JPS63115554A - Artificial blood vessel excellent in pseudo-endothelium forming property - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to an artificial blood vessel with excellent preclotting properties and pseudo-endometrium formation properties as a pretreatment for actual implantation into the body, and a method for producing the same. be.

(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. Additionally, there remain problems that seem difficult to resolve, such as incompatibility with living organisms at the anastomotic site.

Therefore, it is desirable to develop an artificial blood vessel based on the first concept, which is ideally 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 trade-off is an important issue, and until now no solution has been developed that satisfactorily meets this requirement.In particular, conventionally, highly porous structures avoid blood leakage by preclonoting. Although methods have been adopted to do so, it has been extremely difficult to block highly porous objects to an extent that poses no problem simply by using countermeasures. Furthermore, the ease with which preclonting can be performed is also related to the diameter of the artificial blood vessel; in particular, in the case of an artificial blood vessel with a small diameter of 6 mm or less, preclonting becomes extremely difficult and requires highly specialized techniques. The difficult point in this case is that the thrombus that coagulates during preclotting 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 blood vessel in a network or three-dimensional bridge formation. This is because the inside is likely to become blocked and shut down. Furthermore, if the porosity is made so low that preclonoting is unnecessary, uniform fibrin film formation and the accompanying indoor film formation will be seriously targeted.

(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) The present inventors have conducted intensive studies to address the above-mentioned conventional drawbacks, and as a result, have discovered an artificial blood vessel with excellent preclotting properties and pseudo-endometrium formation properties, and a method for manufacturing the same, by the following means. It was.

(1) An artificial blood vessel with excellent pseudointima-forming properties, which is formed from fibers and has a wettability coefficient of 50 seconds or less on its 6 surfaces.

(2) The artificial blood vessel excellent in pseudointima-forming properties according to claim 1, wherein the artificial blood vessel contains ultrafine fibers of 1 dtex or less.

(3) The artificial blood vessel excellent in pseudo-intima-forming properties according to claim 1, wherein the artificial blood vessel includes a portion having a diameter of 6IIlnA or less.

(4) A patent claim in which the Mi weave of the artificial blood vessel is composed of a basic structure such as 9 weaves and 1 braid, and ultrafine fibers of 1 dtex or less are scattered in the gaps between the basic structure tissues. The artificial blood vessel excellent in pseudoendometrium formation properties according to item 1.

(5) A method for producing an artificial blood vessel with excellent pseudo-intima-forming properties that is substantially formed of fibers, characterized in that the fibers are hydrophilized in advance or after tube formation. Method for producing an artificial blood vessel (6) The method for producing an artificial blood vessel with excellent endomembrane formation according to claim 5, wherein the R hydration treatment is performed by plasma treatment.

(7) Hydrophilic treatment with acrylic acid or acrylamide.

Vinylpyrrolidone, polyethylene glycol.

Claim 5 is carried out using at least one selected from chitin, chitosan, and cellulose 5-alginic acid.
A method for producing an artificial blood vessel with excellent pseudointima-forming properties as described in Section 2.

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 can be obtained by forming a tube using fibers that have been previously treated to make them hydrophilic, or by subjecting them to hydrophilic treatment after forming the tube. In the present invention, the wetting coefficient of the surface, which will be explained later, is extremely important, and this has a decisive influence on the biocompatibility and preclotting effect of interlayer film formation. 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 to improve briquetting properties, the conventional general idea is that the surface is made hydrophilic (i?
There is a concern that water (blood) will easily seep into the wall surface and leak easily, which may actually have the opposite effect on briquetting properties. However, by performing such a hydrophilic treatment, unexpectedly uniform and strong fibrin deposition was observed, which resulted in a significant improvement in briquetting properties, uniform fibrin film formation, and intralayer 1! It was discovered that completely unexpected effects such as the formation of pores can be obtained.

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 tries to penetrate further into the interior of the fibrin layer, the fibrinogen in the blood, which is the source of fibrin, is filtered out, and the blood that penetrates into the interior does not contain fibrinogen. This prevents further fibrin from forming internally. Therefore, strong fibrin adhesion extends to the inside of the tissue of the artificial blood vessel, which is involved in blood leakage prevention and cell formation, and the inner surface is uniform and thin (hard fibrin film is difficult to form. However, it is difficult to form a strong fibrin film. In artificial blood vessels, blood containing fibrinogen instantly penetrates into the interior of the artificial blood vessel Mi fabric, where fibrin deposits occur.This results in uniform fibrin adhesion with strong bonds to the fibers that extend into the interior. A state is formed.

Although the present invention can be achieved by directly subjecting a conventional artificial blood vessel to a hydrophilic treatment 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, it is more effective to include ultrafine fibers of 1 dtex or less. Such an artificial blood vessel can be manufactured 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 disclosed in Japanese Patent Publication No. 44-183.
No. 69, Special Publication No. 46-3816, Special Publication No. 53-374
No. 03 or polymer blend fiber 1, etc., and can be made extremely fine by peeling off two or more components, or by decomposing or extracting and removing at least one component.The chain forming method follows the usual method, such as 1 weaving, 1 Al string, This is easily possible with the non-woven fabric method.

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 the fiber is less than 1 dtex, preferably 0.6 d.
t e or less, preferably Q, 3 d t e
When ultra-fine fibers with a diameter of x or less are used, in the initial dry state, they act negatively (-) to repel water (blood), but only after enough time has passed, when the entire fiber begins to get wet and become hydrophilic, does it become positive (+). work. However, at this point, a fibrin film has already been formed on the surface, and the penetration of blood containing fibrinogen is inhibited, so that the strong adhesion of fibrin to the inside does not occur as in the present invention. However, by making the material hydrophilic from the beginning as in the present invention, the capillary phenomenon acts positively (+). Moreover, because of the ultra-fine fibers, it works more strongly and allows blood to penetrate into the blood vessel Mi tissue extremely quickly and uniformly. Furthermore, as an effect of using ultrafine fibers, cell formation is significantly promoted, and when used on one surface, the initial fibrin layer or indoor membrane on the surface becomes extremely thin and uniform in thickness, which is particularly advantageous in the case of small diameter fibers.

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, 500 ml1l/min -cn+”
・120mmH, more than 100100O/win
-am”・120mm1l, more than 100100O0
/ll1in -cva” ・12On+mt1.
The following cases apply. 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 fibrin knotting in the case of such a high water permeability with a narrow diameter of 5 mm or less, but the present invention increases the amount of fibrin attached by improving the hydrophilicity of the fiber surface. We have discovered that briquetting can be performed thinly and uniformly without occluding blood vessels with blood clots.

For imparting hydrophilicity, physical processing such as plasma treatment is most preferable in terms of having little effect on living organisms, but acrylic acid,
It is also possible to carry out the hydrophilic treatment using acrylamide, vinyl pyrrolidone, polyethylene glycol, or other commonly used hydrophilic agents, or cellulose, chitosan, alginic acid, etc., or modified products thereof alone or in combination, as appropriate. In this case, it is sufficient to simply attach it to the fibers in the form of a monomer or polymer, but it can also be used in the form of copolymerization or graft polymerization onto fibers. Moreover, as a more effective method, -C00H, or -3O3
It is also possible to use a polymer obtained by copolymerizing hydrophilic groups such as , OH, etc. at the polymer stage and making it into fibers. Providing such a parent tree group is particularly preferable in terms of fibrin precipitation and affinity with cells. Further, such hydrophilic treatment may be performed in advance at the polymer stage before fiber formation or after fiber formation, and then tubes are formed, but it is preferable to perform the treatment after tube formation from the viewpoint of flexibility.

Further, the plasma treatment can be carried out by adjusting the applied voltage using common gases used in plasma treatment, such as argon, oxygen, nitrogen, ammonia, hydrogen, etc., singly or in a mixed state.

The conditions for hydrophilic treatment are difficult to determine depending on each case, but 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 even 5 seconds or less. The surface wettability coefficient follows the definition and method below.

To measure, first cut open the artificial blood vessel and fix it horizontally on a frame with as much tension as possible without applying any extra force. A syringe with an lcc capacity is fixed in the holder so that the tip of the needle is 3 cm above the syringe. The injection needle used is TE.
It is similar to RUMO26G1/20.45 x 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 point until the water droplet on the test piece no longer shows any particular reflection (until it is absorbed by the test piece) is 0.1.
Reads down to the second wheel position. This is done at three locations and the average value is defined as the wetting coefficient of the sample. In the present invention, by setting the wetting coefficient to 50 seconds or less, preferably 30 seconds or less, the initial briquetting condition is stabilized and extremely smooth briquetting is possible, thereby forming a thin and uniform indoor membrane in living organisms. It becomes possible.

As a more effective means of the present invention, when the structure is formed by a structure such as one weave, five braids, etc., a smaller proportion of ultrafine fibers than in the basic structure is substantially present in the voids of each weave, mesh, etc. The idea is to create a structure that looks like it is scattered horizontally and vertically. More specifically, it is a structure in which one or more ultrafine fibers are scattered individually or in groups in the voids of the Mi weave to the extent that they do not impede water permeation, and more ideally, independently separated ultrafine fibers are In order to achieve high water permeability, for example, in the case of a wi structure, it is necessary to make the mesh coarse, but this has sufficient briclotting properties, i.e., thin The anti-dish effect is lost.However, if even a small amount of ultrafine fibers exist vertically and horizontally in the gaps between the weaves, they become nuclei for blood coagulation, allowing for good blood clotting.Moreover, ultrafine fibers are thin and spread out. It is sufficient to exist in a small amount in such a state, and the mass is extremely small, so it does not substantially inhibit the highly water-permeable structure that is considered preferable for the formation of biological cells. Further effects can be expected by further treating the material to make it hydrophilic.Part 1
A conceptual diagram of this structure is shown in Fig. 2. These are typical examples of cars, and in reality there are many situations in which these are mixed (there are many), so this should not be taken as such. Although they run in a nest-like pattern and do not substantially impede water permeability, they significantly increase pre-clotting properties.Another alarming explanation of this phenomenon is that they are composed of ultra-fine fibers that are almost invisible to the normal eye. Spider webs, which appear to be thin, allow air to pass through well, but act as a nucleus for dew, causing large dew beads to form along the threads of the web.

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 preclotting property can be significantly improved.

When constructing such a structure, weave, knit, etc.
The tubes made by weaving can be used with high-speed fluids such as water jets and air jets.

This can be achieved by appropriately disturbing the structure by processing with a similar process, by stacking cotton-like webs and integrating them by a similar process, or by combining these methods with surface raising. The artificial blood vessel according to the present invention includes a part 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 represented by polytetrafluoroethylene, polyolefins, polyethers, and copolymers thereof. Although such methods may include merging, they are not particularly applicable as long as they are applicable to such artificial blood vessels. However, polyesters are generally preferred.

Further, when performing briquetting, it is relatively easy to perform briquetting with a large diameter, but with a small diameter, it is difficult to perform briquetting as it tends to cause internal clogging. Particularly in the case of high water permeability, if you try 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. For example, rods, pipes, tubes, etc. that are made of a state or substance that approximately matches the inner diameter of the artificial blood vessel and that is easier to peel off from coagulated blood than the artificial blood vessel material are preferably hydrophobic materials such as fluorine-based materials or polyacetal. The method of inserting a rod, pipe, tube, etc. made of silicone, silicone, polyolefin, etc. or whose surface is coated, performing preclonoting, and then pulling out the rod is extremely effective and widely recommended.ii! This is an idiosyncratic method.This method can be effectively utilized in the present invention as well.

(Examples) Example 1 A plain weave V60 chain was produced using polyethylene terephthalate with a warp of 55 dtex-48 f and polymer array fibers with a weft of 220 dtex-72 f. The polymer array fibers used at this time were 20 parts of sea component polystyrene, 80 parts of island component polyethylene terephthalate, and had a product number of 16/f. This tube was sufficiently treated with hot water containing soda ash at 80° C., then immersed in toluene, raised with a napper, and further subjected to water jet punching. After performing the crimp treatment, plasma treatment was performed in the presence of Ar gas. The inner diameter of this artificial blood vessel was 3 mmΦ, and the water permeability was 3700 m1/m1n-120+n+nH. Between the weaves, 0.16 dtex ultra-fine fibers (4 fibers) were running randomly in a spider web pattern. The wetting coefficient of the surface was measured and found to be 3.6 seconds. When a polytetrafluoroethylene rod with a thickness of about 3 mm was passed through this artificial blood vessel and a preclotting test was performed with dog blood, the blood flowed well and there was no internal blockage, and good preclotting was achieved. This artificial blood vessel was used to transplant into a dog, and after treatment with a combination of glycidyl-trimethyl-ammonium chloride and heparin, blood flow was resumed, and the progress was observed 30 days later.

As a result, some pseudointimal membrane 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.

This thing has bad blood<, J! When X Samurai was formed and I tried to complete the preclotting, blood clots formed inside each other and three of the five tubes were already completely occluded at this stage.

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 3 Showing Good Pre-Clotting Properties Like Example 1 Using the polymer array fibers in Example 1, a tube was formed with a torsion lace structure. The wetting coefficient of this sample, which was similarly treated with toluene and then brought into contact with acrylic acid gas without exposure to air immediately after plasma treatment, was 0.9 seconds.

When this sample was subjected to preclotting treatment in the same manner as in Example 1, the blood was coated well (the preclotting treatment was performed extremely well).

Comparative Example 2 55dtex-35f polyethylene terephthalate fibers were used for the warp and weft, and a tube with an inner diameter of 3IΦ had a water permeability of 3.
A tube of 300ml/min-120mmH9 was formed. When this was subjected to preclotting treatment, it showed only non-uniform preclotting properties.

Example 3 A tube was fabricated using a plain weave structure using polyethylene terephthalate of 55 dtex-48f for the warp and polymer array fibers of 170 dtex-5Of for the weft. The polymer array fibers used at this time were 10 parts of sea component hot water soluble polyester copolymer and 90 parts of island component polyethylene terephthalate.
The number of items in the department was 16/f. A tube was formed from this combination by plain weaving, immersed in hot water, and then subjected to water jet treatment. Furthermore, using an artificial blood vessel with an inner diameter of 3Iφ prepared by crimping, plasma treatment was performed at the following level. As a wetting test for blood, drop a large amount of blood onto a slide glass and place 3 lengths of blood in contact with it.
．． A 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 levels 1 to 4 all penetrate well instantly compared to comparative level 5, which penetrates only half the height and takes a long time.

In addition, as an effect of the amount of fibrin adsorbed in these samples,
The blood vessel is completely immersed in blood, and after 10 minutes (after the blood has completely coagulated) it is immersed in physiological saline, and then in distilled water to destroy blood cells with osmotic pressure, removing only the fibrin that is firmly formed between the fibers. After drying, the remaining weight was measured and the adhesion rate was calculated.

As a result, in Levels 1 to 4 according to the present invention, fibrin was twice as strong as that in Comparative Level 5 and was formed. The wetting coefficients of the plasma-treated artificial blood vessels were all 1 second or less, and the comparative products were *10 seconds or less and **15 seconds or less (effects of the present invention). Excellent, thin < good preclotting and thin, uniform indoor film formation are possible, and occlusion in small diameters can be significantly reduced.

[Brief explanation of the drawing]

Figures 1 and 2 show 14I! in a state in which ultrafine fibers are separated and thinly scattered in the mesh of &11 weave according to the present invention! ! As a conceptual diagram, FIG. 1 shows a typical example in which the ultra-fine fibers are crisscrossing each other, while FIG. 2 shows a typical example in which the ultra-wfi fibers are simply protruding.

Claims (7)

[Claims] (1) An artificial blood vessel with excellent pseudointima-forming properties, which is formed from fibers and has a surface wetting coefficient of 50 seconds or less. (2) The artificial blood vessel excellent in pseudointima-forming properties according to claim 1, wherein the artificial blood vessel contains ultrafine fibers of 1 dtex or less. (3) The artificial blood vessel with excellent pseudointima-forming properties according to claim 1, wherein the artificial blood vessel includes a portion with a diameter of 6 mm or less. (4) The tissue of the artificial blood vessel is composed of basic structures such as weaving, knitting, and braiding, and ultrafine fibers of 1 dtex or less are scattered in the gaps between the basic structural tissues. The artificial blood vessel having excellent pseudoendometrium formation properties as described in item 1. (5) A method for producing an artificial blood vessel with excellent pseudo-intima-forming properties that is substantially formed of fibers, characterized in that the fibers are hydrophilized in advance or after tube formation. Manufacturing method for artificial blood vessels. (6) The method for producing an artificial blood vessel with excellent pseudointima-forming properties according to claim 5, wherein the hydrophilic treatment is performed by plasma treatment. (7) Pseudointima-forming property according to claim 5, in which 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 results.