JPH0459901B2 - - Google Patents

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to an artificial blood vessel with excellent performance. The present invention relates to an artificial blood vessel that has excellent properties, ease of handling, and durability.

[Conventional technology]

Conventional artificial blood vessels include cloth artificial blood vessels using polyester fibers, non-fabric artificial blood vessels typified by polytetrafluoroethylene tubes, and artificial blood vessels derived from living tissue such as human umbilical vein and bovine carotid artery.
Neither of the former two has sufficiently satisfactory antithrombotic properties. For this reason, it has not yet been developed into particularly small-diameter artificial blood vessels. Artificial blood vessels derived from living tissue have problems in terms of quality variation, sufficient strength, size, etc., and their use is limited to only a few. For this reason, hybrid artificial blood vessels are being considered for the purpose of complementing the artificial and biological systems. A typical example of this is the mandrill graft developed by Sparks. The purpose of this mandrill graft was to insert a silicone rod into a silicone-treated Dacron mesh, which was then implanted into the body to form a connective tissue gap, which could then be used as an artificial blood vessel.

However, this artificial blood vessel had a serious flaw.
First of all, connective tissue formation in the body was slow, requiring a long period of time of 6 weeks or more. As a result, it was not possible to respond in time to emergencies that were actually needed.

The second problem was that it was extremely susceptible to infection. The reason for this is that the Dacron fibers that make up the mesh were processed with silicone. As a result, connective tissue did not adhere to the mesh, tissue gaps were created around the fibers, and tissue fluid was accumulated at a micro level in these gaps. For this reason, when a portion of the artificial blood vessel becomes infected, the bacteria spread throughout the tissue through the tissue fluid, resulting in the artificial blood vessel floating in the pus.

Thirdly, an earlier problem is that the artificial blood vessel wall is fragile due to poor affinity between fibers and connective tissue. Fourth, as a structural defect of the mesh, the stump easily frays, and there are major problems in suturing properties, anastomotic properties, etc.

Because of these shortcomings, the mandrill graft developed by Sparks has now been completely neglected.

[Problem that the invention seeks to solve]

As described above, the present invention aims to improve the insufficient antithrombotic properties, biocompatibility, and handling properties of conventional hybrid artificial blood vessels, and in particular, to improve the biological effects of connective tissue derived from living organisms, Hybrid artificial blood vessels that complement the advantages of artificial blood vessels do not suffer from the above-mentioned drawbacks, namely, delayed connective tissue formation, weak points that are susceptible to infection, and poor integration of connective tissue and base material (problems with stability and strength). The object of the present invention is to provide an ideal hybrid artificial blood vessel with improved ease of fraying (handling problem).

[Means to solve the problem]

The present invention is based on the discovery of an essential error in the artificial blood vessel caused by Sparks, and the discovery that by improving it, an unprecedented and superior artificial blood vessel can be obtained. The present invention is achieved by the following means.

(1) An improved hybrid artificial blood vessel comprising an ultrafine fibrous base material of 0.8 dtex or less that does not substantially deteriorate in vivo, and a living body-derived tissue firmly bonded to the ultrafine fibrous base material.

(2) The improved hybrid artificial blood vessel according to claim 1, wherein the artificial blood vessel has an inner diameter of 6 mm or less.

(3) Claim 1, characterized in that the tissue derived from a living body has temporary antithrombotic properties due to an antithrombotic agent.
The improved hybrid vascular graft described in Section 1.

(4) The improved hybrid artificial blood vessel according to claim 1, wherein the tissue derived from a living body is an autologous connective tissue.

(5) The improved hybrid artificial blood vessel according to claim 1, wherein the biological tissue is derived from an animal other than a human and has been subjected to antigen suppression treatment.

(6) The improved hybrid artificial blood vessel according to claim 5, wherein the biological tissue is mainly composed of animal-derived collagen.

(7) The improved hybrid artificial blood vessel according to claim 1, wherein the base material made of ultrafine fibers has a fraying resistance coefficient of 500 or more.

In obtaining the artificial blood vessel of the present invention, first,
Prepare an ultrafine fiber base material of 0.8 dtex or less. 0.8dtex
The following ultrafine fiber base material refers to a tube-shaped ultrafine fibrous polymer that substantially exhibits little mechanical strength deterioration inside a living body.

More specifically, synthetic fibers in the general sense,
Materials that are resistant to deterioration in the living body, materials made by stretching plastic tubes to form fibrils, and materials that are naturally derived but have undergone special treatment to prevent deterioration in the living body. . Particularly preferred examples include polyester, polyurethane, polysulfone, polyamide,
Polyolefin, polyvinyl chloride, soft resin,
It is composed of fibrous materials such as polyacetal, polycaebonate, and polyphenylene sulfide. Among these, polyesters mainly composed of polyethylene terephthalate and polybutylene terephthalate are particularly preferred. A tube is formed from ultrafine fibers made of these polymers.

Regarding the formation of ultrafine fibers, USP3531368,
As seen in US Pat. No. 3,350,488, there is a method of forming multi-component fibers and removing or exfoliating one component to form ultra-fine fibers.

This ultra-fine fiber treatment can be performed in advance and then processed into a cylindrical shape, or alternatively, after being processed into a cylindrical shape, the ultra-fine fiber treatment can be performed. Of course, it is also possible to use microfibers directly formed into ultrafine fibers without going through such a method.

In the method of linearly ultra-thin filament, in order to obtain a continuous filament, the thickness must be restricted to some extent. Currently commercially available fibers have a denier of 0.1 denier or more, and in order to obtain a fiber of less than 0.1 denier, it is better to use multicomponent fibers. If it is available in the form of a filament, it can be used as is and made into a tube using ordinary tube forming means such as weaving, knitting, braiding, etc. to form a cylindrical body.

If it is in the form of a staple, it can be spun into a thread and then processed in the same manner, or it can be made into a cylindrical body by forming it into a nonwoven fabric, needle punching, high pressure fluid, heat, or other treatment. Such means are already within the range of known techniques, and these techniques can be used in combination as appropriate. It is also possible to form a cylindrical object even more directly. An example of this is melt blowing, in which a molten polymer is extruded or drawn at high speed through fine holes and then blown onto a mandrel to form a cylindrical body. With such direct methods, fiber deniers can be relatively small. However, it should be noted that in this case, the degree of crystallinity of the polymer cannot be increased in many cases, and the physical properties of the fibers often deteriorate. Therefore, in the case of polymers that easily crystallize with slight shear stress or have relatively high strength even without stretching, for example, polybutylene terephthalate, polyurethane,
It is likely to be limited to liquid crystal polymers (liquid crystal polyester, etc.). Furthermore, even if it is in the form of plastic, it is also possible to use a material that can be fibrillated into fibers by stretching. This can be achieved by making a plastic tube and then stretching it.

Although the present invention has been described as having a cylindrical shape for convenience, the present invention is not necessarily limited to this. After the fiber sheet-like material is formed, it may be made into a cylindrical shape.

The preferred points of the present invention are that the porosity is as high as possible and that it is difficult to fray.

As porosity Q, under a pressure of 120mmHg,
It is defined as the amount of water permeation in ml per minute per 1 cm ² area.

This value is usually 300 ml or more, preferably 100 ml or more, more preferably 2000 ml or more.

The preferred value when using ordinary thick fibers is
It is 4000ml or more. The appropriate value of this porosity is delicately related to the thickness of the fiber, and as the fiber becomes thinner, there is a tendency for good results to be obtained even if the porosity is small. However, such high porosity does not provide sufficient mechanical strength, and it is difficult to prevent the cut ends from fraying, which poses a practical problem.

Since the present invention uses ultrafine fibers, the formation of biological connective tissue is performed quickly and firmly integrated with the fibers without increasing the porosity as much as in the past, and the artificial blood vessel has a function similar to that of a biological body with less infection. is obtained. A feature of the present invention and the ultrafine fibers is that fraying can be easily prevented without interfering with the flexibility of blood vessels. As a measure of this fraying resistance, the fraying resistance value T is defined as follows: Surgical thread is passed in a semi-loop shape at a distance of 3 mm from the cut end of the fibrous cylindrical body, and when it is pulled using a tensile tester. Maximum load (g) In the present invention, it is desirable that TxQ>300 between T and the above-mentioned porosity Q. In this case, it is more preferable that Q>500.

The value of T can be controlled by improving the weaving, knitting, and braiding structures. Examples of ways to increase the T are, for example, weaving in the case of woven fabrics, warp knitting with increased loop density in the case of knitting,
In the case of braided cords, it is also possible to improve the structure by adding torsion lace. Partial fusion by heat is also an effective means. Furthermore, as a means to maintain flexibility and porosity, the value of T can be significantly increased by spraying a high-speed fluid to entangle the fibers with each other. In particular, in order to entangle the fibers with each other using high-speed fluid, it is preferable that the fiber thickness be small, and in this case, a thickness of 0.5 denier or less is particularly effective. In addition, the fibers can be used not only alone but also in combination with thick fibers, or can be entwined by placing other fibers on a large mesh.

In addition, in the present invention, the key point is how quickly and uniformly the tissue can be formed so that the fiber base material and the tissue are firmly integrated when implanted in the living body. In order to more effectively form cells and integrate them with the fiber base material, the thickness of the fibers must be
It is preferably 0.8 dtex or less, preferably 0.5 dtex, more preferably 0.1 dtex or less.

Although such fibers may be in a bundled state, it is more preferable that they are separated and have micro voids. In particular, in the case of high water permeability, it is preferable to use a material in which split ultrafine fibers cross the voids between the meshes of the tissue. Means for achieving this state include rubbing, disturb by applying high-speed fluid, and forming an artificial blood vessel by directly spraying each fine wire. Further, the fibers constituting the fiber base material may be hydrophobic as long as they are extremely fine, but it is more preferable that the fibers are made of a material having a hydrophilic group. Such materials include, for example, those having hydrophilic functional groups;
For example, materials with sulfone groups, carboxyl groups, etc., copolymers with polyethylene glycol, vinyl pyrrolidone, acrylamide, hydrophilic materials treated with high electric field plasma as physical means, collagen, cellulose, and other naturally derived materials. There are other ways to develop this, such as using hydrophilic fibers in combination. By appropriately using these means, the present invention exhibits its effects even more.

The most effective method of the present invention is to utilize connective tissue of a living body as the living body-derived tissue.
In this method, a so-called mandrill graft, in which a material with good detachability from cells is inserted as a core, into the thus prepared tube is implanted at an appropriate site within the living body, such as in the abdominal cavity or under the skin of the thigh. Forms connective tissue in and around the fibrous matrix. The state of this living cell is a key point, and it is necessary to manage the timing at which this state is formed.

When using autologous tissue, the preferable state of the formed connective tissue is that countless small blood vessels invade from the surrounding area.
Granulation tissue is forming, and it is best to collect it at this stage. In this state,
When used as an artificial blood vessel, the endothelial cells contained in the small blood vessel reach the lumen surface and form a colony.
This is because it is thought to be in a state of preparation to cover the lumen surface. In addition, fibroblasts in the connective tissue are active and produce collagen, which provides a good place for new cells to invade and operate, promoting the activity of cells that make up the walls of new blood vessels, and creating new cells. This is because it is thought to promote intimal formation.

When using a foreign tissue, it is preferable to use it at a time when collagen is more developed. In this case, the purpose is to utilize the promoting function of the heterologous biological connective tissue as a scaffold for cell formation, mainly due to collagen.

In this way, it is taken out of the body at an appropriate time depending on the purpose, and if necessary, the flesh that bulges out on the outside is scraped off and shaped, and the mandrel is removed to create a connective tissue artificial blood vessel (or this order can be changed as appropriate). ).

The advantage of this method, which is generally called the mandrill method, is that biological cells (membranes) are formed along the surface of the mandrel, so the surface of the base material in contact with the mandrel is extremely smooth and uniform. ) is formed. That is, because of the cylindrical shape into which the mandrel is fitted, tissue attachment is first formed from the outside toward the inside, and as the tissue formation progresses, it passes through the fibrous material base material and reaches the top of the mandrel. At this time, by leaving an appropriate gap between the mandrel and the cylindrical base material, it is possible to form a biological tissue layer (membrane) that does not impair tissue formation and has a uniform, almost constant thickness from the base material surface. Can be done. In the present invention, an extremely important point is how to remove the mandrel without damaging tissue as much as possible when it is taken out of the body. Therefore, the material that can be used for the mandrel is one that fills the inner space of the cylindrical fiber base material and can control tissue formation on its surface in a regional sense. In addition, the mandrel must be easily removed without damaging tissue, that is, it must have low adhesion to tissue. It is also important that when implanted into a living body, it does not give the living body a sense of discomfort (feeling like a foreign body). For this purpose, it is desirable that it be as flexible as possible and that there is no risk of damaging the living body during movement.

From this point of view, materials for the mandrel include inorganic materials such as aluminum, stainless steel, steel, ceramics, etc., and organic materials such as silicone, fluorine, vinyl, polyester, polyamide, and other general plastics. Available for use. When using such materials, those that have weak adhesion to living tissue can be used as is, but for those that have strong adhesion, measures to weaken the adhesion, such as
It is effective to make the surface as smooth as possible or to treat the surface with a treatment material that weakens the adhesion of living tissue.

As such treatment materials, it is effective to subject silicone, fluorine resin, generally known antithrombotic agents such as heparin, urokinase, hydrogel, aspirin, etc. to simple treatment, ionic bonding, or covalent bonding. Plastic is particularly preferred when a flexible material is required. Also, in this case, more flexibility can be achieved by forming the tube into a hollow tube shape. Particularly preferable examples of the mandrel material include silicone, fluorine, vinyl-based plastics, and the like. The thickness of the mandrel cannot be determined unambiguously because it varies depending on the purpose. However, in general, it is better if it is slightly thinner than the tube. This is because if the gap between the mandrel and the tube is too tight, the biofilm layer formed on the inner surface of the tube will not develop sufficiently, and if it is too loose, the membrane thickness will be uneven and a uniform inner wall surface will not be formed. It would be best if the tubes could be moved relatively smoothly to this degree, and the gap between them should not be too large. As a more specific guideline, the diameter D(i) of the stem relative to the inner diameter D(t) of the tube should be approximately 0.1 mm<D(t)-D(i)<1 mm. However, the present invention is not necessarily limited to this.

In applying the present invention, connective tissue formation by implantation into a living body has been described above, but as another method, there is a tissue culture method outside the body. This method involves soaking a microfiber tube base material in a culture solution.
This is a method in which living cells are injected and formed on (inside) this base material. Although cell mounting (proliferation) was insufficient for conventional thick fiber base materials, the cell formation using the ultrafine fibers of the present invention was rapid, thin, uniform, stable, and strong. It will be done.

However, it goes without saying that the most preferred biological tissue of the present invention is a biological connective tissue, and the patient's own autologous tissue. In such cases, the mandrill graft according to the present invention is implanted in an appropriate site of the patient, and cells are allowed to form sufficiently. The best results can be obtained by removing it, performing appropriate treatment, and using it as a connective tissue artificial blood vessel.

Also, depending on the site used, even autologous tissue may be used.
Alternatively, in the case of a xenobiotic tissue implanted in the body of another animal, such as a cow, pig, or goat, or a tissue cultured outside the body, appropriate treatments such as antigen suppression treatment or antithrombotic treatment may be applied. You will need to use it after doing so. For antigen suppression treatment, the collagen fiber tissue is treated as it is or after the cells are removed, it is treated with an appropriate treatment agent. Cells can be easily removed by immersion in water or by decomposition using a proteolytic enzyme such as pepsin, followed by ultrasonic cleaning. The purpose of antigen suppression treatment is to block the amino groups of collagen. For example, aldehydes such as glutaraldehyde, di- or triisosocyanates such as hexamethylene isocyanate, and polyfunctional compounds such as polyglycerol-polyglycidyl ether are used. This can be achieved by treatment with epoxies, etc. Antithrombotic treatments include heparin, urokinase, hydrogel,
This means treatment with other known antithrombotic agents such as aspirin.

In such a treatment, an auxiliary agent may be used or it may be applied chemically or physically as is. As a method of using an auxiliary agent, for example, a method such as attaching heparin to protamine, glutaraldehyde, glycidyl ammonium chloride, etc., which have been previously bound to the collagen of biological tissue, can be adopted.

In the present invention, this antithrombotic function does not necessarily have to be permanent. Fibroblasts contained in connective tissue produce collagen, provide a good scaffold for new cell invasion and activity, and serve as a link until the formation of new blood vessel endothelial membranes. It is. In fact, the function of this antithrombotic agent gradually wears off.

The thus obtained artificial blood vessel of the present invention is flexible,
The stump does not easily fray and has sufficient strength, and the connective tissue and base fibers are firmly integrated, making it an extremely stable connective tissue state against infection. This is an epoch-making device that can be used effectively for pulmonary arteries, peripheral arteries, portal veins, veins, etc., which had previously been considered impossible.

〔Example〕

The present invention will be described in more detail below with reference to Examples, but the present invention is not limited thereto.

Example 1 55Dtex-48f polyester fiber was used for the warp and weft, and 82Dtex-24f was used as the weft by sea-island multicomponent fiber, sea component polystyrene 10 parts, island component polyethylene terephthalate 90 parts, number of islands 36/
The inner diameter is made of 5-ply satin weave with double weave.
A tube of 3.4 mm and 15 cm in length was formed. This was soaked in toluene, dried, and then lightly brushed. At this point, the single yarn of the ultrafine fiber was 0.085 dtex.

The tube's porosity Q is 2470 by spraying high-pressure water through a 0.25 mm hole to entangle the ultra-fine napped fibers with each other.
ml and T were 974. A silicone tube with an outer diameter of 3 mm was fitted into this, and after sterilization with ethylene oxide gas, it was implanted into the subcutaneous tissue of the dog's chest. 4
After a week, take it out and evenly level the outside with a scalpel.
The silicone tube was then pulled out. This extraction was relatively smooth. This was immersed in a 3% protamine sulfate solution and treated within 40 minutes with a hydrophilic epoxy crosslinking agent (Denacol, manufactured by Nagase Kasei) and a 1% heparin solution. This autologous connective tissue artificial blood vessel was cut into a length of 6 cm and transplanted into both carotid arteries of a dog. The anastomosis and suturing during the transition were extremely easy. The stitches were sewn approximately 1.5 mm from the residual limb, but there was no fraying at all. This was performed on five dogs, and patency was observed over time using the Doppler method. One of the five animals weakened and died on the 12th day. 3 out of the remaining 4
Heads were sacrificed on days 30, 50, and 80. The last one has been confirmed to be patent as of 85 days ago. Samples from 4 dead and sacrificed animals were collected and macroscopically and histologically observed. In the deceased, one side was occluded, but the other side was patent. Already 30
The inner surface of the day-old sample is a glossy white color.
On day 50, the central part was almost completely covered with endothelial cells, and a good neointima had been formed. On day 80, a complete neointima had been formed and no thrombus was observed. Very good results were obtained with such a small diameter.

Example 2 In the same manner as in Example 1, a mandrill graft with an inner diameter of 8 mm and a length of 6 cm was implanted subcutaneously into an adult dog and harvested after 3 weeks to obtain an artificial blood vessel made of connective tissue of the adult dog.

This was implanted as it was into the descending thoracic aorta of the same dog as an artificial blood vessel for aortic transplantation.

This experiment was conducted using 80 dogs, samples were collected at intervals up to 828 days after implantation, and macroscopic, light microscopic, and scanning microscopic observations were performed.

When implanted, the present artificial blood vessel was much softer and easier to handle than conventional cloth artificial blood vessels. No postoperative bleeding was observed.

No thrombus was observed in the sample collected, and smooth muscle cells had invaded the blood vessel, forming a blood vessel wall whose inner surface was covered with endothelial cells, indicating that good organization into the living body was almost completely achieved. It was done.

Example 3 (Heterogeneous structure example) Using a 55Dtex-72f polybutylene terephthalate fiber (single yarn 0.76Dtex), the inner diameter was 8 mm using a circular knitting machine.
A tube was formed. A stainless steel rod of the same diameter was passed through this, and the top was lightly rubbed with grinding paper to raise it. A jet of high-pressure water was sprayed over this. After drying, the stainless steel rod was removed, and then plasma treatment was performed at a voltage of 2.1 kV in the presence of oxygen gas.

A polyacetal rod is inserted into this, and after birth
It was implanted subcutaneously in a calf on the 30th day and removed 3 weeks later. Furthermore, this was soaked in distilled water, subjected to ultrasonic cleaning treatment, then treated with glutaraldehyde, and then stored in 70% ethanol.

Next, a portion of the thoracic aorta of the adult dog was excised, and the artificial blood vessel described above, in which ethanol had been sufficiently replaced with physiological saline, was implanted therein.

The T value of this artificial blood vessel is 980, and the strength is per cm.
It weighed 3.7Kg.

When planting, it is extremely easy to handle,
No fraying was observed at all.

No bleeding was observed postoperatively.

After 85 days, this artificial blood vessel was harvested and observed, and found that good endothelial membrane formation had been completed over almost the entire surface, indicating an extremely good state of healing.

〔Effect of the invention〕

The artificial blood vessel of the present invention can be applied to a wide range of areas including areas where it could not be used conventionally. In addition, it organizes into living organisms extremely smoothly and quickly, and exhibits outstanding biocompatibility. Furthermore, it is flexible, has good fraying resistance, good anastomotic properties, and is easy to handle. It is extremely strong and safe during use.

Claims (1)

[Scope of Claims] 1. An improved hybrid artificial blood vessel comprising an ultrafine fibrous base material of 0.8 dtex or less that is substantially free from in vivo deterioration, and a tissue of biological origin firmly bonded to the ultrafine fibrous base material. 2. The improved hybrid artificial blood vessel according to claim 1, wherein the inner diameter of the artificial blood vessel is 6 mm or less. 3 Claim 1, characterized in that the tissue derived from a living body has temporary antithrombotic properties due to an antithrombotic agent.
The improved hybrid vascular graft described in Section 1. 4. The improved hybrid artificial blood vessel according to claim 1, wherein the biological tissue is an autologous connective tissue. 5. The improved hybrid artificial blood vessel according to claim 1, wherein the living tissue is derived from an animal other than a human and has been subjected to antigen suppression treatment. 6. The improved hybrid artificial blood vessel according to claim 5, wherein the biological tissue is mainly composed of animal-derived collagen. 7. The improved hybrid artificial blood vessel according to claim 1, wherein the base material made of ultrafine fibers has a fraying resistance coefficient of 500 or more.