JPH0638852B2 - Antithrombotic material and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to an antithrombotic material and a method for producing the same. In particular,
The present invention relates to a medical polymer material having excellent antithrombotic properties and biocompatibility suitable for use in artificial blood vessels, artificial organs, etc., and a method for producing the same.

[Prior Art] In the field of medical materials, many synthetic polymer materials such as polyester, polyethylene, polypropylene, and polyurethane are used, and many achievements are recognized, but they are used in places where they come into direct contact with blood. Material, eg
When used as an artificial blood vessel, blood coagulates, causing thrombus formation. In order to solve this problem, various polymer materials have been devised to have antithrombogenicity. For example,
A method for chemically bonding a natural anticoagulant such as heparin to the surface of the material (see Japanese Patent Publication No. 51-103190);
Alternatively, a method is known in which a synthetic fibrinolytically active compound such as a 1,2-diphenyl-3 or 5-dioxypyralisone derivative is added to a polymer (see Japanese Patent Publication No. 52-142772). Currently used heparin is an anticoagulant mainly derived from non-human animals obtained from porcine organs, and thus has a problem of biocompatibility. Moreover, when it is covalently bound to a polymer carrier, it has an activity. Problems remain with the method of binding heparin to the carrier, such as loss. In order to solve these problems, a polymer material surface coated with a polymer containing heparin by an ionic bond showed good antithrombotic property (Shoji Nagaoka et al., Organs, 1988 Vol. 17, No. 2, 598-). 60
(P. 1) or a ternary block copolymer of polystyrene-PEO-heparin incorporating heparin in one of the microdomains was synthesized and its antithrombotic property was tested (Vuli.
c, I.Transactions of 13th Annual Meeting of Society
for Biomaterials, P. 81, 1987) is not sufficient for practical use as an artificial blood vessel, and a satisfactory one has not been obtained yet. Furthermore, thrombolytic enzyme urokinase, have been widely used in clinical as thrombosis therapeutic agent, during bloody alpha ₂ - plasmin inhibitor and alpha ₂ - for plasmin inhibitor macroglobulin, and the like are contained in a large amount However, the action of urokinase is suppressed, and the effect expected from the in vitro activity has not been confirmed. In addition to the method of imparting antithrombogenicity to the above polymer material, a series of researches on segmented polyurethane series are known as a method of making the material itself less likely to cause thrombus. From the conventional trial-and-error method, a research method by molecular design was tried, and the relationship between the phase separation property and the antithrombotic property of the microdomain polymer is becoming more clear (Atsushi Takahara et al. Molecular Symposium Proceedings, page 21, 1987 :), and
A method using a highly porous polyurethane as a material has been studied (see Martz, H. et al. Biomaterials, 8, 3, 1987 :), but in this case, neointimal formation does not occur even after transplantation. Or, they are still too slow to be put to practical use (Koichi Tamura et al., Artificial Organs, 16, 1)
500, 1987: see).

In contrast to these studies, after transplantation of an artificial blood vessel, early thrombotic occlusion can be prevented and good short-term results can be obtained, but long-term results of 1 month or more often cause occlusion, and the cause of them is neonatal. The report that it is due to intimal insufficiency (Shinichi Sato et al .; Nikkaikai, pages 89-109, 1988)
Year: Ryo Kubo et al .; Angiology; 27, 8, 567-571.
Page, 1987: Norio Morimoto et al .; Artificial organs; 14, 941.
~ 944, 1985: Sakai, Fuuko et al .; Artificial organs, 15,
367-370, 1986), the limit of imparting both antithrombotic properties and early tissue healing properties only with synthetic polymer materials has been pointed out. Under such circumstances, recently, a method of forming a collagen layer on the surface of a polymer material (Japanese Patent Publication No. 61-58196), and a polyglycerol having a side chain and a terminal epoxy group as a reactive group in a natural blood vessel Polyglycidyl ether (PGPG
E) method of cross-linking (Chiri Nojiri et al .; artificial organ, 1
6, 1470, 1987, etc.), a so-called hybrid type artificial blood vessel has been attempted to actively promote neointimal formation, but much of the research is still required.

In addition, the use of conventional tubular body consisting only of natural tissue,
When left in the body for a long period of time, there is a problem of mechanical properties such as aneurysm-like expansion, and the use of heparin suppresses cell proliferation (Wolfgang Lankes, et.
al, Biochem. J. 251, 831-842, 1988 :), there is a possibility that neointimal formation is delayed.

[Problems to be Solved by the Invention] In view of such circumstances, the present inventors have eliminated the drawbacks of the conventional antithrombotic polymer materials, and have excellent antithrombotic properties and biocompatibility, In addition, in order to obtain a material having a good mechanical strength, earnest research was repeated. That is, by preparing a model animal for intimal injury of the blood vessel, and performing a detailed search on how the natural blood vessel is injured and then repaired,
The present invention was made by finding the conditions that an artificial blood vessel should have and applying the knowledge. As a result, when the intima of the natural blood vessel is damaged, a single fibrin thrombus formed on the exposed inner elastic lamina is inevitable, and the neointima is not obstructed thereafter and the neointima is formed in only one week. It was found to be formed. Based on this finding, the present invention has been completed by paying attention to fibrin that is temporarily formed on the inner elastic plate after intimal injury as a material having antithrombotic property and also early tissue healing property. .

[Means for Solving Problems] The gist of the present invention is an antithrombotic material comprising a polymer material and a polymerized protein layer substantially free of red blood cells and white blood cells provided on the surface thereof. . Here, the term "substantially free of red blood cells and white blood cells" means
It means that red blood cells and white blood cells have been removed to such an extent that they do not have a significant adverse effect on the antithrombotic property. Further, the present invention is an antithrombotic material comprising a polymer layer on the surface of which a polymer component protein is treated with a protein-acting enzyme to provide a polymerized protein layer. The protein acting enzyme is an enzyme having a thrombin-like action such as thrombin or leptylase, and the polymerized protein is preferably fibrin. The present invention also provides that the antithrombogenic material is produced by treating the polymer surface with a protein-acting enzyme, and then with a solution containing plasma constituent protein. Is an enzyme having a thrombin-like action such as thrombin or reptilase, and the plasma constituent protein is preferably fibrinogen, cryoprecipitate or plasma.

The present invention is to provide a polymerized protein layer on the surface of a polymer material by treating a plasma constituent protein with a protein-acting enzyme. That is, an enzyme-treated polymerized protein layer is formed on the surface of a polymer material to impart antithrombogenicity and other excellent biocompatibility. As the substance immobilized on the surface, fibrin is suitable as described above. And
According to the present invention, a polymer surface is treated with a protein-containing enzyme-containing solution (solution A) and then with a plasma constituent protein-containing solution (solution B) to obtain the target antithrombotic material. To be The protein-acting enzyme is an enzyme having a thrombin-like action such as thrombin or reptilase, and snake venom, and fibrinogen, cryoprecipitate or plasma is preferable as the plasma constituent protein. That is, the plasma constituent proteins used in the present invention are all derived from plasma, and "plasma" means that whole blood is subjected to anticoagulation treatment with citrate or the like, and blood cell components are removed by centrifugation or the like. It refers to the plasma content. This "plasma" contains fibrinogen, but it does not contain it in a high concentration. Therefore, plasma is repeatedly frozen and refrigerated to increase the concentration of fibrinogen, and the obtained product is called "cryoprecitate". And is marketed by the Japanese Red Cross Society as a cryoprecipitate formulation. Further, fibrinogen is commercially available as a preparation from various pharmaceutical companies.

In the present invention, a “protein layer polymerized by treating a plasma constituent protein with a protein-acting enzyme” on the surface of a polymer material means “a solution of A solution and a solution of B solution”.
It is formed by the contact of two liquids and is substantially free of red blood cells and white blood cells. " Specifically, it is an immobilized “fibrin”, which is a fibrinogen consisting of α, β and δ chains, and thrombin, Ca ²⁺ , FXII.
It was the action of I and eventually cross-linking to insoluble fibrin. The solution A is composed mainly of a solution containing thrombin or a protein-acting enzyme such as an enzyme having a thrombin-like action such as reptilase or snake venom. Furthermore, calcium solution, FXIII, etc. can be appropriately added to the liquid A.
And as the solution B, plasma constituent protein such as fibrinogen, cryoprecipitate or plasma can be mentioned.

Further, the protein immobilized on the surface of the polymer material can be crosslinked by a known method.

The so-called "fibrin" according to the present invention obtained as described above, unlike fibrin obtained in the past, has no unevenness and is a layer having a dense directionality by observation with an optical microscope, and substantially eliminates red blood cells and white blood cells. It is not included.

[Action] Insoluble fibrin, which is the final product of blood coagulation used in the present invention, is important in the process of wound healing, and formation of granulation tissue requires formation of an insoluble fibrin network by cross-linking that progresses between fibrin bodies. Yes (Maektl,
W.et al, Thromb.Diath Haemorrh, 32,578〜581: Lorand,
L. et al, Arch. Biochem. Biophys. 105.58-67, 1964 :). In addition, in general, thrombus follows the process of increasing in a state in which blood cell components are taken up by the fibrin fiber network, and thus it is strongly considered that fibrin leads to an increase in thrombus. Here, it should be noted that the fundamental function is different between the state in which the crosslinking reaction is progressing and the fibrin fiber in which the crosslinking reaction is completed. Also, unlike collagen and the like, fibrin is a protein that does not exist physiologically and appears in non-physiological situations, but when blood vessels are injured or artificial materials are applied in vivo. Sometimes it is an essential substance.

The inventors of the present invention have found that the fibrin formation immediately after the natural vascular injury is a substance capable of controlling the subsequent tissue repair process, through the search for the tissue repair process in the model animal. However, so-called mixed thrombus containing a lot of blood cells contains many physiologically active substances such as arachidonic acid metabolites derived from blood, activated complement, lysosomal enzyme, etc. It should be strictly distinguished from fibrin. Also, the fibrin site formed in the model animal study was organized by the neointima in just one week, and in vitro
That fibrin contributes to the promotion of capillary formation and migration by endothelial cells (J. Volander, et al, J. Ce.
ll Physiol. 125, 1-9, 1985), and further, the degradation products at each stage have various physiologically active actions due to fibrin fragmentation, which affects cell migration and proliferation. Things (Teruka Ishida et al., Atherosclerosis, 8,605,
1981) has various physiological functions possessed by fibrin, or the role of fibrin in the field of inflammation is expected as a medical material in the future.

In addition to the properties of fibrin described above, the present inventors have further investigated that plasma constituent protein is treated with a protein-acting enzyme, whereby the polymerized protein layer is composed of fibers having a dense directional property. It was found that a smooth surface is formed.

Suitably the polymerized protein is fibrin. The present invention also provides that the antithrombogenic material is produced by treating the polymer surface with a protein-acting enzyme, and then with a solution containing plasma constituent protein. Is an enzyme having a thrombin-like action such as thrombin or reptilase, and the plasma constituent protein is preferably fibrinogen, cryoprecipitate or plasma.

The method for producing the antithrombotic material according to the present invention is as follows.
The method for immobilizing fibrin on a polymeric material having a tubular shape will be described below as an example.

For example, Ca ²⁺ is introduced into the porous polyurethane lumen in the form of a tubular body.
The thrombin solution (solution A) containing the solution is put in, for example, a syringe and injected into the lumen. At this time, when a porous polymer material is used, it is desirable to apply pressure so as to spread over the entire pore space. After injecting the solution A, a fibrinogen solution (solution B) of 6% or less is injected into the inner surface of the tubular body while pressurizing with, for example, a syringe, brought into contact with the solution A, and cross-linked at the surface of the inner body of the tubular body. A fibrin film composed of is formed and immobilized.

This is because if the fibrinogen concentration is 6% or more, it is insoluble and inconvenient.

This reaction is preferably carried out in a buffer solution near neutrality. As this buffer solution, HEPES buffer or the like is used.

Further, the thrombin solution containing Ca ²⁺ is used in an appropriate amount, but the thrombin solution is 1 g per 1 g of fibrin.
Units or more, preferably 50 to 500 units are used. Thrombin solution is insufficient to act on fibrinogen below 50 units, reaches a physical strength saturation at about 350 units / ml, and above about 500 units,
This is because the effect does not increase even if the number is increased, and 500 units or less is sufficient.

The Ca ²⁺ solution is used in an amount of 5 mmole or less per 100 ml of the fibrinogen solution. That is, Ca ²⁺ was saturated at 5 mmol, and addition of more than this had no effect, so it was set to 5 mmol equivalent or less.

It is also possible to use a protease inhibitor such as aprotinin in the solution A, and FXIII can be further added in an appropriate amount.

Further, instead of the solution B, proteins such as cryoprecipitate and plasma constituent components such as plasma can be used. Then, by forming a fixed layer of protein substantially free of red blood cells and white blood cells on the surface of the polymer material, the polymer material is provided with antithrombotic property and high biocompatibility.

The polymer forming the base material of the antithrombotic material of the present invention is a synthetic polymer material having excellent mechanical performance such as nylon, polyester, polyethylene, polypropylene, polyurethane, and silicone rubber, or a natural blood vessel, ureter, etc. Tissues, organs and the like derived from the living body can be used.

When a polymer material having high porosity is used as the polymer material, in order to have no blood leakage, to have resistance to fibrinolysis, or to more firmly fix the fibrin layer on the polymer material surface. In addition to the physical adsorption method, known methods such as a reaction with a polyfunctional reagent to crosslink can be applied. For example, after forming a fibrin film on the surface of the polymer material, 0.01 to
By treating the fibrin layer with a physiological saline solution containing 2% by volume of glutaraldehyde, a material having excellent antithrombotic properties can be obtained. The above fibrin-immobilized tubular body is preferably treated with physiological saline while also washing the excess unreacted liquid.

As described above, an antithrombotic material having a fibrin membrane substantially free of erythrocytes and leukocytes fixed on the inner surface of the tubular polymeric material can be obtained.

The antithrombotic material of the present invention has excellent antithrombogenicity and biocompatibility, and has good mechanical performance, and is a material for various medical devices used in a portion in direct contact with blood, for example, Artificial blood vessels, vascular catheters, artificial kidney tubes,
It is extremely valuable as a material for heart-lung machines, blood bypass tubes, artificial heart pumping chambers and balloon pumping.

In the antithrombotic material of the present invention, since it covers fibrin substantially free of red blood cells and white blood cells, even when used for a long time in vivo, there is no risk of increasing thrombus,
Highly safe.

Next, the production of the antithrombotic material of the present invention will be described by way of specific examples, but the present invention is not limited to the following description.

[Example 1] [Fibrin membrane fixing method] Syringe A was charged with 5 ml of 50 units / ml pharmacopoeial thrombin solution (manufactured by Mochida Pharmaceutical Co., Ltd.) containing 3 mmol / l of CaCl ₂ (manufactured by Takeda Pharmaceutical Co., Ltd.). A liquid A was prepared.
On the other hand, 5 ml of 3% human fibrinogen solution (Midori Cross Co., Ltd.) was prepared as a solution B in a syringe B. Next, with the configuration shown in FIG. 2, that is, the inner wall surface of the tubular body 3 made of porous polyurethane bonded to the syringe 1 (cylinder) and the connector 2 is treated according to the present invention. That is, first, the liquid A was injected into the porous polyurethane elastic body (made by Kanebo Co., Ltd.) 3 composed of a tubular body by the cylinder 1 while applying pressure from above. Then, the solution B was injected in the same manner to form a fibrin film on the inner surface of the polyurethane 3 as a single layer. After standing for 5 minutes, the excess reaction solution was washed with 20 ml of physiological saline to obtain a fibrin membrane-immobilized tubular body.

[Example 2] [Crosslinking method of immobilized fibrin] In addition to the fibrin membrane-immobilized tubular body shown in Example 1,
A fibrin membrane-immobilized tubular body having a fibrin layer firmly bonded was obtained by immersion treatment in physiological saline containing 0.1% glutaraldehyde. After thorough washing, the antithrombotic property was examined by a circulation experiment for evaluating the antithrombotic property as described below. As a result, the red thrombus was scarcely admitted after the circulation test for 3 hours.

[Ex-vivo Circulation Experiment] Anti-thrombogenicity (ex vivo) circulation: Pentobarbital was added to healthy Japanese white rabbits (male and female weighing 2.3 to 3.0 kg) with no abnormalities in clinical findings.
92 mg / kg was administered through the ear vein, and general anesthesia was performed. After fixing in the supine position, the jugular arteries and veins were exposed by a method similar to the general surgical procedure. The AV shunt (A
-Vshunt) Place the specimen in the circuit, prime with physiological saline, and then connect to the exposed jugular vein 15 via a 14G indwelling needle (Terumo; Surflo [registered trademark]) and start the circulation test. did. That is, blood is guided from the carotid artery of the rabbit to the specimen 11 through the indwelling needle 8, the connector 9, and the infusion set 12, the taco tube 13 for sampling, and returned to the rabbit jugular vein 15. It is a thing. Immediately after the start of the circulation test, blood was collected from the sampling tube 13 of the circulation circuit and injected into a blood collection tube containing EDTA-2k as an anticoagulant (manufactured by Terumo: Benoject [registered trademark]). This anticoagulated blood is treated with ELT
The number of platelets was calculated by -8 (Ortho Instrument (manufactured by Ortho Instrument). Further, after circulation for 60 minutes, 120 minutes and 24 hours, blood was collected and the number of platelets was determined in the same manner as above. It is calculated and calculated by the formula [platelet number after 24 hours] / [platelet number immediately after the start of circulation] × 100, and expressed as a platelet reduction rate.

Further, after the 24-hour circulation test was completed, the sample was taken out from the circulation circuit, lightly washed with physiological saline, and then fixed with 10% neutral buffered formalin solution. After fixing, a paraffin section was prepared by a method according to the general method for preparing a histopathological specimen (how to prepare a histopathological specimen: Yonosuke Watanabe: Medical Institute, 6th edition, 1986), stained with HE, and stained with a mirror. I went to the inspection. As an evaluation method, the properties of the thrombus and the thickness of the formed thrombus were measured. For the thickness of thrombus,
90 times micrographs of 8 parts were taken,
The thickness was measured on the photograph and used as a thrombus point. Also, 2
The state of thrombus adhesion after the circulation test for 4 hours was observed by a scanning electron microscope (JEOL Ltd .; JSM-840).

[Example 3] Human fibrinogen preparation Fibrinogen HT-Midori (manufactured by Midori Cross Co., Ltd.) was dissolved in distilled water, passed through a Lysine-Sepharose 4B column (Pharmacia), and plasminogen (plasmin) was added. Removed. The amount of plasminogen in the solution after passing through the column was measured with a Test Team (registered trademark) PLG kit (manufactured by Daiichi Pure Chemicals Co., Ltd.), and it was confirmed that it was not detected. In addition, the amount of fibrinogen was measured by the coagulation time measurement kit (Data-F
i (registered trademark); Dido Inc.) and concentrated by freeze-drying to prepare a plasminogen-free 3% human fibrinogen solution, which was designated as solution B. On the other hand, the pharmacopoeia thrombin (manufactured by Mochida Pharmaceutical Co., Ltd.) was added with 2 mM Ca
5 mM HEPES buffer containing Cl ₂ , 2 mM MgCl ₂ and 150 mM NaCl
It was dissolved at (pH: 7.4) to be 50 units / ml, and this was designated as solution A.

The porous polyurethane tubular body used in Example 1 (4 mm
Φ, 45 mm) 3 into the inner cavity of the structure shown in Fig. 2, 3 ml of solution A is press-fit with a syringe, and then 2.5 ml of solution B
Similarly, by injecting, a single-layer fibrin film was formed on the surface of the polyurethane lumen. Further, after leaving it to stand at room temperature for 5 to 10 minutes, the inner cavity was washed with 10 ml of physiological saline to obtain a fibrin-immobilized tubular body. FIG. 1 shows the particle structure of the surface of the polyurethane which was formed on the surface of the polyurethane and observed under a microscope.

[Example 4] The plasminogen-removed fibrinogen solution prepared in Example 3 was further subjected to gelatin-cellulophin (Gelatin-Cel).
lulofine) column (manufactured by Seikagaku Corporation) to remove fibronectin. The solution after passing through the column is SD
S-polyacrylamide electrophoresis machine (made by TEFCO)
Then, it was confirmed that no fibronectin band was detected. Furthermore, by the same operation as in Example 3, a 3% human fibrinogen solution from which plasminogen and fibronectin were removed was prepared.

Using the fibrinogen solution thus prepared, a fibrin-coated polyurethane tubular body was produced in the same manner as in Example 3.

Observation of the fibrin-coated polyurethane tubular inner wall with an optical microscope and an electron microscope confirmed that one fibrin layer having a smooth surface similar to that in Example 3 was formed on the polyurethane surface.

Example 5 Using the fibrinogen solution obtained in Examples 3 and 4,
According to the present invention, a tubular body having a fibrin membrane immobilized on a polyurethane surface was subjected to the same in vitro circulation experiment as described in Example 2 together with a comparative sample as follows.

That is, according to the present invention, 3 specimens (A) of the material obtained in Example 3 and 2 specimens (B) of the material obtained in Example 4 were compared with the porous polyurethane without fibrin coating. About elastic body 3 samples (C) and Gore-tex artificial blood vessel (Gore-Tex [registered trademark])
(Gore-Tex) 3 samples (D) [Note that GORE-TEX is a Teflon fiber material, which is a commercially available material for artificial blood vessels that is generally said to have antithrombogenicity. ], On the other hand, a circulation experiment was carried out using 13 rabbits for a total of 13 specimens of 2 specimens (E) only in the circuit without placing the specimen in the circulation circuit. The results are shown in FIGS. 4 to 6 and Tables 1 and 2.

FIGS. 4A, 4B, 4C, and 4D are micrographs showing the structure of the surface of the inner wall, and A to D correspond to those in the above cases and are shown. As shown in FIG. 4C, the polyurethane surface without the fibrin coating has a fibrin network formed with a rough surface containing many red blood cells. On the other hand, as shown in FIGS. 4A and 4B, it was clarified that a red blood clot was not observed and a smooth surface was obtained when the polyurethane surface was previously coated with fibrin according to the present invention.

5A, 5B and 5C are electron micrographs showing the surface of the inner wall of the polyurethane tubular body. D indicates a Gore-Tex artificial blood vessel.

In the case of polyurethane without fibrin coating, a strong fibrin network containing many blood cell components is remarkably observed (Fig. 5C), whereas in the case of polyurethane with fibrin coating, a thin fibrin membrane containing almost no red blood cells. Are only recognized (Fig. 5, A, B).

The following Table 1 shows thrombus points showing the amount of thrombus adhered after the 24-hour circulation test. Group A, Group B, Group C, Group D
Are corresponding to the symbols A to D shown above.

As shown in Table 1, groups A and B show thrombus points for the fibrin-coated polyurethane, the adhesion of thrombus is significantly suppressed, and the adhesion amount is group D, that is, Goretex artificial blood vessel. It is clear that it is significantly smaller than that of

Next, with respect to the samples A to D, a decrease in the number of platelets in the blood after the start of the circulation experiment was observed, and blood was collected at the start, 60 minutes, 120 minutes, and 24 hours,
The number of platelets therein was measured, and the results are shown in Table 2. That is, the number of platelets at the start was set as 100%, and the number of platelets at the following time was shown as% of the number of platelets at the start.

In addition, E shows the circulation experiment only in the circuit in which the sample is not placed.

Then, FIG. 6 is a graph showing Table 2, that is, a graph showing the reduction rate of the platelet count with respect to the elapsed time of the circulation test for the samples A to D.

That is, in the case of immobilization of fibrin (curves A and B in the graph of FIG. 6), the decrease in the number of platelets was suppressed more than in the case without immobilization, and further, in the case of Gore-tex (curve D), the number of platelets was decreased. It was revealed that the decrease in

EFFECTS OF THE INVENTION The present invention provides a novel antithrombotic material, and by using the same, a polymer material having mechanical strength is used as a material used in a site in direct contact with blood in the medical field. ,
An antithrombotic material having mechanical strength, antithrombogenicity and biocompatibility is provided by immobilizing the formed fibrin membrane substantially free of red blood cells and white blood cells on the surface of the material by an enzymatic reaction. What can be done, that is, to immobilize on the surface a protein substantially free of red blood cells and white blood cells, which is polymerized with an enzyme having a thrombin-like action such as thrombin or leptylase using fibrinogen, cryoprecipitate, plasma, etc. as a starting material. Thus, remarkable technical effects such as preventing blood from coagulating and increasing thrombus and providing an antithrombotic material having excellent biocompatibility are obtained.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a photomicrograph showing the particle structure of the surface of a monolayer fibrin membrane immobilized on the surface of a porous polyurethane according to the present invention. FIG. 2 is a cross-sectional view showing a structure used in the method for immobilizing fibrin on a tubular body according to the present invention. FIG. 3 shows a circulation circuit diagram in a rabbit AV shunt circulation test for the antithrombotic material of the present invention. FIG. 4 shows an optical micrograph of the particle structure of a tissue section showing thrombus properties and thickness after a 24-hour circulation test. FIG. 5 is an electron micrograph showing the particle structure of the surface by a scanning electron microscope after the circulation test for 24 hours. FIG. 6 is a graph showing changes in the number of platelets in the 24-hour circulation test.

Claims (6)

[Claims] 1. An antithrombotic material comprising a polymer material and a polymerized protein layer substantially free of red blood cells and white blood cells on the surface thereof. 2. An antithrombotic material comprising a polymer layer provided on the surface of a polymer material by treating a plasma constituent protein with a protein-acting enzyme. 3. The antithrombotic material according to claim 2, wherein the protein acting enzyme is an enzyme having a thrombin-like action such as thrombin or leptylase, and the polymerized protein is fibrin. 4. A medical device formed from the antithrombotic material according to any one of claims 1 to 3. 5. A method for producing an antithrombotic material, which comprises treating a polymer surface with a protein-acting enzyme, and then treating it with a solution containing a plasma constituent protein. 6. The protein acting enzyme is an enzyme having a thrombin-like action such as thrombin or leptylase, and the plasma constituent protein is fibrinogen,
The method for producing an antithrombotic material according to claim 5, which is cryoprecipitate or plasma.