow, so even the slightest pannus causes the blood flow to become disturbed, causing thrombus formation and causing blood clots. In addition, the pannus itself grows in search of a binding partner, and gradually grows into a large lump of flesh that can stop the blood flow at the anastomosis. As described above, troubles at the anastomosis of polyurethane and/or polyurethane urea artificial blood vessels are often caused by pannus growth.
To solve these problems, the structure of polyurethane or polyurethane urea can be modified to accept cells that grow from the stump of the host blood vessel and heal naturally, or the structure can be modified to accept other growing cells. Must be granted. Furthermore, an increase in intravascular caliber due to pulsatile pressure is a factor that hinders the long-term patency of polyurethane and/or polyurethane urea artificial blood vessels.
polyurethane and/or polyurethane urea grafts every minute for an extended period of time, up to several years.
If a pulsating pressure of 60-90% is continued to be applied, the internal diameter will gradually increase, and there is a built-in risk that it will eventually become like an aneurysm and rupture, and this is a serious problem for artificial blood vessels as transplant materials. It has become a serious problem. [Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors believe that polyurethane (or polyurethane urea)
Rather than providing all the required functions to one type of material, by combining two or more types of materials with different characteristics, we can compensate for the shortcomings of one type of material and improve the characteristics of each material. The inventors came up with the idea of adding to the advantages of the present invention and developed the novel artificial blood vessel of the present invention. The artificial blood vessel of the present invention comprises (A) polyurethane and/or
or (B) an artificial blood vessel comprising a composite layer of polyurethane urea and (B) a layer of fiber aggregate, wherein () the lumen surface is made of polyurethane and/or polyurethane urea, and () at least at the anastomosis part, On the outside of the layer made of polyurethane and/or polyurethane urea, there is a layer made of a fiber aggregate made of fibers of 0.01 to 10 denier and having a gap between the fibers in which pores can grow;
() The two layers are characterized in that they are partially bonded. The layer made of (A) polyurethane and/or polyurethane urea used in the present invention must have hardness, strength, biocompatibility, elasticity, compliance, etc. that can function as an artificial blood vessel. Such polyurethanes or polyurethane ureas include segmented polyurethanes or polyurethane ureas, those containing polydimethylsiloxane in the main chain, and those containing fluorine in the hard and soft segments, but in that they are not susceptible to biodegradation, Polyether type polyurethanes or polyurethane ureas are preferred over polyester types. 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. The thickness of the layer (A) is usually 0.1 to 6.0 mm, preferably 0.5 to 4.0 mm,
The bore diameter is typically 2 to 30 mm. Next, (B) a layer consisting of fiber aggregates will be described. Examples of the substance constituting the fiber aggregate include polyesters such as polyethylene terephthalate, polytetrafluoroethylene, collagen, etc., which have been conventionally used as artificial blood vessel materials.Particularly preferably, substances that have been conventionally used alone as materials for artificial blood vessels It is a polyester used as The fiber aggregate obtained by spinning the above-mentioned substance usually has a single fiber degree (fiber thickness) of 0.01 to 10 deniers, preferably 0.1 to 8 deniers, and more preferably 0.2 to 6 deniers. Monofilament degree
If it is smaller than 0.01, it is too thin and the growth of infiltrated cells is hindered, and if it is larger than 10 denier, it is undesirable because it is too rigid and difficult to bend when formed into a tube. Such fiber aggregates form a layer having a tube-like configuration, and the layer consisting of the fiber aggregates must have gaps between the fibers that can accommodate growing cells. The gap is usually expressed in terms of water permeability (ml/min.120 mmHg.cm ² ), which is 10 to 5000, preferably 30 to 4000. Below this range, the structure is too dense, and above this range, there are too many spaces, making it impossible for cells to grow, which is undesirable. Furthermore, if the gap is filled with another substance, such as a fiber aggregate immersed in a polyurethane solution and then dried, cells will not be able to grow, which is undesirable. The layer made of fiber aggregates having such gaps is preferably a woven fabric, a knitted fabric, or a nonwoven fabric of polyester fibers. It is also given bellows processing and crimps (folds) so that it can be bent freely. In addition, in the case of knitted fabrics, elasticity can be imparted to the tube by considering the knitting method, such as a slightly loose stockinette stitch. The thickness of the layer made of such a fiber aggregate is determined by the degree of monofilament of the fibers and the form of the aggregate, but is usually 10 to 700 μm. The inner diameter of the tube in (B) may be slightly larger than the outer diameter of the tube in (A). In the artificial blood vessel of the present invention, (A), which has excellent antithrombotic properties, is placed on the lumen surface that comes into direct contact with blood, and from (A) on the outer wall side, it has excellent compatibility with growing cells and has a healing effect. (B) is at least partially arranged. Among the artificial blood vessels of the present invention, FIG. 1 shows one having a two-layer structure;
This is just an example, and a three-layer structure may be formed in which (A) is placed on the outside, a four-layer structure in which (B) is placed further outside, and furthermore, the innermost layer may be (A). )
If so, a multilayer structure in which (A) and (B) are mutually arranged is also possible. Preferably, it has a two-layer structure. Artificial blood vessels whose outer walls are covered and reinforced with different materials are known, but these only function as reinforcing materials, and there are no known artificial blood vessels that have a function for cell growth. do not have. Among such known reinforcing materials, there are net-like and spiral-like reinforcing materials, and the spacing between the threads is at least 1 mm or more, and in this state, there is enough space between the fibers to allow the growth of the aforementioned cells. Therefore, the gap cannot be obtained. The structure of the artificial blood vessel of the present invention further includes a second structure.
It also includes the form shown in the figure. In other words, (B) does not need to be present uniformly over the entire surface outside (A), and the layer consisting of fiber aggregates is continuous but non-uniformly dispersed. The present invention also includes those in which (B) is intermittently present outside of (A). In this case, it is desirable that (B) exists at least at one location outside (A) of the anastomotic cut surface of the artificial blood vessel. If (A) and (B) are in contact, they may be glued together, but (A) and (B) may It is preferable that the artificial blood vessel is partially bonded with a plurality of bonding points because the artificial blood vessel is easily bent. A reinforcing material or the like may be present between (A) and (B). In this case, for example, polypropylene, polyethylene terephthalate, or the like in a spiral, net, or linear form is used. The artificial blood vessel of the present invention can be manufactured, for example, as follows. First, (A) converts glycol such as polytetramethylene glycol, polyethylene glycol, polypropylene glycol into 4,4'-diphenylmethane diisocyanate, toluidine 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 form diamines such as ethylenediamine, propylene diamine, tetramethylene diamine, etc.
It is obtained by molding polyurethane synthesized using a conventional method of chain extension using a diol such as ethylene glycol, propylene glycol, or butanediol into a tube shape using a wet method. Next, (B) is obtained by forming a fiber aggregate of a predetermined monofilament degree into a tube shape by means such as knitting, weaving, or gluing so as to form a layer having a predetermined gap. The thus obtained (A) is covered entirely or partially with (B), and as the case may be, it is adhered. When using an adhesive, for example, polyurethane, polyurethane urea, or the like is used. Furthermore, an artificial tube having a multilayer structure of three or more layers can also be manufactured by alternately stacking (A) and (B) in the same manner. [Function] The artificial blood vessel of the present invention has polyurethane (urea) with excellent antithrombotic properties arranged in the part that comes into contact with blood, and fiber aggregates with gaps in which cells from the host blood vessel can infiltrate and grow. Since it is composite, there is no problem with the anastomosis with the host blood vessel. Furthermore, since the fiber aggregate also serves as a reinforcing material, there are concerns about aneurysm-like morphological changes that may occur during long-term transplantation and associated rupture phenomena, which are a concern with artificial blood vessels made only of polyurethane (urea). Another major feature is that it can be completely prevented, and even with a small diameter, it can be used for a long period of time. [Examples] Example 1 Polytetramethylene glycol having a molecular weight of 1350 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. The obtained polyurethane was made into a 35% by weight dimethylacetamide solution, and a stainless steel rod precisely set to be concentric with the orifice was extruded through a circular orifice at a constant speed.
The polyurethane solution was uniformly extruded so that it was spread over the entire circumferential surface of the rod through a uniform gap between the extruded stainless steel rod and the orifice, and the rod was introduced into water at 30° C. and solidified.
After 3 hours, the rod was taken out and soaked in running water overnight to thoroughly remove the solvent. The thus solidified polyurethane tube was peeled off from the stainless steel rod and air-dried. Thus, the inner diameters are 3 mm and 4 mm.
Polyurethane tubes (A) with thicknesses of 0.8 and 1.1 mm, respectively, were obtained. Next, a plain weave (water permeability 150ml/
min・120mmHg・cm ² ) The tube has bellows processing, and the inner diameter is 4.6mm and 6.2mm, and the thickness is 0.3mm each.
A polyester fiber tube (A) was obtained. The polyester fiber tube (B) with an inner diameter of 4.6 mm was placed over the polyurethane tube (A) with an inner diameter of 3 mm obtained as described above so as to be in contact with the outer wall of (A). (A) with an inner diameter of 4 mm was similarly covered with (B) with an inner diameter of 6.2 mm. The valley part of the crimp of the polyester fiber tube (B) is adhered to the outer wall of the polyurethane tube (A) using a polyurethane dimethylacetamide solution to form an artificial blood vessel with a two-layer structure as shown in Figure 1a. Obtained. In this artificial blood vessel, the cross section at the valley of the polyester fiber tube (B) is as shown in Figure 1 b, and the cross section at the crimp peak is as shown in figure c. Example 2 The outer wall of a polyurethane tube (A) produced in the same manner as in Example 1 was reinforced with spiral polypropylene threads. This was covered with a bellows-treated polyester fiber tube (B) produced in the same manner as in Example 1. No adhesive is used,
The inner wall of the polyester fiber tube (B) is not bonded to the outer wall of the polyurethane tube (A). In this way, artificial blood vessels with inner diameters of 3 mm and 4 mm having a two-layer structure with a reinforcing material interposed between (A) and (B) were obtained. Test Example 1 The artificial blood vessels of the present invention manufactured in Examples 1, 2, and 3 were each cut to a length of 5 cm and anastomosed end-to-end to the celiac artery of an adult mongrel dog.
Both (A) and (B) were anastomosed together. The development status of pannus and the patency of blood vessels related thereto were investigated 3 months and 5 months after transplantation, and the results are shown in Table 1. As a comparative example, a similar test was conducted using only the polyurethane tube manufactured in Example 1.
The results are also listed in Table 1.

[Table] 4 None None Open
Comparative example 3 Slight growth
Occurrence
4 Occurrence Growth Partial
Closed

Claims (1)

[Scope of Claims] 1 () The lumen surface is made of polyurethane and/or polyurethane urea, and () at least at the anastomosis part, the outer side of the layer made of polyurethane and/or polyurethane urea is made of fibers of 0.01 to 10 denier. An artificial blood vessel comprising: a layer made of a fiber aggregate having a gap between the fibers in which cells can grow; and () the two layers are partially adhered. 2. The artificial blood vessel according to claim 1, wherein the layer consisting of the fiber aggregate is a woven fabric, knitted fabric, or nonwoven fabric of polyester fibers.