JPH0548132B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Field of Application) The present invention relates to an artificial blood vessel that has excellent preclotting properties and pseudointima-forming properties as a pretreatment for actual implantation into the body, and a method for producing the same. (Prior Art) Characteristics required for artificial blood vessels include ease of handling and biocompatibility. Handlability refers to factors such as anastomotic properties, suturing properties, fraying resistance, and blood leakage prevention properties regarding implantation into the body. Biocompatibility is antithrombotic. Various methods have been studied in the past to impart this biocompatibility, but there are basically two methods. The first method is to form a thin, biological pseudointima inside a blood vessel at an early stage to provide antithrombotic properties through biological functions. Another method uses antithrombotic substances to form blood vessels and attempts to semi-permanently prevent the formation of blood clots. In the latter case, the steady-state existence of microthrombus formation and its shedding (exfoliation) has recently been highlighted as a major and essential problem. In addition, there remain problems that seem difficult to solve, such as incompatibility with the living body at the anastomotic site. Therefore, it is desirable to develop an artificial blood vessel based on the first concept, which ideally is closer to the living body. Particularly in this method, in order to improve biocompatibility, it is necessary to have a highly porous structure. However, if the device has a highly porous structure, blood leaks from the wall surface when implanted in the body, which poses a major problem. Therefore, how to resolve this antinomy is an important problem, and so far no product has been developed that can fully meet this challenge. Particularly in the past, measures have been taken to avoid blood leakage by pre-clotting for highly porous structures, but it is extremely difficult to block highly porous structures to an extent that does not cause problems. It was hot. Furthermore, the ease with which preclotting can be performed is also related to the caliber of the artificial blood vessel; in particular, in the case of an artificial blood vessel with a narrow diameter of 6 mm or less, preclotting is extremely difficult and requires highly specialized techniques. The difficulty in this case is that the thrombus that coagulates during pre-clotting acts relatively more strongly than when it is thick, and it develops further and connects with the thrombus on the side of the body inside the artificial thrombus in a network or three-dimensional bridge formation, and the blood vessel This is because the inside is likely to become blocked. Furthermore, if the porosity is made so low that such pre-clotting is unnecessary, the formation of a uniform fibrin membrane and the accompanying formation of pseudointima will be significantly inhibited. (Problems to be Solved by the Invention) An object of the present invention is to provide an artificial blood vessel that is excellent in preventing blood leakage and having pseudointimal formation properties, and a method for manufacturing the same. (Means for Solving the Problems) As a result of intensive studies on the above-mentioned conventional drawbacks, the present inventors have developed an artificial blood vessel with excellent pre-clotting properties and pseudo-intimal formation properties and its manufacturing method by the following means. I found it. (1) The tube structure is composed of ultrafine fibers of 1 dex or less, and the basic structure is a woven, knitted or braided structure, and the ultrafine fibers are scattered vertically and horizontally in the hollow spaces of these basic structures, and , an artificial blood vessel with excellent pseudointima-forming properties, characterized by a surface wetting coefficient of 50 seconds or less. (2) The artificial blood vessel excellent in pseudointima-forming properties according to item 1 above, characterized in that the artificial blood vessel includes a portion with a diameter of 6 mm or less. (3) A method for producing an artificial blood vessel with excellent intima-forming properties, the tube structure of which is substantially comprised of ultrafine fibers of 1 dtex or less, which involves forming the fibers in advance or forming a tube, and then subjecting the fibers to a high-speed fluid punching process. A method for producing an artificial blood vessel with excellent pseudo-endometrium formation properties, which is characterized by performing a combination of hydrophilic treatment and making the surface wettability coefficient less than 50 seconds. (4) The method for producing an artificial blood vessel with excellent pseudointima-forming properties as described in 3 above, characterized in that the hydrophilic treatment is performed by plasma treatment. (5) Pseudointima formation according to 3 above, wherein the hydrophilic treatment is performed using at least one selected from acrylic acid, acrylamide, vinylpyrrolidone, polyethylene glycol, chitin, chitosan, cellulose, and alginic acid. A manufacturing method for artificial blood vessels with excellent performance. The present invention will be explained in detail below. The artificial blood vessel of the present invention is an artificial blood vessel formed using fibers, and the tube is formed using fibers that have been previously treated to make them hydrophilic, or after the tube is formed, a combination of high-speed fluid punching treatment and hydrophilic treatment is performed. obtained by In the present invention, the wettability coefficient of the surface, which will be explained later, is extremely important, and this has a decisive influence on the biocompatibility and preclotting effect as pseudo-endomembrane formation, and this effect is also particularly important for ultrafine particles. We have discovered that this effect becomes even more noticeable when combined with fibers. For example, when considering the method of making the surface (inner surface) hydrophilic as in the present invention in order to improve pre-clotting properties, the conventional general idea is that if the surface is made hydrophilic (easier to wet), water (blood) will be transferred to the wall surface. There is a concern that this may have the opposite effect on the pre-closing properties, as it tends to soak into the surface and become wet. However, by performing such water immersion treatment, unexpectedly uniform and strong fibrin deposition was observed, which resulted in completely unexpected effects such as marked improvement in preclotting properties, uniform fibrin film formation, and pseudointima formation. I found out what I can get. The reason for this is that conventional artificial blood vessels are highly hydrophobic and fibrin is deposited on the surface of the blood vessel while blood does not penetrate sufficiently into the blood vessel. When blood attempts to penetrate further into the interior due to this deposited fibrin layer, the fibrinogen in the blood, which is the source of fibrin, is filtered out, and the blood that penetrates into the interior becomes fibrinogen-free. .
This prevents further fibrin from forming internally. Therefore, it is difficult to form strong fibrin adhesion to the inside of the tissue of the artificial blood vessel, which is involved in preventing blood leakage and cell formation, and to form a uniform, thin, and strong fibrin film on the inner surface. However, in the artificial blood vessel made hydrophilic as in the present invention, blood containing fibrinogen instantly penetrates into the interior of the artificial blood vessel tissue, where fibrin is deposited. For this reason, a uniform state of fibrin adhesion is formed that has strong bonds to the inside and to the fibers. Although the present invention can be achieved by directly subjecting a conventional artificial blood vessel to a hydrophilic treatment as described below, the artificial blood vessel may also be formed using fibers that have been previously subjected to a hydrophilic treatment. In the present invention, in order to obtain good pre-clotting properties, which is the intended aim of the present invention,
The tubular structure is composed of ultrafine fibers of 1 dtex or less, and the basic structure is a woven, knitted, or braided structure, and the ultrafine fibers are scattered vertically and horizontally in the voids of these basic structures, and the surface is wet. It is important that the coefficient satisfies the requirement of less than 50 seconds. Such an artificial blood vessel can be produced by a conventional method using synthetic or regenerated ultrafine fibers of 1 dtex or less. However, when ultra-fine fibers are used, thread breakage tends to occur during production and there are many manufacturing problems, so a method using fibers that can be made ultra-fine after tube formation is recommended. Such fibers that can be made ultra-fine include fibers that can be made ultra-fine through physical or chemical treatment, such as those described in Japanese Patent Publication No. 44
−18369, Special Publication No. 1973-3816, Special Publication No. 1973-37403
or polymer blend fibers, etc., and it is possible to make them extremely fine by peeling off two or more components, or by decomposing or extracting and removing at least one component. The tube can be easily formed by conventional methods such as weaving, knitting, braiding, and non-woven fabric. In the present invention, in addition to ultrafine fibers, ordinary thick fibers may be used in combination for reinforcement or prevention of kinking. In the present invention, when an artificial blood vessel is fabricated simply using hydrophobic fibers as in the past, capillary action occurs when it comes into contact with water (blood), but in particular
By using ultrafine fibers of 1 dte or less, the capillary phenomenon can work well. However, if ultrafine fibers of 1 dtex or less, preferably 0.6 dtex or less, preferably 0.3 dtex or less, are used, water (blood) will be repelled in the initial dry state.
It acts positively (+) only after enough time has passed and the entire surface starts to get wet and becomes hydrophilic. However, at this point, a fibrin film has already been formed on the surface, and the penetration of fibrinogen-containing blood is inhibited, and the strong adhesion of fibrin to the interior, which is the aim of the present invention, does not occur. However, by making the material hydrophilic from the beginning as in the present invention, capillary action acts positively (+) from the beginning. Moreover, because of its ultra-fine fibers, it works more strongly, allowing blood to penetrate into the blood vessel tissue extremely quickly and uniformly. Further, as an effect of using ultrafine fibers, cell formation is significantly promoted, and when used on the surface, the thickness of the initial fibrin layer or pseudointima on the surface becomes extremely thin and uniform, which is particularly advantageous in the case of a small diameter. In a more preferred embodiment, it is possible to form a thinner and more uniform endothelial membrane not only by using such ultrafine fibers but also by creating a structure with more voids, that is, a higher water permeability. Although the present invention is effective even with a low water permeability, its characteristics are more pronounced when the water permeability is high.
For example, 500ml/min・cm ²・120mmHg or more, or 1000ml/min・cm ²・120mmHg or more 10000ml/
This is the case when it is less than min・cm ²・120mmHg. The features of the present invention are particularly noticeable when the diameter is small and the water permeability is high. Conventionally, it was extremely difficult to perform preclotting for fibers with a narrow diameter of 6 mm or less and such high water permeability, but the present invention improves the hydrophilicity of the fiber surface to increase the amount of fibrin attached and prevent blood vessels from becoming clots. It was discovered that preclotting can be performed thinly and uniformly without causing blockage. For imparting hydrophilicity, physical processing such as plasma treatment is most preferable from the viewpoint of having little effect on living organisms, but materials commonly used as hydrophilic agents such as acrylic acid, acrylamide, vinylpyrrolidone, and polyethylene glycol, or cellulose, It is also possible to carry out hydrophilic treatment using chitosan, alginic acid, etc., or modified products thereof, alone or in combination, as appropriate. In this case, monomer, polymer,
It is possible to simply attach it to fibers in this state, but it can also be used in the form of copolymerization or graft polymerization onto fibers. Also, a more effective method is −
It is also possible to use a polymer obtained by copolymerizing hydrophilic groups such as COOH, -SO ₃ , -OH, etc. at the polymer stage and making it into fibers. Providing such hydrophilic groups is particularly preferable in terms of fibrin precipitation and affinity with cells. Further, such hydrophilic treatment may be carried out in advance at each stage of the polymer before fiber formation or after fiber formation and then tubes are formed, but it is preferable to carry out the treatment after tube formation from the viewpoint of flexibility. On the other hand, plasma processing can be carried out using common gases used in plasma processing, such as argon, oxygen, nitrogen, ammonia, hydrogen, etc., singly or in a mixed state, and by adjusting the applied voltage. Although it is difficult to determine the conditions for the hydrophilic treatment depending on each case, as a guideline for hydrophilicity, for example, the wettability coefficient of the surface is 50 seconds or less, more preferably 30 seconds or less, and furthermore, 2 seconds or less. The surface wettability coefficient follows the definition and method below. The measurement method is to first cut open the artificial blood vessel and fix it horizontally on a frame with as much tension as possible without applying excessive force. Fix a 1 c.c. capacity syringe in the holder so that the tip of the needle is 3 cm above it. The injection needle used is TERUMO26G1/2 0.45×
It is equivalent to 13mm and can drop 0.005cc of water. One drop of distilled water is dropped onto the test piece using this syringe needle, and the time from this time to the time when the water droplet on the test piece no longer shows any particular reflection (when it is absorbed by the test piece) is 0.1. Read down to the second. This is done at three locations and the average value is defined as the wetting coefficient of that sample. In the present invention, by setting the wetting coefficient to 50 seconds or less, preferably 30 seconds or less, the initial preclotting state is stabilized and extremely smooth preclotting is possible, thereby forming a thin and uniform biological pseudointima. It becomes possible. As mentioned above, the artificial blood vessel of the present invention has a tube structure containing ultrafine fibers of 1 dtex or less, and has a surface wetting coefficient of 50 seconds or less due to hydrophilic treatment. Although the initial objective can be achieved by satisfying the configuration, weaving,
When it is formed by a structure such as knitting or braiding, the structure is such that ultra-fine fibers of a smaller proportion than the basic structure are substantially scattered in the vertical and horizontal directions in the voids of each weave, stitch, etc. be. More specifically, it is a structure in which one or more ultrafine fibers are scattered individually or in groups to the extent that they do not impede water permeation in the pores of the tissue, and more ideally, independently separated ultrafine fibers form a spider web. It is in a state where it is thinly scattered in a shape. In order to achieve high water permeability, for example, in the case of a woven structure, it is necessary to make the mesh coarse, but this will not provide sufficient pre-clotting properties, that is, the effect of preventing blood leakage. However, if even a small amount of ultrafine fibers are present vertically and horizontally in the interstices of the weave, they serve as nuclei for blood coagulation, allowing for better preclotting. In addition, ultrafine fibers are thin and only a small amount of them need to be present in a spread state, and their mass is extremely small. Therefore, they are essentially a factor that inhibits the highly water-permeable structure that is considered preferable for the formation of biological cells. Must not be. In addition, further effects can be expected by further treating the material in such a state to make it hydrophilic. A conceptual diagram of this structure is shown in FIGS. 1 and 2. That is, Fig. 1, Fig. 2
The figures are between the eyes of the tissue according to the present invention.
This is a conceptual diagram for explaining the state in which ultrafine fibers are separated and thinly scattered in the process. Figure 1 shows the overall image and shows the state in which the ultrafine fibers are crisscrossing in all directions. , FIG. 2 is a partially enlarged view of FIG. 1, and shows a state in which one or more ultrafine fibers are scattered in the pores of the tissue. These are just typical examples, and in reality there are many situations in which these are mixed, so the situation is not limited to these. This principle is based on the fact that ultrafine fibers are split into large spaces in the tissue and run in a thin spider web pattern, which does not substantially impede water permeability, but significantly increases preclotting properties. To further explain this phenomenon metaphorically, a spider's web, which is made up of ultra-fine fibers and can hardly be detected by the normal eye, allows air to pass through well, but it becomes a core of dew and a large dew stream forms along the threads of the web. It's a phenomenon where balls are formed. That is, in the case of an artificial blood vessel in which blood is the object, by adopting the structure of the present invention, although it has sufficient water permeability in a general sense, it acts as a coagulation nucleus for blood, and the pre-clotting property can be significantly improved. In creating such a structure, a tube made of a structure such as weaving, knitting, or braiding is used to inject a high-speed fluid such as water jet, air jet, etc.
This can be achieved by appropriately disturbing the tissue by punching, etc. The artificial blood vessel according to the present invention includes a portion with a diameter of 6 mm or less, and can be applied to any type, such as a simple straight type, a branched type, a tapered type, etc. Examples of fiber polymers applicable to the present invention include polyester, polyamide, polyurethane, collagen, cellulose, polyphenylene sulfide or polysulfone, fluorine-based polymers typified by polytetrafluoroethylene, polyolefins, polyethers, and their co-products. The material may be a polymer, but is not limited to these as long as it can be applied to such an artificial blood vessel. However, polyesters are generally preferred. Further, when performing pre-closing, it is relatively easy to perform pre-closing with a large-diameter device, but with a small-diameter device, it is difficult to perform pre-clotting because it tends to cause internal clogging. Particularly in the case of high water permeability, if an attempt is made to completely fill the space between the eyes with blood clots, the degree and thickness of the blood clots will increase, making internal occlusion more likely to occur. As a means to perform this pre-clotting more easily, for example, a rod, pipe, tube, etc., which is made of a state or substance that approximately matches the inner diameter of the artificial blood vessel and which is easier to peel off from coagulated blood than the artificial blood vessel material, etc. More preferably, a rod, pipe, tube, etc. made of a hydrophobic substance such as fluorine-based, polyacetal-based, silicone-based, polyolefin-based, etc. or whose surface is coated is inserted, and then the rod is pre-clotted. The extraction method is extremely effective and is an epoch-making method that can be widely recommended to the general public. This method can also be effectively utilized in the present invention. (Example) Example 1 A tube was fabricated with a plain weave structure using polyethylene terephthalate of 55Dtex-48f for the warp and polymer array fiber of 220Dtex-72f for the weft. The polymer array fiber used at this time was sea component polystyrene 20.
The number of islands was 16/f with 80 parts of polyethylene terephthalate as the island component. The tube was thoroughly treated with hot water at 80°C to which soda ash had been added, then immersed in toluene, raised with a fluffing machine, and then waterjet punched. After the crimp treatment, plasma treatment was performed in the presence of Ar gas.
The inner diameter of this artificial blood vessel is 3 mmΦ, and the water permeability is
It was 3700ml/min・cm ²・120mmHg. Between the weaves, ultra-fine fibers of 0.16 dtex were separated and thinly (4 fibers) ran randomly in a spider web pattern. The wetting coefficient of the surface was measured and was 3.6 seconds. When a polytetrafluoroethylene rod approximately 3 mm in diameter was passed through this artificial blood vessel and a preclotation test was performed using dog blood, the blood flowed well and there was no internal blockage, resulting in uniform and good preclotation. This artificial blood vessel was transplanted into a dog, and blood flow was resumed after treatment with a combination of glycidyl triethyl ammonium chloride and heparin, and the progress was observed 30 days later. As a result, some pseudoendomembrane formation was already observed on the inner surface, but it was extremely thin and uniform at about 20 μm. Comparative Example 1 Pre-clotting treatment was performed in the same manner as in Example 1 without plasma treatment.
Blood does not transfer easily to these clots, resulting in uneven thickness, and when I try to completely precloat the clots, internal thrombus bridges between each other occur, and 3 out of 5 clots have already been completely occluded at this stage. In addition, in a wetting coefficient test, this artificial blood vessel had difficulty absorbing water droplets and had a sewing coefficient of 60 seconds. Example 2 A sample with a surface wetting coefficient of 38 seconds was produced by changing the applied voltage under the plasma treatment conditions in Example 1. Example 1
It also showed good pre-clotting properties. Example 3 Using the polymer array fibers in Example 1, a tube was formed with a torsion lace structure. After being similarly treated with toluene, it was brought into contact with acrylic acid gas without being exposed to air immediately after the plasma treatment. This sample number was 0.9 seconds. When this sample was subjected to pre-clotting treatment in the same manner as in Example 1, the blood flowed well and the pre-clotting treatment was performed extremely well. Comparative Example 2 A tube with an inner diameter of 3 mmΦ and a water permeability of 3300 ml/min·cm ² ·120 mmHg was formed using 55Dtex-36f polyethylene terephthalate fibers for the warp and weft. When this was subjected to preclotting treatment, it showed only non-uniform preclotting properties. Furthermore, this artificial blood vessel has a wetting coefficient of 51.
It was a second. Example 3 A tube was fabricated with a plain weave structure using polyethylene terephthalate of 55 dtex-48 f for the warp and polymer array fiber of 170 dtex-50 f for the weft. The polymer array fiber used at this time had a sea component of 10 parts of a hot water soluble polyester copolymer, an island component of 90 parts of polyethylene terephthalate, and an island number of 16/f. A tube was formed from this combination by plain weaving, immersed in hot water, and then treated with waterjet. Further, using an artificial blood vessel with an internal diameter of 3 mmΦ prepared by crimping, plasma treatment was performed at the following level.
As a wetness test for blood, drop dog blood onto a slide glass and touch it with each length.
A 3.5 cm sample was held vertically and the time and height (cm) for blood to soak in, rise and reach equilibrium were observed.
Levels 1 to 3 were all 10 seconds or less, and level 4 was 15 seconds or less. This result shows that for levels 1 to 4,
This shows that the comparison level 5 penetrates only half the height and takes a long time, but it penetrates quickly and well. In addition, as for the effect of the amount of fibrin adsorbed in these samples, blood vessels are completely immersed in blood, 10 minutes later (after the blood has completely coagulated), immersed in physiological saline, and then immersed in distilled water to destroy blood cells with osmotic pressure. After drying, only the fibrin firmly formed in the fiber gaps was left and the weight was measured to calculate the adhesion rate. As a result, in Levels 1 to 4 according to the present invention, twice as strong fibrin was formed as compared to Comparative Level 5. The wetting coefficient of these plasma-treated artificial blood vessels was less than 1 second, compared to the comparative products.
It took 61 seconds.

[Table] (Effects of the present invention) The artificial blood vessel according to the present invention has excellent preclotting properties, enables thin and good preclotting and thin and uniform pseudointimal formation, and can significantly reduce occlusion in small diameters. .

[Brief explanation of the drawing]

Figures 1 and 2 are conceptual diagrams of a state in which ultrafine fibers are separated and thinly scattered in the gaps of the tissue according to the present invention, and Figure 1 shows ultrafine fibers crisscrossing the tissue. In this case, Figure 2 is a typical example of a state in which the ultrafine fibers are simply protruding.
Figure 1 shows the overall image, showing the ultrafine fibers crisscrossing each other, and Figure 2 is an enlarged view of a portion of Figure 1, showing the structure of the tissue.
This indicates a state in which one or more ultrafine fibers are scattered throughout.

Claims (1)

[Scope of Claims] 1. The tube structure is composed of ultrafine fibers of 1 dtex or less, and the basic structure is a woven, knitted or braided structure, and the ultrafine fibers are arranged vertically and horizontally in the hollow spaces of these basic structures. Scattered and surface wetting coefficient of 50
An artificial blood vessel with excellent pseudo-endometrium formation that takes less than a second. 2. The artificial blood vessel with excellent pseudoendometrium formation properties according to claim 1, wherein the artificial blood vessel includes a portion with a diameter of 6 mm or less. 3. A method for producing an artificial blood vessel with excellent intima-forming properties, the tube structure of which is substantially comprised of ultrafine fibers of 1 dtex or less, in which the fibers are formed in advance or after tube formation, followed by high-speed fluid punching and hydrophilization. A method for producing an artificial blood vessel with excellent pseudo-endometrium formation properties, which is characterized in that the wetting coefficient of the surface is made to be 50 seconds or less by performing a combination of treatments. 4. The method for producing an artificial blood vessel with excellent pseudointima-forming properties according to claim 3, wherein the hydrophilic treatment is performed by plasma treatment. 5. The synthetic material according to claim 3, wherein the hydrophilic treatment is carried out using at least one selected from acrylic acid, acrylamide, vinylpyrrolidone, polyethylene glycol, chitin, chitosan, cellulose, and alginic acid. A method for manufacturing artificial blood vessels with excellent intimal formation.