JP2013121430A - Biocompatible material, medical instrument and method for using medical instrument - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a biocompatible material excellent in antithrombogenic property, a medical instrument and a method for using a biocompatible material.SOLUTION: The biocompatible material contains a mixture of a polymer which maintains a glassy mixed phase with polyacrylic acid 2-methoxyethyl in a room temperature and the polyacrylic acid 2-methoxyethyl. Here, a ratio of the polyacrylic acid 2-methoxyethyl to polymethyl methacrylate as a mixed weight ratio of the polymethyl methacrylate to the polyacrylic acid 2-methoxyethyl in the mixture is within a range of 1:99-90:10. The mixture has an inclined structure in which the polyacrylic acid 2-methoxyethyl is segregated on a surface side.

Description

  The present invention relates to a biocompatible material, a medical device, and a method for using the medical device.

  Since medical devices such as catheters, stents, membranes and tubes for heart-lung machines, artificial blood vessels, and blood storage packs come into contact with blood, blood coagulation and thrombus formation are problematic. In general, blood coagulation can be prevented by using an anticoagulant such as heparin or sodium citrate. For this reason, the above-mentioned medical device is particularly required to have antithrombogenicity.

  Examples of the biocompatible material having antithrombogenicity include poly (2-methoxyethyl acrylate) (also referred to as polymethoxyacrylate 2-methoxyethyl; hereinafter simply referred to as “PMEA”) (see Patent Document 1). . PMEA is considered to be water that is weakly bound to the polymer chain due to the interaction with the polymer chain, so-called intermediate water (the exothermic peak derived from the low-temperature crystal formation of water in the temperature rising process from -100 ° C). It is known to have biocompatibility such as antithrombogenicity by having water stably observed at around -40 ° C.

  On the other hand, PMEA is inferior in form stability because it is in a rubber state at room temperature. In order to solve this problem, there is a thin film made of a polymer blend in which PMEA is mixed with polymethyl methacrylate (hereinafter simply referred to as “PMMA”) (see Non-Patent Document 1). Non-Patent Document 1 describes that PMEA tends to segregate on the surface side by applying heat treatment to a thin film made of the polymer blend.

JP 2004-161954 A

Surface segmentation of poly (2-methylethyl acrylate) in a mixture with poly (methyl methacrylate), K.S. Tanaka et al. Phys. Chem. Chem. Phys. 13, 4928-4934, 2011

  However, although the thin film containing PMEA described in Non-Patent Document 1 is excellent in form stability in that the film thickness can be adjusted to be thin, it has not been evaluated for antithrombogenicity. Generally, a polymer blend has a non-uniform structure, and it is known that various properties of the polymer blend are greatly influenced by the structure and the like. For this reason, it is unclear whether a membrane containing PMEA and other polymers has antithrombogenicity, and it has been difficult to use the membrane as a biocompatible material.

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a biocompatible material having higher antithrombogenicity, a medical device using the biocompatible material, and a method of using the medical device. And

  The present inventor has examined in detail a polymer blend of a polymer and PMEA having compatibility with PMEA at room temperature and capable of forming a glassy mixed phase. It has been found that a thin film made of a polymer blend has biocompatibility such as antithrombogenicity. In particular, the inventors have shown that anti-thrombogenicity is superior to pure PMEA by making PMEA in the polymer blend a predetermined proportion. Furthermore, this inventor discovered that the antithrombogenic property of the surface of a thin film improves more by exposing the thin film by the said polymer blend to water before use. The present inventor completed the present invention based on these findings.

That is, the biocompatible material according to the first aspect of the present invention is
Comprising a mixture of 2-methoxyethyl polyacrylate and a polymer capable of maintaining a glassy mixed phase at room temperature with 2-methoxyethyl polyacrylate;
The mixture is
The 2-methoxyethyl polyacrylate has an inclined structure segregated on the surface side,
It is characterized by that.

In this case, the mixture is
By maintaining the temperature above the glass transition temperature and below the cloud point of the mixture, the 2-methoxyethyl polyacrylate is segregated on the surface side, and is formed.
It is good as well.

Further, the polymer is a mixed weight ratio of the polymer to 2-methoxyethyl polyacrylate in the mixture: 2-methoxyethyl polyacrylate: the polymer is
In the range of 1:99 to 90:10,
It is good as well.

The polymer is
Polymethyl methacrylate,
It is good as well.

In addition, the mixture is
It is formed in a thin film on the substrate,
The 2-methoxyethyl polyacrylate is segregated on the surface side not in contact with the substrate,
It is good as well.

The medical device according to the second aspect of the present invention is:
A medical device comprising the biocompatible material described above,
Provided that the surface of the mixture is in contact with a biological component or biological tissue;
It is characterized by that.

The method of using the medical device according to the third aspect of the present invention is as follows:
A method of using the medical device described above,
After exposing the surface of the mixture to water, contacting the biological component or biological tissue;
It is characterized by that.

In this case, the time of exposure to water is
At least 8 hours,
It is good as well.

  The biocompatible material and medical device according to the present invention have higher antithrombogenicity. Moreover, the usage method of the medical device which concerns on this invention improves the antithrombogenicity of the said biocompatible material.

FIG. 1A is a diagram showing the relationship between the PMEA volume fraction (φ ^S _PMEA ) and the depth from the surface in a PMEA / PMMA blend film. FIG. 1B is a model profile of PMEA volume fraction (φ ^S _PMEA ) in a PMEA / PMMA blend film. It is a figure which shows the number of the platelets adhering to the surface of the homopolymer film | membrane of PMMA, a PMEA / PMMA blend film | membrane, and the homopolymer film | membrane of PMEA.

(Embodiment 1)
Embodiment 1 of the present invention will be described in detail. In this embodiment, a biocompatible material containing PMEA according to the present invention will be described, in particular, an example in which PMMA is mixed with PMEA.

  Here, the biocompatibility in the present invention means an attribute capable of coexisting with a biological component, a biological tissue and a biological substance while performing an original function without giving a bad influence or a strong stimulus to the living body for a long period of time. To do. Typically, biocompatibility means antithrombogenicity, which is a property of suppressing the formation of thrombus, anticoagulant property, which is a property of suppressing blood coagulation, and the like.

  PMMA can be easily formed into various shapes and thin films by having shape stability. In addition, a mixture of PMEA and glass at room temperature can be formed by a method such as removing the solvent after mixing with PMEA in the solvent. Here, room temperature usually means 25 to 45 ° C., more typically about the body temperature (35 to 40 ° C.) to which the biocompatible material is exposed. The glassy mixture thus produced has a gradient structure in which PMEA is segregated on the surface side of the mixture by performing a heat treatment such as maintaining the temperature above the glass transition point and below the cloud point of the mixture. Become. More specifically, in the gradient structure of the heat-treated mixture, the composition of PMEA and PMMA continuously changes along the direction from the inside to the surface, and the PMEA is concentrated as it is closer to the surface than the inside. . The cloud point is a temperature at which devitrification occurs as a whole due to precipitation of a crystalline or amorphous heterogeneous phase in a uniform amorphous mixed phase. The specific glass transition temperature and cloud point depend on the polymer mixed with PMEA and can be obtained from, for example, the phase diagram determined for the mixture.

  In general, it is known that at the surface and interface of the polymer mixture, polymers with low surface energy tend to be selectively concentrated in order to minimize the free energy of the system. As described above, the reason why PMEA is segregated on the surface of the mixture by the heat treatment is that the surface energy of the polymer mixed with PMEA such as PMMA is larger than the surface energy of PMEA. PMEA with a small surface energy segregates to the surface side by bringing the mixture close to a thermodynamic quasi-equilibrium state by heat treatment.

  The polymer mixed with PMEA is not limited to PMMA, and is a polymer that can be mixed with PMEA to maintain a glassy mixed phase at room temperature, and the temperature of the mixture with PMEA is equal to or higher than the glass transition temperature of the mixture and Any polymer may be used as long as the polymer has an inclined structure in which PMEA is segregated on the surface side by being kept below the cloud point. Examples of the polymer mixed with PMEA include those in which the phase diagram when mixed with PMEA is LCST type or UCST type. Furthermore, depending on the intended use of the biocompatible material, the polymer mixed with PMEA can be selected from other polymers having a surface energy smaller than that of PMEA in addition to PMMA. Further, PMEA can be segregated on the surface by examining the conditions of heat treatment.

  In particular, by using a polymer having excellent shape stability such as PMMA as a polymer mixed with PMEA, a biocompatible material utilizing the biocompatibility of PMEA can be formed.

  Specifically, the polymer mixed with PMEA is preferably, for example, poly (meth) acrylate, such as polyethyl methacrylate, polybutyl methacrylate, polymethyl acrylate, polyethyl acrylate, polybutyl acrylate, etc. It may be. Here, the carbon number of the alkyl group of (meth) acrylate is about 1-8 normally. The polymer may be polyester, polysiloxane, polylactic acid or the like. In addition, the polymer mixed with PMEA may be one type or a plurality of types depending on the intended use of the biocompatible material.

  The number average molecular weight (Mn) of PMEA is 5,000 to 50,000, more preferably 10,000 to 40,000, and particularly preferably 15,000 to 30,000. On the other hand, when using PMMA as a polymer mixed with PMEA, the number average molecular weight (Mn) of PMMA is 20,000 to 200,000, more preferably 35,000 to 150,000, and particularly preferably 50, 000 to 120,000. The glass transition temperature (Tg) of PMMA is 300 to 450K, more preferably 300 to 430K, and particularly preferably 300 to 410K.

  Polymers mixed with PMEA such as PMEA and PMMA are synthesized by various methods. For example, the polymer can be synthesized by a known method such as free radical polymerization, ionic polymerization, coordination polymerization, or ring-opening polymerization. Moreover, the polymer mixed with PMEA, such as PMEA and PMMA, can be prepared by polymerizing monomers by, for example, a solution polymerization method using water or an organic solvent as a solvent. More specifically, a polymer mixed with PMEA such as PMEA and PMMA is prepared by dissolving a predetermined amount of monomer in purified water or an organic solvent, adding a polymerization initiator to the solution while stirring the resulting solution, It can be obtained by polymerizing monomers in an inert gas atmosphere such as nitrogen gas or argon gas.

  Examples of the organic solvent used in the polymerization of the monomer include alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, ethylene glycol, and propylene glycol, ketones such as acetone and methyl ethyl ketone, diethyl ether, and tetrahydrofuran. Ethers, aromatic compounds such as benzene, toluene and xylene, aliphatic hydrocarbon compounds such as n-hexane, alicyclic hydrocarbon compounds such as cyclohexane, and acetates such as methyl acetate and ethyl acetate. However, it is not limited to these.

  The concentration of the monomer in the monomer solution used in the solution polymerization method is not particularly limited, but is preferably about 10 to 80% by weight in consideration of the operability and efficiency of polymerization.

  The polymerization initiator used above is not particularly limited. For example, azobisisobutyronitrile (hereinafter simply referred to as “AIBN”), azoisobutyronitrile, methyl azoisobutyrate, azobisdimethylvaleronitrile, Azo polymerization initiators and peroxide polymerization initiators such as benzoyl oxide, potassium persulfate, ammonium persulfate, benzophenone derivatives, phosphine oxide derivatives, benzoketone derivatives, phenylthioether derivatives, azide derivatives, diazo derivatives, disulfide derivatives, etc. A photoinitiator etc. are mentioned. The amount of the polymerization initiator is not particularly limited, but usually it is preferably about 0.01 to 5 parts by weight with respect to 100 parts by weight of the monomer.

  As the polymerization initiator used for polymerization, a chain transfer agent can be used as necessary. Examples of the chain transfer agent include compounds having a mercaptan group such as lauryl mercaptan, dodecyl mercaptan, and thioglycerol, and inorganic salts such as sodium hypophosphite and sodium hydrogen sulfite. It is not limited to only. The amount of the chain transfer agent is not particularly limited, but usually it is preferably about 0.01 to 10 parts by weight with respect to 100 parts by weight of the monomer.

  The reaction temperature of the monomer polymerization reaction is not particularly limited because it varies depending on the type of polymerization initiator used. Usually, it is preferable to set it as the 10-hour half life temperature of a polymerization initiator. The reaction time for the polymerization reaction is 2 hours or more, preferably about 2 to 24 hours, in order to avoid the unreacted monomer remaining.

  The biocompatible material according to this embodiment is prepared so as to include polymers mixed with PMEA such as PMEA and PMMA at various mixing weight ratios according to the purpose of use. In general, when the weight mixing ratio of PMEA is high, its biocompatibility such as antithrombogenicity and anticoagulability tends to be high. On the other hand, when the weight mixing ratio of PMEA is high, form stability and moldability are high. There is a tendency to decrease. Moreover, when the weight mixing ratio of the polymer mixed with PMEA is high, the form stability and moldability tend to be improved. On the other hand, when the weight mixing ratio of the polymer mixed with PMEA is high, biocompatibility tends to be low.

  As shown in Experimental Example 2 below, the biocompatible material according to the present embodiment may exhibit high antithrombogenicity in a predetermined weight mixing ratio range when compared with pure PMEA. The weight mixing ratio should be set flexibly in accordance with the intended use of the biocompatible membrane. As a typical example, for example, when using PMMA as a polymer mixed with PMEA, PMEA: PMMA, which is a weight mixing ratio of PMEA and PMMA, is 1:99 to 90:10, preferably 5:95 to 80:20, more preferably 10:90 to 60:40, and even more preferably 20:80 to 60:40 is selected. In particular, when a weight mixing ratio of 40:60 to 60:40 is selected, it is preferable in that good form stability by PMMA and higher biocompatibility than pure PMEA tend to be obtained.

  As shown in Experimental Example 2 below, the biocompatible material according to the present embodiment has a property of suppressing adhesion of platelets on the surface on which PMEA is segregated. Since adhesion of platelets to the material surface is one of the causes of thrombus formation, it is suitable for use as a member for antithrombosis as a use of the biocompatible material according to the present invention. More specifically, the antithrombotic member includes, for example, hemodialysis membranes, artificial kidney membranes, plasma separation membranes, catheters, stents, membranes and tubes for cardiopulmonary devices, artificial blood vessels, blood storage packs, artificial It is a material of a part that comes into contact with blood in an organ, an in-vivo implantable device or the like, and in particular, the biocompatible material according to the present invention is preferably used for a part, preferably all, of the part that comes into contact with blood.

  Next, the manufacturing method of the biocompatible material which concerns on this embodiment is demonstrated. Here, as an example of the manufacturing method, a case where PMMA is used as a polymer mixed with PMEA and a biocompatible material is formed on the surface of the substrate will be described.

  First, a mixed solution is prepared by dissolving in an organic solvent such as toluene in which both can be dissolved so that PMEA and PMMA have the desired composition. Furthermore, the prepared mixed solution is formed into a film by applying and spreading on a suitable substrate to a substantially uniform thickness by a suitable means. The application of the mixed solution is preferably performed by a spin coating method or the like when the substrate is flat, and when the substrate has a complicated shape such as unevenness, a method such as spraying the mixed solution by spraying is used. Is preferred. Subsequently, using a vacuum oven or the like, the organic solvent contained in the formed film is sufficiently removed at room temperature to dry the film. Although depending on the organic solvent used, typically, the drying time is about 24 hours, and the organic solvent can be sufficiently removed. In addition, although the thickness of the film after drying is determined according to the use of the biocompatible material, it can be set to a thickness of about several tens to several hundreds nm. The thickness of the dried film can be adjusted by the concentration of PMEA or the like in the mixed solution with the organic solvent and the thickness when the mixed solution is applied.

  The film formed by drying the organic solvent is heated to a temperature not lower than the glass transition temperature and lower than the cloud point, so that the polymer can be easily diffused while maintaining an amorphous state in the film, A heat treatment is performed to segregate PMEA on the film surface. In the case of using PMMA as a polymer mixed with PMEA, the ratio of PMEA on the film surface can be increased by setting the heat treatment conditions to, for example, a temperature of about 350 to 450 K for 3 hours to 12 hours. it can.

  For example, the surface energy of PMEA and PMMA is 36.7 mN / m and 42.2 mN / m, respectively, and the surface energy of PMEA is smaller. For this reason, PMEA is thermodynamically concentrated on the surface, and PMEA is segregated on the film surface side. Even before the heat treatment, PMEA having a smaller surface energy is segregated on the film surface side.

  In the above, an example in which a biocompatible material is produced using a thin-film mixture has been described. However, the present invention is not limited to this, and the mixture is molded into a three-dimensional shape by an appropriate method and then heat-treated. It is also possible to use PMEA as a biocompatible material by segregating PMEA on the surface.

  As described above in detail, the biocompatible material according to this embodiment has PMEA segregated on the surface, and has excellent antithrombogenicity. Moreover, as shown in Experimental Example 2, this antithrombogenicity was shown to be higher than that of a single PMEA. As a result, the excellent biocompatibility of PMEA can be specifically applied to various biocompatible materials. In other words, by providing the biocompatible material according to the present embodiment on the surface of an arbitrary substrate determined in consideration of mechanical characteristics, the surface is biocompatible while maintaining the physical properties and mechanical characteristics as a whole. Can have sex.

  In addition, the said biocompatible material may be used as a biocompatible material with a base | substrate. Further, the biocompatible material formed into a thin film by an appropriate means may be used by being attached to the surface of a member constituting a medical device or the like.

  In the above description, as a typical embodiment of the thin-film biocompatible material according to the present invention, the mixture containing PMEA is applied to a substrate, dried, and then subjected to a heat treatment, whereby PMEA is formed on the membrane surface side. The example which segregates was demonstrated. The present invention is not limited to this, and a surface in which PMEA is segregated is obtained by forming a thin film in which PMEA is segregated on the side of the substrate mainly by a combination of a polymer constituting the mixture and the substrate, and then peeling the thin film from the substrate. May be used by being attached so as to be in contact with a biological component or biological tissue.

  In addition, the PMEA polymer can be used by increasing the substantial thickness of PMEA by supplying and fixing the PMEA polymer to the surface of the biocompatible material by an appropriate method.

  In addition, the biocompatible material according to the present invention may contain an additional blood coagulant such as heparin and sodium citrate as long as the characteristics are not impaired.

(Embodiment 2)
Embodiment 2 of the present invention will be described in detail. The medical device according to the present embodiment is provided at a location where the biocompatible material described in the first embodiment is in contact with a biological component or a biological tissue. Examples of the medical device include hemodialysis membranes, artificial kidney membranes, plasma separation membranes, catheters, stents, membranes and tubes for cardiopulmonary devices, artificial blood vessels, blood storage packs, artificial organs, in vivo implantable devices, etc. It is. However, the medical device is not limited to this example.

  In particular, the thickness of the biocompatible material used for the medical device may be several tens of nm to several hundreds of nm, or may have a thickness greater than that. In addition, the medical device according to the present embodiment may be covered directly or partially with the biocompatible material according to the invention, or may be invented via a layer or membrane made of other substances. It may be coated with a biocompatible material.

  As described above in detail, since the medical device according to the present embodiment includes a coating containing the biocompatible material according to the present invention, formation of a thrombus on the surface can be suppressed. In addition, the biocompatible material according to the present invention can be easily processed as a raw material for a medical device or the like because characteristics such as form stability at room temperature can be added.

(Embodiment 3)
Embodiment 3 of the present invention will be described in detail. In the third embodiment, a method of using the biocompatible material according to the present invention for use in a medical device will be described.

  In the method of using the biocompatible material according to the present embodiment, the surface is exposed to water and then brought into contact with a biological component or biological tissue. As shown in Experimental Example 2 below, by exposing the surface of the biocompatible material to water before contacting with blood, the number of platelet adhesion on the surface when contacting with blood is reduced, and antithrombotic It became clear that improved. As described in Patent Document 1, it is known that PMEA exhibits biocompatibility such as antithrombogenicity by retaining a large amount of intermediate water that is weakly constrained by interaction with a polymer chain. Even on the surface of the biocompatible material according to the present invention, the amount of intermediate water retained by PMEA existing on the surface is increased by exposure to water before contact with blood. It is thought that compatibility will increase.

  As described above in detail, the method of using the biocompatible material according to the present embodiment further improves the biocompatibility such as antithrombogenicity of the biocompatible material.

  The water for exposing the biocompatible material may be any water that can increase the intermediate water retained on the surface. For example, ultrapure water, physiological saline, phosphate buffer solution, or the like may be used. it can. Further, the time of exposure to water is preferably equal to or longer than the time when the amount of intermediate water held on the surface reaches equilibrium, for example, at least 8 hours is preferable.

The following examples further illustrate the present invention, but the present invention is not limited to the examples.
Example To prepare a PMEA / PMMA blend membrane using PMMA as a polymer mixed with PMEA to form a thin film, first a toluene solution of PMEA and a toluene solution of PMMA were prepared.
PMEA was synthesized by free radical polymerization. For 15 g of 2-methoxyethyl acrylate, 15 mg of AIBN was used as an initiator for the polymerization reaction. 1,4-Dioxane was used as a solvent for the polymerization reaction. The reaction temperature was 75 ° C., and the reaction time was 8 hours. The synthesized PMEA was reprecipitated into n-heptane.
PMMA is available from Polymer Source Inc. A monodispersed product purchased from the company was used by reprecipitation in methanol. The number average molecular weights (Mn) of PMEA and PMMA were 26,000 and 85,000, respectively. The molecular weight distribution index (Mw / Mn) of PMEA and PMMA was 3.23 and 1.09, respectively. The glass transition temperatures (Tg) of PMEA and PMMA were 240K and 401K, respectively, as evaluated by differential scanning calorimetry (DSC).
Next, a PMEA / PMMA blend solution was prepared by mixing the two toluene solutions. Here, the PMEA / PMMA blend solution was prepared so that two mixing weight ratios, that is, PMEA / PMMA were 10/90 and 50/50, respectively. The obtained PMEA / PMMA blend solution was uniformly mixed without causing polymer separation or the like.
The coating film of the PMEA / PMMA blend solution was prepared by spin coating the PMEA / PMMA blend solution on a silicon substrate. The coating film of the prepared PMEA / PMMA blend solution was vacuum-dried at room temperature for 24 hours to obtain a PMEA / PMMA blend film. After drying, the PMEA / PMMA blend film was heat treated to obtain a PMEA / PMMA blend heat treated film. In the case of a PMEA / PMMA blend film prepared from a PMEA / PMMA blend solution having a PMEA / PMMA of 10/90, the heat treatment conditions were set at 410K for 6 hours under vacuum. On the other hand, in the case of a PMEA / PMMA blend film prepared from a PMEA / PMMA blend solution having a PMEA / PMMA of 50/50, it was set at 6 hours at 353 K under vacuum, or 12 hours under different conditions. The film thickness of the PMEA / PMMA blend heat-treated film was about 400 nm when evaluated using an atomic force microscope (AFM).
Hereinafter, a PMEA / PMMA blend heat treatment film prepared from a PMEA / PMMA blend solution having a PMEA / PMMA ratio of 10/90 is simply referred to as “PMEA / PMMA blend heat treatment film (10/90)”, and PMEA / PMMA is 50/50. The PMEA / PMMA blend heat treatment film prepared from the PMEA / PMMA blend solution is simply referred to as “PMEA / PMMA blend heat treatment film (50/50)”.

Comparative Example 1
As a control, a homopolymer membrane of PMEA was prepared. PMEA was the same as that used in the above example. PMMA is available from Polymer Source Inc. A monodispersed product purchased from the company was used by reprecipitation in methanol. The number average molecular weight (Mn) of PMMA was 85,000. The molecular weight distribution index (Mw / Mn) of PMMA was 1.09.
First, a PMMA homopolymer coating film was prepared by spin coating a toluene solution of PMMA on a silicon substrate. The prepared PMMA homopolymer coating film was subjected to a heat treatment at 433 K for 6 hours under vacuum to obtain a PMMA homopolymer heat treatment film. The film thickness of the PMMA homopolymer film was about 55 nm when evaluated using ellipsometry measurement.
Next, a PMEA homopolymer coating was prepared by preparing a methanol solution of PMEA and spin-coating it on the PMMA homopolymer film. The prepared PMEA homopolymer coating film was heat-treated at 410 K for 6 hours under vacuum to obtain a PMEA homopolymer heat treatment film. The film thickness of the PMEA homopolymer heat treatment film was about 70 nm when evaluated using ellipsometry measurement.

Comparative Example 2
As a control, a homopolymer film of PMMA was prepared. PMMA is available from Polymer Source Inc. A monodispersed product purchased from the company was used by reprecipitation in methanol. The number average molecular weight (Mn) of PMMA was 85,000. The molecular weight distribution index (Mw / Mn) of PMMA was 1.09. The glass transition temperature (Tg) of PMMA was 401 K as evaluated by DSC.
A PMMA homopolymer coating film was prepared by spin-coating a toluene solution of PMMA on a silicon substrate. The prepared PMMA homopolymer coating film was vacuum dried at room temperature for 24 hours to obtain a PMMA homopolymer film. After drying, the PMMA homopolymer film was heat-treated to obtain a PMMA homopolymer heat-treated film. The heat treatment conditions were 433 K and 6 hours under vacuum with respect to the PMMA homopolymer film. The film thickness of the PMMA homopolymer heat-treated film was about 70 nm when evaluated using ellipsometry and atomic force microscope (AFM).

Experimental example 1
(Chemical composition evaluation for z-axis direction of PMEA / PMMA blend heat treatment film)
The chemical composition in the vicinity of the surface of the PMEA / PMMA blend heat-treated film (50/50) was evaluated based on angle-dependent X-ray photoelectron spectroscopy (ADXPS) measurement. An X-ray photoelectron spectrometer (PHI 5800 ESCA system, Physical Electronics Co., Ltd.) was used for the ADXPS measurement. The X-ray source was a monochromatic Al K ray. The applied voltage was 14.0 kV, the power was 50 W, and the degree of vacuum was 1.33 × 10 ⁻⁷ Pa (1 × 10 ⁻⁹ Torr). The ADXPS measurement was performed at room temperature. The photoelectron extraction angles (θ) were 15 °, 30 °, 45 °, 60 °, and 90 °.
The analysis depth (d) at an arbitrary angle θ was calculated based on d = 3λ sin θ. Here, λ is an inelastic mean free path. The λ of the C _1s- derived photoelectron calculated from the Ashley equation was 3.1 nm (J. C. Ashley, IEEE Trans. Nucl. NS-2731, 1454-1458, 1980). The analysis depth (d) of carbon 1s electrons in the PMEA / PMMA blend film for each θ is about 2, 5, 7, 8, and 10 nm, respectively. During the measurement, the PMEA / PMMA blend heat-treated film was charged up, so that the binding energy shifted, but this was corrected by using a neutralizing gun.

(result)
(1) FIG. 1A is a plot of the surface PMEA volume fraction (φ ^S _PMEA ) in a PMEA / PMMA blend heat treated film (50/50) versus sin θ. Since sin θ is proportional to the analysis depth (d), it means that the smaller sin θ, the closer to the surface. According to FIG. 1 (A), as sin θ decreased, φ ^S _PMEA increased, indicating that more PMEA was segregated on the surface side.
(2) FIG. 1 (B) shows the relationship between φ ^S _PMEA and sin θ in FIG. 1 (A) by mean field approximation (I. Schmit and K. Binder, J. Phys. (Paris) 46, 1631-1644. It is the figure which carried out the model profile with respect to analysis depth (d) based on 1985 and a nonpatent literature 1 reference. According to this model profile, it was suggested that the surface of the PMEA / PMMA blend heat-treated film (50/50) was almost covered with PMEA.

Experimental example 2
(Platelet adhesion experiment to PMEA / PMMA blend film)
In order to investigate the antithrombogenicity of the membrane surface against blood, the PMEA / PMMA blend heat-treated film of the above example (PMEA / PMMA blend heat-treated film (50/50) used was subjected to heat treatment for 6 hours), comparative example With respect to 1 PMEA homopolymer heat-treated film and PMMA homopolymer heat-treated film (8 mm × 8 mm) of Comparative Example 2, platelet adhesion to the surface was conducted. Each membrane used was one that was not exposed to ultrapure water (Milli-Q water, hereinafter the same), and one that was exposed to ultrapure water for 8, 16, and 24 hours.
The blood used in the experiment was prepared as platelet-rich plasma obtained by anticoagulating the blood collected from the human cubital vein with sodium citrate. 200 μl of the prepared platelet-rich plasma was brought into contact with the surface of each membrane for 60 minutes. After rinsing with a phosphate buffer solution, it was fixed with glutaraldehyde, and observed with an electron microscope, and the number of platelets adhered per 1 × 10 ⁴ μm ² surface of each membrane was counted.

(result)
(1) As shown in FIG. 2, in the PMEA / PMMA blend heat-treated film, the number of platelets equivalent to the PMEA homopolymer heat-treated film of Comparative Example 1 was observed even when not exposed to ultrapure water. That is, it was shown that the PMEA / PMMA blend heat-treated film has the same antithrombogenicity as the PMEA homopolymer film. In particular, when a plurality of components are mixed, it is common that the characteristics of each component show a tendency to decrease with a decrease in the proportion thereof. However, a PMEA / PMMA blend heat treatment film (10 / 90) has the same antithrombogenicity as the homopolymer film of PMEA, which is a remarkable effect shown by the present invention.
(2) In any of Example, Comparative Example 1 and Comparative Example 2, exposure to ultrapure water for 8 to 24 hours resulted in a film without exposure to ultrapure water (“0 hour” in FIG. 2). The number of platelets adhering to the surface was decreased as compared with. In particular, in the PMEA / PMMA blend heat-treated film (10/90 and 50/50) prepared in the examples, the degree of decrease in the number of platelets adhered to the surface by exposure to ultrapure water was compared with Comparative Example 1. It was shown to be larger than the homopolymer membrane of 2.
(3) In the PMEA / PMMA blend heat-treated film (10/90), the number of platelets adhered to the surface decreased depending on the exposure time to ultrapure water. On the other hand, in the PMEA / PMMA blend heat-treated film (50/50), the number of platelets adhered to the surface decreased by exposure to ultrapure water. The number of adherent platelets was greatly reduced. In particular, the number of platelets is smaller than the PMEA homopolymer film of Comparative Example 1 that the biocompatibility is further improved by blending PMMA with PMEA to form a PMEA / PMMA blend heat-treated film. This is a remarkable effect shown by the present invention. The details of improving the platelet adhesion suppression ability in the PMEA / PMMA blend heat-treated film by exposure to ultrapure water are unclear, but are thought to be due to the surface properties of PMEA.
PMEA has been suggested to have so-called intermediate water on its surface (M. Tanaka et al., Polym. Int. 49, 1709-1713, 2000). The intermediate water is considered to be water that is weakly bound to the polymer chain due to the interaction with the polymer chain. In the PMEA / PMMA blend heat-treated membrane in which PMEA and PMMA were mixed in a predetermined range, the platelet adhesion suppression ability was improved by exposure to ultrapure water because the state of intermediate water etc. on the membrane surface changed. It is also estimated.

  Further, the PMEA / PMMA blend heat-treated membrane having improved biocompatibility by exposure to water gives added value as a biocompatible material. This is because, if exposure to water improves biocompatibility, for example, when the present invention is used for contact lens applications, the sense of incongruity is further alleviated and the feeling of wear is increased by exposure to body fluids.

  Various embodiments and modifications can be made to the present invention without departing from the broad spirit and scope of the present invention. Further, the above-described embodiment is for explaining the present invention, and does not limit the scope of the present invention. That is, the scope of the present invention is shown not by the embodiments but by the claims. Various modifications within the scope of the claims and within the scope of the equivalent invention are considered to be within the scope of the present invention.

  The present invention is suitable for materials used for medical devices and the like.

Claims (8)

Comprising a mixture of 2-methoxyethyl polyacrylate and a polymer capable of maintaining a glassy mixed phase at room temperature with 2-methoxyethyl polyacrylate;
The mixture is
The 2-methoxyethyl polyacrylate has an inclined structure segregated on the surface side,
A biocompatible material characterized by that. The mixture is
By maintaining the temperature above the glass transition temperature and below the cloud point of the mixture, the 2-methoxyethyl polyacrylate is segregated on the surface side, and is formed.
The biocompatible material according to claim 1. The 2-methoxyethyl polyacrylate: the polymer is the mixing weight ratio of the polymer to the 2-methoxyethyl polyacrylate in the mixture:
In the range of 1:99 to 90:10,
The biocompatible material according to claim 1 or 2, characterized by the above. The polymer is
Polymethyl methacrylate,
The biocompatible material according to any one of claims 1 to 3, wherein: The mixture is
It is formed in a thin film on the substrate,
The 2-methoxyethyl polyacrylate is segregated on the surface side not in contact with the substrate,
The biocompatible material according to any one of claims 1 to 4, wherein the biocompatible material is characterized in that A medical device comprising the biocompatible material according to any one of claims 1 to 5,
Provided that the surface of the mixture is in contact with a biological component or biological tissue;
A medical device characterized by that. A method of using the medical device according to claim 6,
After exposing the surface of the mixture to water, contacting the biological component or biological tissue;
A method of using a medical device characterized by the above. The time of exposure to water is
At least 8 hours,
The use method of the medical device of Claim 7 characterized by the above-mentioned.

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