JP2009153586A - Antithrombogenic material and its manufacture process - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To enable the realization of an antithrombogenic material that has reduced both the adhesion of blood platelets and the activation of blood coagulation factors. <P>SOLUTION: The antithrombogenic material is a carbonic film formed over the surface of base material of medical treatment instruments. The antithrombogenic material has this film where carbon is mutually combined. There are amino and carboxyl radicals combined with the carbon constituting the film body. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an antithrombotic material and a method for producing the same, and more particularly, to an antithrombotic material used for a medical instrument or the like that is in direct contact with blood and a method for producing the same.

  With advances in medical technology, opportunities for contact between medical devices and blood are increasing. For this reason, the importance of compatibility (biocompatibility) with blood and living tissue is increasing. Among these, antithrombogenicity that prevents blood coagulation is very important in medical devices that come into contact with blood. At present, as a method for imparting antithrombogenicity to a medical device, the medical device is mainly covered with a hydrophilic polymer material. There are also known methods of fixing an antithrombotic material such as heparin on the surface of a medical instrument or a polymer material that releases heparin.

  However, when a medical instrument is covered with a polymer material, there is a problem that it is difficult to sufficiently adhere the medical instrument and the polymer material. In many cases, the base material of the medical device is made of metal, and the polymer material is often peeled off from the base material. The same problem occurs when fixing heparin or the like. In particular, when heparin is used, it is known that problems of infectious diseases occur due to animal origin, and problems such as an increase in blood volume due to overdose occur.

  As a method for solving these problems, coating medical devices with a carbonaceous thin film typified by a diamond-like thin film (DLC film) has attracted attention. The carbonaceous thin film can be formed as a strong film on the surface of metals and other materials. For this reason, the effect that it is hard to peel from the base material of a medical device compared with a polymeric material is acquired. Furthermore, since the carbon thin film is excellent in wear resistance and corrosion resistance, it has a feature that the durability of the medical device can be improved.

Since the carbon thin film is a smooth and inert material, it itself has a certain degree of biocompatibility. As a method to further improve the antithrombogenicity of the carbon thin film, a reactive site is formed in the carbon thin film by irradiating the carbon thin film covering the medical device with plasma, and the formed reactive site is used. A method of imparting hydrophilicity to a carbon thin film is known (see, for example, Patent Document 1).
International Publication No. 2005/97673 Pamphlet

  However, the present inventors have found that the improvement of antithrombogenicity by making the conventional carbon thin film hydrophilic has the following problems.

  Coagulation of blood that causes thrombosis is related to activation of blood coagulation factors by platelet aggregation and activation of blood coagulation factors by foreign substances. For this reason, in order to impart antithrombogenicity to a medical device, it is necessary to prevent adhesion of platelets to the surface of the medical device and to prevent activation of blood coagulation factors by the medical device.

  As a result of the study by the present inventors, it has become clear that the carbonaceous thin film imparted with hydrophilicity has a very high effect of reducing the adhesion amount of platelets, but has a low effect of preventing the activation of blood coagulation factors. It was.

  The present invention has been made based on the above findings found by the inventors of the present application, and is intended to realize an antithrombotic material in which both adhesion of platelets and activation of blood coagulation factors are reduced. Objective.

  In order to achieve the above-mentioned object, the present invention is configured so that the antithrombotic material has an amino group and a carboxyl group.

  Specifically, the antithrombogenic material according to the present invention is directed to an antithrombogenic material comprising a carbonaceous thin film formed on the surface of a substrate, and a membrane body formed by bonding carbon to each other, and a membrane body It is characterized by having an introduced amino group and carboxyl group.

  The antithrombogenic material of the present invention has an amino group and a carboxyl group. By adopting such a zwitterionic structure, both adhesion of platelets and activation of blood coagulation factors can be suppressed. Therefore, an excellent antithrombogenic material can be realized.

  The antithrombogenic material of the present invention may be configured such that the abundance ratio of carboxyl groups is 0.02 or less. Moreover, it is good also as a structure whose abundance ratio of an amino group is 0.05 or more.

  The antithrombogenic material of the present invention may be configured such that the ratio of amino group to carboxyl group is 2.5 or more. In addition, the ratio of an amino group and a carboxyl group is the value calculated | required by X-ray photoelectron spectroscopy (XPS) method.

  In the antithrombogenic material of the present invention, the oxygen content is preferably 0.1 or less.

In the antithrombogenic material of the present invention, the membrane main body may contain silicon, and the silicon abundance ratio may be 0.0375 or less.
Are preferred.

  The method for producing an antithrombotic material according to the present invention includes a step (a) of forming a carbonaceous thin film on the surface of a substrate, and irradiating the carbonaceous thin film with plasma to form amino groups and carboxyl groups on the carbonaceous thin film. And a step (b) of introducing.

  The method for producing an antithrombogenic material of the present invention includes a step of introducing an amino group and a carboxyl group into a carbonaceous thin film by irradiating the carbonaceous thin film with plasma. For this reason, both the compatibility with platelets and the compatibility with blood coagulation factors can be improved by the balance between the functional group having a negative charge and the functional device having a positive charge on the surface of the carbonaceous thin film.

  In step (b) in the method for producing an antithrombotic material of the present invention, the abundance ratio of amino groups may be 0.05 or more and the abundance ratio of carboxyl groups may be 0.02 or less.

  In the method for producing an antithrombogenic material of the present invention, in the step (b), the ratio of the amino group to the carboxyl group may be 2.5 or more.

  In the method for producing an antithrombotic material of the present invention, in the step (b), ammonia plasma may be irradiated, or oxygen plasma and ammonia plasma may be sequentially irradiated.

  In the method for producing an antithrombogenic material of the present invention, in step (a), a carbonaceous thin film containing Si may be formed, and the Si content may be 0.0375 or less.

  According to the antithrombogenic material and the method for producing the same according to the present invention, an antithrombogenic material in which both adhesion of platelets and activation of blood coagulation factors are reduced can be realized.

  The antithrombogenic material according to the present invention is a carbonaceous thin film formed on the surface of a substrate. The carbonaceous thin film is a thin film represented by a so-called diamond-like thin film (DLC film) having a carbon skeleton containing SP2 (graphite) bonded carbon and SP3 (diamond) bonded carbon as a main component.

  By irradiating the carbon thin film with plasma, a carbon-carbon bond or the like is cleaved to form a reactive site. This reactive site and oxygen react to generate a carboxyl group. Thereby, the surface of the carbonaceous thin film becomes hydrophilic. In the past, attempts have been made to improve antithrombogenicity by making the surface of the carbonaceous thin film hydrophilic.

  By making the surface of the carbon thin film hydrophilic, adhesion of platelets can be suppressed, and compatibility with platelets is improved. However, as a result of the study by the inventors of the present application, it has been clarified that the production amount of thrombin-antithrombin III complex (TAT) increases and the suitability for blood coagulation factors decreases.

As will be described in detail later, in order to improve the compatibility with blood coagulation factors, a carboxyl group component (O = C—O) and an amino group component (—NH ₂ ) are introduced into the carbonaceous thin film. cage, and found that it is preferable -NH ₂ and O = ratio of _{C-O (-NH 2 / O} = C-O) is 2.5 or more.

  Hereinafter, the antithrombotic material according to the present invention will be described in more detail using examples.

(Example)
-Formation of carbonaceous thin film-
In this example, a stainless steel (SUS316) plate was used as the base material. A 6 mm square sample was prepared for the platelet adhesion test, and a 46 mm diameter sample was prepared for quantification of the thrombin / antithrombin III complex.

Set the substrate into the chamber of the ionization vapor deposition apparatus, after introducing to argon gas (Ar) pressure becomes ^{10 -1 Pa~10 -3 Pa (10 -3} Torr~10 -5 Torr) in the chamber Then, Ar ions were generated by discharging, and bombard cleaning was performed for about 30 minutes to cause the generated Ar ions to collide with the surface of the substrate.

Subsequently, tetramethylsilane (Si (CH ₃ ) ₄ ) was introduced into the chamber for 3 minutes to form an amorphous intermediate layer having a thickness of 20 nm with silicon (Si) and carbon (C) as main components.

After forming the intermediate layer, C ₆ H ₆ gas was introduced into the chamber, and the gas pressure was adjusted to 10 ⁻¹ Pa. The C ₆ H ₆ ionized by performing continuously introduced while discharging the C ₆ H ₆ at 30ml / min, it was ionized evaporation for about 2 minutes. A carbonaceous thin film which is a DLC film having a thickness of 30 nm was formed on the surface of the substrate.

  When forming a carbon thin film, the target voltage is 1.5 kV, the target current is 50 mA, the filament voltage is 14 V, the filament current is 30 A, the anode voltage is 50 V, the anode current is 0.6 A, the reflector voltage is 50 V, and the reflector current is The current was 6 mA. Moreover, the temperature of the base material at the time of formation was about 160 ° C.

  The intermediate layer is provided to improve the adhesion between the substrate and the carbonaceous thin film, and may be omitted if sufficient adhesion between the substrate and the DLC film can be secured.

  In this embodiment, metal is used for the base material, but any material may be used. Specifically, although not particularly limited, for example, a metal such as iron, nickel, chromium, copper, titanium, platinum, tungsten, or tantalum can be used as the base material. Further, these alloys are stainless steel such as SUS316L, shape memory alloy such as Ti—Ni alloy or Cu—Al—Mn alloy, Cu—Zn alloy, Ni—Al alloy, titanium alloy, tantalum alloy, platinum alloy or An alloy such as a tungsten alloy can also be used. Moreover, bioactive ceramics, such as oxides, such as aluminum, a silicon | silicone, or a zircon, nitride, or a carbide | carbonized_material, or ceramics which have bioactivity, such as apatite or a biological glass, may be sufficient. Further, it may be a polymer resin such as polymethyl methacrylate (PMMA), high-density polyethylene or polyacetal, a silicon polymer such as polydimethylsiloxane, or a fluorine polymer such as polytetrafluoroethylene.

  Further, the shape is not limited to a plate shape, and may be any shape. The shape may be a state of a medical instrument or the like, or a state of a material before being formed.

  The carbon thin film is formed by replacing the sputtering method with a DC magnetron sputtering method, an RF magnetron sputtering method, a chemical vapor deposition method (CVD method), a plasma CVD method, a plasma ion implantation method, a superimposed RF plasma ion implantation method, An ion plating method, an arc ion plating method, an ion beam evaporation method, a laser ablation method, or the like may be used.

  The thickness of the carbon thin film is not particularly limited, but is preferably in the range of 0.005 μm to 3 μm, more preferably in the range of 0.01 μm to 1 μm.

  The carbonaceous thin film may contain silicon (Si). When forming a carbon thin film, if a silicon source is simultaneously supplied in addition to a carbon source, a carbon thin film containing Si can be formed.

  The carbon thin film may contain fluorine (F). When forming a carbon thin film, if a fluorine source is simultaneously supplied in addition to a carbon source, a carbonaceous thin film containing F can be formed.

  Various intermediate layers can be used depending on the type of substrate, but silicon (Si) and carbon (C), titanium (Ti) and carbon (C), or chromium (Cr) and carbon (C). A known film such as an amorphous film can be used. Although the thickness is not specifically limited, the range of 0.005 micrometer-0.3 micrometer is preferable, More preferably, it is the range of 0.01 micrometer-0.1 micrometer.

  The intermediate layer may be formed using a CVD method, a plasma CVD method, a thermal spraying method, an ion plating method, an arc ion plating method, or the like instead of the sputtering method.

-Plasma irradiation-
Next, plasma irradiation was performed in order to improve the antithrombogenicity of the obtained carbonaceous thin film. Plasma irradiation was performed using a parallel plate type plasma irradiation apparatus as shown in FIG. After setting the base material 11 on which the carbonaceous thin film was formed in the chamber 10 of the plasma irradiation apparatus, the pressure in the chamber 10 was exhausted to a predetermined pressure. When the pressure in the chamber 10 was changed to a high vacuum state, the turbo molecular pump was used for evacuation. Next, a gas was introduced into the chamber 10 at a predetermined flow rate, and plasma was generated by applying high-frequency power between the parallel plate electrodes 12A and 12B. High frequency power was applied using a high frequency power supply 15 connected via a matching box 14. The gas flow rate was adjusted by the mass flow controller 13.

In this example, 5 of argon (Ar), oxygen (O ₂ ), acetylene (C ₂ H ₂ ), ammonia (NH ₃ ), and a mixed gas of C ₂ H ₂ and O ₂ (Ar / O ₂ ). Plasma irradiation was performed under the seven types of conditions shown in Table 1 using different types of gases. Note that the plasma irradiation time was 15 seconds per gas.

In Table 1, “high vacuum” indicates that the gas was introduced after the inside of the chamber was once brought into a high vacuum state using a turbo molecular pump. In this example, the ultimate vacuum in a high vacuum state was 5 × 10 ⁻³ Pa, and the ultimate vacuum in normal plasma irradiation was 2 Pa.

  Note that a plasma irradiation apparatus having any structure may be used. Also, any type of discharge may be used. For example, a parallel plate method, an after glow discharge method, an electromagnetic induction type, a magnetic field type, or the like may be used. Plasma irradiation conditions are not particularly limited. For example, as the power source for generating plasma, various power source frequencies such as a commercial frequency (50 Hz or 60 Hz), a high frequency (radio frequency), or a microwave region can be used. Furthermore, the pressure control method and supply structure of the source gas are not particularly limited. However, if plasma irradiation conditions with a very high etching rate are used, the carbonaceous thin film may be damaged.

-Composition evaluation-
The composition of the obtained plasma-irradiated carbonaceous thin film was evaluated using an X-ray photoelectron spectroscopy (XPS) method. For the measurement, a photoelectron spectrometer JPS-9010MC manufactured by JEOL Ltd. was used. Al was used as the X-ray source, and X-rays were generated under the conditions of an acceleration voltage of 12.5 kV and an emission current of 17.5 mA. Measurement was performed on an area of 5 mm in diameter arbitrarily selected from the sample. Further, the composition up to a depth of about 5 nm is measured by making X-rays incident on the sample perpendicularly and setting the detection angle to 0 degree.

  The measurement range of the binding energy was 274 eV to 294 eV, 389 eV to 409 eV, and 522 eV to 542 eV, and peaks of C1s, N1s, and O1s were obtained, respectively. By comparing the area ratios of the obtained peaks, the abundance ratio of oxygen to carbon O / C and the abundance ratio of nitrogen to carbon N / C were determined. Further, the C1s peak was divided into a C—C component, a C—O component, a C═O component, and an O═C—O component by curve fitting. The abundance ratio O = C—O / C of the carboxyl group component (O═C—O) with respect to the total carbon was determined by determining the area ratio of the O═C—O component to the C1s peak.

-Evaluation of compatibility with platelets-
The suitability for platelets was determined based on the number of platelets adhered to the surface of the sample for a predetermined period of time and the quality of the suitability.

  The amount of platelet adhesion to the sample was measured as follows. First, 130 μl of platelet suspension plasma is placed on the surface of a sample adjusted to 6 mm × 6 mm. Subsequently, the cells were incubated at 37 ° C. for 60 minutes in a normal state covered with a plastic petri dish. After completion of the incubation, the sample was washed 3 times with a phosphate buffer (PBS) having a pH of 7.4. Subsequently, the sample was immersed in 1% glutaraldehyde / PBS and allowed to stand at 4 ° C. for 60 minutes to fix the adhered platelets. Subsequently, the sample was washed three times using PBS, PBS / distilled water (75/25), PBS / distilled water (50/50), PBS / distilled water (25/75) and distilled water in this order. After lyophilizing the washed sample, platinum vapor deposition was performed on the sample. Using a scanning electron mirror (JEOL, SEM-840), the surface of the platinum-deposited sample was randomly photographed for 5 fields of view at a magnification of 1000 times. Per platelet count was determined.

  Platelet suspension plasma was prepared as follows. Whole blood collected from healthy individuals was citrated (whole blood / 3.8% sodium citrate solution = 95/5 vol / vol), and this was centrifuged at 1500 rpm for 10 minutes at room temperature. 1 ml of platelet rich plasma (PRP) was collected. The remaining blood was further centrifuged at 3000 rpm for 10 minutes, and 1 ml of platelet poor plasma (PPR) was collected from the supernatant. Subsequently, the number of platelets in PRP and PPP was measured with a blood cell counter (Sysmex K-1000). Platelet suspension plasma having a platelet count of 100,000 / μl was prepared by diluting PRP with PPP.

-Evaluation of compatibility with blood coagulation factors-
The suitability for blood coagulation factors was determined by quantifying the amount of thrombin / antithrombin III complex (TAT) produced.

  Thrombin, which is produced by the activation of blood coagulation factor (coagulation system) and is the enzyme mainly responsible for blood coagulation reaction, is quickly deactivated by antithrombin III as thrombin / antithrombin III complex (TAT). . Therefore, it is known that it is difficult to directly quantify the amount of thrombin produced, and it is generally performed to estimate the amount of thrombin produced by determining the blood concentration of TAT. Therefore, the suitability for the coagulation system was judged from the amount of TAT produced when the sample and whole blood were contacted for a predetermined time.

  A polyethylene terephthalate (PET) sheet (φ = 46 mm) coated with poly (2-methoxyethyl acylate) on one side of an acrylic C-shaped spacer (inner diameter: 40 mm, outer diameter: 46 mm, thickness: 0.8 mm) Adhere with double-sided adhesive tape. A sample with a diameter of 46 mm is attached to the other surface of the C-shaped spacer with a double-sided adhesive tape to produce a sample chamber with a volume of 1000 μl.

  1000 μl of heparinized whole blood (2 IU / ml) collected from a healthy person was injected into the sample chamber and sealed with cellophane tape. In order to prevent blood cell sedimentation, this chamber was attached to a vertical rotating rotor and incubated at 37 ° C. for 120 minutes while rotating (about 4.7 rpm). After the incubation was completed, whole blood was collected from the chamber, added with 110 μl of 3.8% Na citrate aqueous solution, and centrifuged at 10 ° C., 3000 rpm, and 10 minutes.

  The TAT concentration in the plasma obtained as the supernatant was quantified using a commercially available enzyme immunoassay kit for TAT (TAT-EIA manufactured by Enzyme Research Laboratories) and a microplate reader (Thermo Max manufactured by Molecular Device). The ELISA operation was performed according to the manual attached to the kit (measurement wavelength: 450 nm). In addition, the case where the PET film which coat | covered poly (2-methoxyethyl acylate) on both surfaces of C-type spacer was adhere | attached was set as control.

-Evaluation results of carbonaceous thin films-
FIG. 2 shows the results of evaluating the compatibility of the obtained sample with platelets. In addition to the carbon thin film subjected to plasma irradiation, measurements were also made on untreated carbon thin film, PET film and stainless steel (SUS316) plate not irradiated with plasma as a control sample.

As shown in FIG. 2, by irradiating the carbon thin film with plasma, the adhesion amount of platelets is greatly reduced as compared with the untreated carbon thin film. From this, it is clear that plasma compatibility improves the blood compatibility of platelets of carbonaceous thin films. Further, among the samples subjected to plasma irradiation, when O ₂ plasma irradiation is performed, the compatibility with platelets tends to increase. This is thought to be due to the introduction of functional groups such as carboxyl groups and hydroxyl groups on the surface of the carbonaceous thin film by plasma irradiation.

FIG. 3 shows the results of evaluating suitability for blood coagulation factors. In FIG. 3, the vertical axis indicates the ratio of the TAT amount in the blood before and after the evaluation. As shown in FIG. 3, the carbon thin film subjected to the plasma irradiation was divided into one having a very large TAT production amount and one having a small amount of TAT production. When Ar plasma is irradiated (Ar), Ar plasma and NH ₃ plasma are sequentially irradiated (Ar + NH ₃ ), C ₂ H ₂ plasma and O ₂ plasma are sequentially irradiated (C ₂ H ₂ + O ₂ ) When the plasma of the mixed gas of C ₂ H ₂ and O ₂ and O ₂ plasma were sequentially irradiated (C ₂ H ₂ / O ₂ + O ₂ ), the amount of TAT produced was very large. On the other hand, when a high vacuum state is once applied and then irradiated with NH ₃ plasma (NH ₃ (high vacuum)) and when O ₂ plasma and NH ₃ plasma are sequentially irradiated (O ₂ + NH ₃ (high vacuum)) Exhibited a low level of TAT production and excellent compatibility.

  FIG. 4 shows the abundance ratio of oxygen to carbon (O / C) and abundance ratio of nitrogen to carbon (N / C) obtained by XPS for each sample. A sample having a high compatibility with the blood coagulation factor had a relatively small O / C value, and a material with a low compatibility with the blood coagulation factor tended to have a relatively large O / C value. In addition, the sample having high compatibility with the blood coagulation factor tended to have a high N / C value.

Therefore, the contents of O / C and N / C were examined in more detail. 5 and 6 show an example of the result of XPS measurement performed on the obtained sample. FIG. 5 shows the result when the plasma irradiation is O ₂ + NH ₃ , and FIG. 6 shows the result when C ₂ H ₂ + O ₂ is used.

As shown in FIG. 5, in O ₂ + NH ₃ , N1s peak and O1s peak are observed, and it is clear that nitrogen and oxygen are introduced into the carbonaceous thin film. The N1s peak appears at 398.9 eV. This is deviated from the N1s binding energy (400 ± 1 eV) of amines and amides, and the nitrogen introduced when irradiated with NH ₃ plasma is in the state of an amino group (—NH ₂ ) component. Conceivable. For this reason, the value of N / C was regarded as the abundance ratio of amino groups, and the following examination was performed. When the C1s peak is decomposed into C—C, C—O, C═O and O═C—O components by curve fitting, it can be seen that almost no O═C—O component is introduced.

On the other hand, as shown in FIG. 6, in the case of C ₂ H ₂ + O ₂ plasma, the N1s peak was not observed, but a large O1s peak was observed. Further, from the result of curve fitting of the C1s peak, it became clear that the O = C—O component was considerably contained.

Thus, even if the process of irradiating the same O ₂ plasma is included, the introduction amount of the O═C—O component into the carbonaceous thin film varies greatly depending on the combination with other plasmas such as type and order. . For this reason, in the following, antithrombogenicity is evaluated by paying attention to the amount of O═C—O component introduced into each sample.

  FIG. 7 shows the abundance ratio O = C—O / C of the O═C—O component with respect to carbon obtained by XPS for each sample. It can be seen that the sample having high compatibility with the blood coagulation factor has a relatively small value of O = C-O / C, and the sample having low compatibility has a relatively large value of O = C-O / C.

  FIG. 8 plots the TAT generation amount and the platelet adhesion amount against the value of O = C−O / C. As shown in FIG. 8, the platelet adhesion amount is hardly affected by the value of O = C−O / C. However, the amount of TAT produced increases rapidly as the value of O = C−O / C increases. For this reason, in order to realize both compatibility with platelets and compatibility with blood coagulation factors, it is necessary to reduce the value of O = C−O / C, and the value of O = C−O / C. Is preferably 0.02 or less. Further, since the value of O = C−O / C tends to be smaller as the value of O / C is smaller, the value of O / C is preferably 0.1 or less.

  On the other hand, as shown in FIG. 4, the sample having a large N / C value has a tendency to be more compatible with the blood coagulation factor than the sample having a low N / C value. Therefore, the antithrombogenicity was also evaluated from the viewpoint of paying attention to the value of N / C that is an index of the amount of amino group introduced.

FIG. 9 shows the relationship between N / C (—NH ₂ / C), TAT production and platelet adhesion for each sample. The amount of platelet adhesion is hardly affected by the value of N / C. However, the amount of TAT produced gradually decreases as the value of N / C increases. Therefore, in order to be compatible with both platelets and blood clotting factors, the value of N / C needs to be large, and the value of N / C (—NH ₂ / C) is 0.05. The above is preferable.

The reason for the excellent compatibility with both platelets and blood clotting factors when the value of O = C—O / C is small and the value of —NH ₂ / C is large is not clear. However, O═C—O / C is a functional group having a negative charge, and —NH ₂ / C is a functional group having a positive charge. Therefore, it is considered that the balance between positive and negative charges on the surface of the carbon thin film may have an effect.

FIG. 10 shows the relationship between the ratio of the —NH ₂ component and the O═C—O component and the suitability for blood clotting factors. Ratio -NH ₂ / O = C-O and -NH ₂ component and O = C-O component 10 is determined by (N / C) / (O = C-O / C). As shown in FIG. 10, the larger the value of —NH ₂ / O═C—O, the better the compatibility with the blood coagulation factor, and at least the value of —NH 2 / O = C—O is 2.5 or more. It is preferable.

The introduction rate of the —NH ₂ component, that is, the value of N / C can be changed by changing conditions such as plasma irradiation time, plasma density, and high-frequency power. It is also considered to be affected by oxygen in the chamber. The N / C value was higher when the degree of vacuum in the chamber before the introduction of the gas was about 2 Pa than when the vacuum was high (5 × 10 ⁻³ Pa). . However, when the degree of vacuum in the chamber is low, the introduction amount of the O = CO component tends to increase.

As described above, with respect to the carbon thin film by irradiating the NH ₃ plasma after the NH ₃ plasma or O ₂ plasma, a carboxyl group and an amino group when introduced into the carbon thin film is platelets and An antithrombotic material excellent in compatibility with both blood coagulation factors could be obtained. In this case, it is preferable that the value of O = C—O / C indicating the introduction amount of the carboxyl group is 0.02 or less and the value of N / C indicating the introduction amount of the amino group is 0.05 or more. Further, the value of (N / C) / (O—C—O / C) indicating the ratio of amino group to carboxyl group may be 2.5 or more.

  Further, the carbon thin film irradiated with plasma may be a carbon thin film containing Si. However, when the Si content is increased, the oxidation of Si is promoted when the plasma is irradiated, and it becomes difficult to introduce functional groups. FIG. 11 shows the relationship between the abundance ratio of Si and the compatibility with platelets. When the value of Si abundance ratio (Si / C) increases, the amount of functional groups introduced decreases, so the compatibility with platelets decreases. For this reason, the abundance ratio of Si is preferably set to 0.0375 or less. In FIG. 11, the abundance ratio of Si is the ratio of Si to the total carbon in the carbonaceous thin film measured by the XPS method.

  Since the antithrombogenic material of the present invention has excellent compatibility with both platelets and blood clotting factors, it is very useful as a material that covers the surface of a medical device that comes into contact with blood. Specifically, by covering the surfaces of stents, catheters, balloon catheters, guide wires, pacemaker leads, indwelling devices, injection needles, scalpels, vacuum blood collection tubes, infusion bags, prefilled syringes, wound holding parts, etc. Excellent antithrombogenicity can be imparted to medical devices. In addition, excellent antithrombotic properties can be imparted to artificial organs such as an artificial heart valve membrane, an artificial dialysis membrane, an artificial heart, an artificial lung, and an artificial joint.

  Various materials such as metal materials, ceramic materials, polymer materials such as rubber and resin, and composites thereof are used as base materials (base materials) for forming medical instruments and artificial organs. However, the carbonaceous thin film shown in the embodiments can be formed on the surface of any material, and an antithrombotic material can be obtained. Furthermore, the antithrombogenic material of the present invention is not only a treatment on the surface of a medical device, but also a material such as a wire, a tube and a flat plate used for the medical device, and those formed on the medical device and those formed on the way. May be.

  The antithrombotic material and the method for producing the same according to the present invention can realize an antithrombotic material in which both the adhesion of platelets and the activation of blood coagulation factors are reduced. It is useful as a functional material and a method for producing the same.

It is the schematic which shows the plasma irradiation apparatus used in one Example of this invention. It is a graph which shows the compatibility with respect to platelet of each sample obtained in one Example of this invention. It is a graph which shows the compatibility with respect to the blood coagulation factor of each sample obtained in one Example of this invention. It is a graph which shows the abundance ratio of nitrogen of each sample obtained in one Example of this invention, and the abundance ratio of oxygen. It is a result of the X-ray photoelectron spectroscopy analysis of the sample obtained by sequentially irradiating O ₂ plasma and NH ₃ plasma in one example of the present invention. It is a result of the X-ray photoelectron spectroscopic analysis of the sample obtained by sequentially irradiating C ₂ H ₂ plasma and O ₂ plasma in one example of the present invention. It is a graph which shows the abundance ratio of the carboxyl group of each sample obtained in one Example of this invention. It is a graph which shows the relationship between the abundance ratio of a carboxyl group, and antithrombogenicity about each sample obtained in one Example of this invention. It is a graph which shows the relationship between the abundance ratio of nitrogen, and antithrombogenicity about each sample obtained in one Example of this invention. It is a graph which shows the relationship between the ratio of an amino group and a carboxyl group, and antithrombogenicity about each sample obtained in one Example of this invention. In one Example of this invention, it is a graph which shows the relationship between the abundance ratio of silicon, and antithrombogenicity.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 Chamber 11 Base material 12A Parallel plate electrode 12B Parallel plate electrode 13 Mass flow controller 14 Matching box 15 High frequency power supply

Claims (12)

An antithrombotic material comprising a carbonaceous thin film formed on the surface of a substrate,
A film body formed by bonding carbon to each other;
An antithrombotic material comprising an amino group and a carboxyl group introduced into the membrane body.   The antithrombogenic material according to claim 1, wherein the abundance ratio of the carboxyl group is 0.02 or less.   The antithrombogenic material according to claim 1 or 2, wherein an abundance ratio of the amino group is 0.05 or more.   The ratio of the said amino group and a carboxyl group is 2.5 or more, The antithrombogenic material of any one of Claims 1-3 characterized by the above-mentioned. The membrane body includes oxygen;
The antithrombogenic material according to any one of claims 1 to 4, wherein an abundance ratio of oxygen is 0.1 or less. The membrane body includes silicon;
The antithrombogenic material according to any one of claims 1 to 5, wherein the abundance ratio of the silicon is 0.0375 or less. A step (a) of forming a carbonaceous thin film on the surface of the substrate;
And (b) introducing an amino group and a carboxyl group into the carbon thin film by irradiating the carbon thin film with plasma.   The antithrombogenic material according to claim 7, wherein, in the step (b), the abundance ratio of the amino group is 0.05 or more and the abundance ratio of the carboxyl group is 0.02 or less. Manufacturing method.   In the said process (b), the ratio of the said amino group and the said carboxyl group shall be 2.5 or more, The manufacturing method of the antithrombogenic material of Claim 7 characterized by the above-mentioned.   The method for producing an antithrombogenic material according to any one of claims 7 to 9, wherein ammonia plasma is irradiated in the step (b).   The method for producing an antithrombogenic material according to any one of claims 7 to 9, wherein in the step (b), oxygen plasma and ammonia plasma are sequentially irradiated.   The antithrombosis according to any one of claims 7 to 11, wherein in the step (a), the carbonaceous thin film containing Si is formed, and the content of Si is 0.0375 or less. Method for producing a functional material.