JP2010070615A - Crosslinked polymer composition for surface treatment of support - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medical material surface having a stable coating. <P>SOLUTION: A homopolymer or copolymer, which is derived from a monomer forming a polymer having a functional group crosslinked to a side chain of a repeating unit by a plasma irradiation at low temperatures under atmospheric pressure and which also is a coating film-forming polymer, is subjected to a plasma irradiation treatment at low temperatures under atmospheric pressure to provide a crosslinked composition. The use of such composition is also disclosed. The monomer is halogenated methylstyrene wherein a halogen is selected from a group consisting of chlorine, bromine, iodine or fluorine, divinylbenzene, 1,3-butadiene, arylalcohol alkyl ether (CH<SB>2</SB>=CHCH<SB>2</SB>Oalk, in which alk represents 1-6C alkyl), vinyl acetate, methyl methacrylate, or acrylonitrile. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a crosslinked composition of a polymer, preferably a copolymer, and more specifically, a halogenated methylstyrene and one or more ethylenically unsaturated polymerizable comonomers immobilized on the surface of a medical material. The present invention relates to a crosslinked composition of a copolymer and a method for producing a surface-treated support by applying the copolymer to the surface of the support and then irradiating the copolymer with atmospheric pressure and low-temperature plasma.

  Currently, for the treatment of myocardial infarction, occlusion vasodilatation using a balloon catheter instead of surgical bypass surgery has become the mainstream. However, reocclusion of dilated blood vessels has become a problem, and newest technologies such as stents are spreading. Stents suppress blood vessel contraction and have an effect on restenosis, but the current situation is that problems with thrombus formation and pannus due to inflammation are inevitable. For this reason, stent surface treatment and drug removal from it have been widely studied. However, these treatments are not sufficient, and due to the adsorption of biological components to the surface and the reocclusion caused by inflammation, anticancer agents showing strong side effects from stents, sustained release of doxorubicin, etc. are performed at the actual site. ing. Because this treatment is highly toxic, it is based on the creation of a so-called dead surface that prevents adhesion of cells and biological components to the surface. Restenosis is avoided, but there are fundamental side effects such as new side effects caused by drugs. It is not.

  In addition, the surface of the catheter is important for its operability, such as the smoothness of the surface of the catheter and the stenosis of the heart and brain and the treatment of aneurysms through the arteries. These are not necessarily completely satisfied.

  In the above description, the catheter has been described as an example. However, the surface of a biomaterial or medical material that directly contacts a living tissue or touches a body fluid, for example, has biocompatibility and is stable. It is extremely important to build the system so that it has the characteristics, and the reality is that precise response to each material is required. For example, not only petri dishes and latex used in enzyme immunoassay (ELISA) and immunolatex agglutination methods, the above-mentioned catheters, but also endoscopes, stents, dialysis hollow fibers, artificial blood vessels and organs, and fine pipette tips Various material surface treatments such as chips and vials have been studied.

  As a method of treating the surface of such a material, various methods such as a method of coating a biocompatible polymer or hydrophilic polymer, a method of plasma surface treatment, etc. have been studied as a method of imparting biocompatibility to the surface. Yes. The coating method is the most common method that can be easily applied to any support (or substrate), but is not always easy to firmly adhere or fix to the support, and a coating film. There are many cases where there is a problem with stability.

Attempts have also been made to impart biocompatibility by hydrophilizing the support surface by plasma treatment or the like, or by chemical reaction on the surface. Although such treatment has the advantage that the reaction is completed in a short time and has excellent stability, it is performed in a special apparatus under reduced pressure or high temperature, and an appropriate surface is not necessarily constructed. The current situation is not limited. Other surface treatment methods include chemical treatment (etching effect), use of coupling agents, monomer and polymer coating, surface grafting, ultraviolet irradiation, ion beam, vacuum deposition, and plasma treatment. However, as a method of polymer treatment to the substrate, polymer coating and surface grafting, introduction of polymer by plasma treatment, etc. are mainly used. Some repeat,
The problems of these conventional techniques are summarized below.

  Polymer coating is a simple method that can completely cover a substrate, but has a problem in stability as a film such as peeling.

  Surface grafting is a method in which polymer chains can be directly introduced to the surface, but there are many partial defects and it is difficult to completely cover them. As a treatment method, a multistage reaction is required.

  Conventional plasma surface treatment can treat various substrate surfaces, but is performed under reduced pressure and is often performed in a special apparatus, so that there is a limit to the material shape. Moreover, it may generate heat, and the influence of temperature and pressure reduction conditions must be taken into consideration. In plasma chemical reactions using plasma under reduced pressure, the polymer structure is often damaged by the impact of ions with a large momentum, and precise control of thin film formation is difficult. In addition, these surface treatments are not necessarily suitable for imparting higher-order functions such as drug release.

  The present invention provides a composition capable of producing a biocompatible surface that can be instantaneously and stably fixed to various substrate surfaces that have reduced or eliminated the disadvantages associated with the prior art described above, and a method for producing the surface. With the goal.

  We have studied polymer compositions and surface treatment operations that can be used for surface treatment of medical materials. Unlike conventional plasma treatment under reduced pressure, atmospheric pressure typified by low-frequency atmospheric pressure microplasma jets. When a polymer composition comprising a repeating unit having a certain reactive group or moiety in the side chain is irradiated with a low temperature plasma, the polymer that is soluble in a certain solvent becomes insoluble and crosslinked. It has been found that a polymer that can be regarded as being can be provided. With regard to the use of atmospheric pressure low temperature plasma, research on in-liquid processing by irradiating the dissolved substance in the liquid is progressing, and plasma reduction of metal ions (for example, chloroauric acid solution) in the liquid is underway. (H. Furusho et al., J. Photopoly Sci. And Tech. 20, p.229 (2007)). Plasma polymerization is also performed by irradiating liquid monomer with atmospheric low temperature plasma (K. Kitano et al., Proceedings of International Conference on Phenomena in Ionized Gases XXVIII, (Prague, July 2007), p. 1131). )). Surprisingly, however, modifications that render the polymer solvent insoluble by irradiating the polymer containing repeating units having certain reactive groups or moieties in the side chain with atmospheric pressure, low temperature plasma, such as crosslinking It is new and cannot be recalled from the prior art at all. For example, a copolymer having repeating units derived from halogenated methylstyrene in the polymer (for example, when poly (2-methoxyethyl acrylate) (PMEA) is used as a comonomer) is subjected to atmospheric pressure low temperature plasma. Irradiation results in modifications such as making the solvent soluble before solvent treatment insoluble in solvent. And when such a polymer is coated on a support as a coating composition, when the composition is irradiated with atmospheric pressure and low temperature plasma, the composition becomes not only solvent insoluble, but also a solvent or solvent, etc. It was also confirmed that it was fixed to the surface of the support as a coating film that was not easily peeled off by the treatment such as cleaning by the above. Furthermore, the polymer composition (or also referred to as a crosslinked polymer composition) after such atmospheric pressure low-temperature plasma treatment does not have a hologenated benzyl (or halogenated methylphenyl) in the side chain of the polymer. Further modifications can also be carried out by reaction of the reaction halogen with an amino compound.

  While not being bound by theory, when a polymer is irradiated with atmospheric pressure low temperature plasma, the repeating unit carrying the side chain reactive group or moiety present in the polymer will have a constant in the reactive group or moiety. It is considered that the modification is caused by the removal of atoms or groups, and / or rearrangement (or rearrangement), resulting in crosslinking or the like.

  In general, in atmospheric pressure plasma, the ion temperature is kept low by frequent collisions with neutral gas, so there is little damage to various polymer materials due to ion bombardment, and plasma treatment for polymer materials is significant. It can be said that it is preferable to carry out under atmospheric pressure. However, plasma generation under atmospheric pressure results in an increase in neutral gas due to frequent collisions between electrons and neutral gas components, and in extreme cases, extremely high temperatures, as represented by arc plasma. Tend to be in a state. Here, it is possible to suppress the rise in plasma temperature by using a method such as a low-frequency atmospheric pressure microplasma jet to suppress the plasma current by inserting a dielectric barrier between the plasma generation electrodes. Thus, an atmospheric pressure low temperature plasma suitable for use in the present invention can be obtained. Plasma generation that does not cause burns when touched with a finger is also possible. In this respect as well, the treatment of the polymer with atmospheric low temperature plasma according to the present invention has advantages.

  Therefore, according to the present invention, a polymer comprising a repeating unit having a reactive group or a moiety in a side chain group by such atmospheric pressure low temperature plasma irradiation, wherein the reactive group or moiety is subjected to certain modifications. The resulting polymer is widely used or treated in the present invention. Thus, according to the present invention, a homopolymer or copolymer derived from a monomer that forms a polymer having a functional group that is modified or cross-linked by irradiation with atmospheric pressure and low temperature plasma in the side chain of the repeating unit, and the coating film There is provided a crosslinked polymer composition comprising a crosslinked polymer obtainable (or obtainable) by irradiating the forming polymer with atmospheric pressure low temperature plasma.

In a more specific embodiment, (1) halogenated methylstyrene selected from the group consisting of chlorine, bromine, iodine and fluorine,
(2) A crosslinked copolymer obtainable by irradiating a low-pressure plasma at atmospheric pressure on a film-forming copolymer produced by copolymerization of a comonomer represented by the following (formula I) Crosslinked polymer compositions are provided.

Formula (I):
_{CH 2 = C (R) -X} -A-B (I)
Wherein (a) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) O—, and A represents linear or branched C ₁ -C ₆ alkylene, and B represents hydroxyl, C ₁ -C ₄ alkyloxy, mono-C ₁ -C ₄ alkylamino, di _-C 1 -C _{4 alkylamino,} C 1 -C ₄ alkyloxycarbonyl, or represents phosphorylcholine,
(B) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) O—, and AB represents a linear or branched C ₁ -C ₂₀ alkyl, C ₃ -C ₆ cycloalkyl, which may be fluorinated with one or more fluorine atoms. C ₁ -C ₄ alkylene-C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkylenephenyl or phenyl,
(C) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) O—, and AB represents the formula — (CH ₂ CH ₂ O) _p R ^a , — (CH ₂ CH (CH ₃ ) O) _q R ^b or — (CH ₂ CH ₂ CH ₂ CH ₂ O) _r R ^c , where R ^a , R ^b and R ^c independently represent C ₁ -C ₄ alkyl, and p, q and r are independently 2-200 Represents an integer, or
(D) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) N (R ¹ ) —, wherein R ¹ represents a hydrogen atom or C ₁ -C ₄ alkyl;
A represents linear or branched C ₁ -C ₆ alkylene or C ₃ -C ₆ cycloalkyl, and B represents a hydrogen atom or amino, mono-C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ Represents alkylamino, carboxy,
(E) R represents the formula —CH ₂ C (O) R ₂ , where R ₂ represents a hydrogen atom or C ₁ -C ₄ alkyl;
X represents -C (O) O-,
Or A-B represents a hydrogen atom or a _C 1 -C ₄ alkyl,
(F) R represents a hydrogen atom,
X represents —O—C (O) — and A—B represents C ₁ -C ₄ alkyl;
(G) R represents a hydrogen atom, or X-A-B represents a hydrogen atom, _methyl, C 1 -C ₄ phenyl optionally substituted by alkyl, 2-pyrrolidone -1-yl,
One or more ethylenically unsaturated polymerizable comonomers represented by:

  Also provided is a coating film in which the above-mentioned crosslinked polymer composition is fixed to a support, for example, a medical material surface.

  According to the present invention, the step of applying the coating film-forming polymer to the surface of the support, and the coating film component thus formed by irradiating the coating film thus formed with atmospheric pressure low temperature plasma There is also provided a method for producing a surface-treated support comprising a step of crosslinking (or modifying) at least a part thereof.

  Furthermore, according to the present invention, by bringing the crosslinked polymer composition into contact with an amino group-containing organic compound in a solvent, methyl halide groups and amino groups remaining in the crosslinked polymer in the composition can be obtained. There is also provided a method of modifying the composition comprising reacting the group-containing compound and thus introducing the amino compound into the crosslinked polymer composition.

  The crosslinked polymer composition comprising the polymer provided by the present invention can be used as such, for example, as a surgical graft, but is preferably used by being fixed to the surface of a medical material. In addition, since the neutral gas occupying most of the components of the atmospheric pressure low-temperature plasma is low-temperature, for example, in the case of a copolymer, the decomposition and reaction of a skeleton derived from a comonomer, such as a PMEA skeleton, is suppressed and halogenated. It enables cross-linking of benzyl groups by plasma reaction and introduction of functional groups at the same time. Furthermore, by simultaneously sterilizing surface bacteria and the like, it can be used as a biomaterial. This surface treatment also reacts effectively with the substrate surface, so that strong and stable immobilization is possible, and drug release from the cross-linked gel generated by mixing the drug into the coating film or the lower layer of the coating film is possible. It is. In general, it is known that a benzyl halide group reacts with an amino group, a hydroxyl group or a carboxyl group, and the benzyl halide group in the composition of the present invention also immobilizes a ligand or a biological substance, and modifies the surface. Etc. can be used efficiently.

Furthermore, according to the present invention, not only is it possible to perform high-level treatment (giving biocompatibility and lubricity, etc.) to the surface of a biomaterial, which has not been sufficient in the past, but, for example, a stent or an artificial blood vessel that is implanted in a living body. Although it is required to form a thin pseudointimal membrane, such as a scaffold for regenerative scaffolding, it can effectively suppress “strong inflammation” and “growth of pseudointimal membrane” and assimilate it with living tissue. Material design becomes possible.

<Detailed Description of Invention>
The atmospheric pressure low temperature plasma referred to in the present invention may be radiated from any device as long as it meets the purpose of the present invention, but representative examples include Katsuhisa Kitano and Satoshi Hamaguchi “ "Atmospheric pressure microplasma jet" Applied physics, Vol. 77, pp. 383-389 (2008) means a "2.3 single electrode type plasma jet" generating device or the like (also WO 2008/072390 A1 (The contents of these documents are incorporated herein by reference.) In summary, a low-frequency atmospheric pressure microplasma jet forms an electric field so that a partial discharge is generated in both directions in the longitudinal direction of a medium gas mass having an elongated shape at room temperature under atmospheric pressure. It shows a plasma that is generated in a simple configuration with high energy efficiency and stably over a wide range of parameters. The medium gas mass is preferably a gas species having a low discharge start voltage such as He or Ar.

In accordance with the present invention, the polymer to be subjected to atmospheric pressure low temperature plasma treatment is not limited, but side chain reactive groups or moieties of any repeating units in the polymer by atmospheric pressure low temperature plasma irradiation as described above. Any polymer can be used as long as they are independent or react with each other to effect modification via transfer (or rearrangement), typically cross-linking such as solvent insolubilization. Such polymers are film-forming for the specific purposes of the present invention. Therefore, the such a polymer, for example, halogen, chlorine, bromine, methyl halide styrene selected from the group consisting of iodine and fluorine, divinylbenzene, 1,3-butadiene, aryl alcohol alkyl ether _{(CH 2 =} CHCH ₂ Oalk a is, alk is C ₁ -C ₆ alkyl), vinyl acetate, polymer repeat units comprising at least a portion derived from a monomer selected from the group consisting of methyl methacrylate and acrylonitrile. Although not limited, specific examples of the polymer that can be used in the present invention in consideration of coating film formability and the like are derived from halogenated methylstyrene, particularly preferably 4-chloromethylstyrene. Any copolymer that contains a repeating unit, can produce a film-forming copolymer, and can induce another repeating unit that is essentially unaffected by atmospheric pressure low temperature plasma irradiation. Although it can use without restrict | limiting, Specifically, the copolymer with the comonomer shown by said Formula (I) is mentioned as a preferable thing.

  The film-forming property is used to have an ordinary meaning commonly used in the art. For example, a polymer film generally having a thickness of 0.2 mm or less can be formed by dissolving in an appropriate solvent and applying to a suitable support by any method such as brushing or knife coating, dipping in a solution, or spin coating. Means nature.

  Hereinafter, for the purpose of simplifying the description of the invention, the above copolymer will be mainly described, but the present invention is not limited to these descriptions.

  Each term used to define each group or moiety in formula (I) will be easily understood with reference to the following description.

  In the definition of X or AB in formula (I), when directionality is an issue, it is understood that it is bound to other parts in formula (I) with the directionality described. For example, when X is —C (O) O—, it means that the carbonyl group of X is bonded to the vinyl group of formula (I), and —O— is bonded to A.

C ₁ -C ₄ alkyl, when it is a group or part of another group, means methyl, ethyl, propyl and butyl, preferably methyl and ethyl. Examples of linear or branched C ₁ -C ₆ alkylene include, but are not limited to, methylene, ethylene, 1 or 2-methylethylene (or propylene), trimethylene, 2-ethyltrimethylene, tetramethylene, hexamethylene, and the like. Can be mentioned. Linear or branched C ₁ -C ₂₀ alkyl that may be fluorinated with one or more fluorine atoms includes, but is not limited to, methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec -Butyl, t-butyl, hexyl, dodecyl, octadecyl, and the like, and such an alkyl group may have one or more of its hydrogen atoms replaced with a fluorine atom.

C ₃ -C ₆ cycloalkyl, means cyclopentane, cyclobutane, cyclohexane, and the like.

  Comonomers that can be preferably used in the present invention are those defined by (a) and (b) in the definition of formula (I).

  Specific comonomers include, but are not limited to, 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 3-hydroxypropyl (meth) acrylate, 2-hydroxyisobutyl (meth) List polymerizable monomers having an alkyl hydroxyl group such as acrylate, 3-hydroxyisobutyl (meth) acrylate, 2-hydroxybutyl (meth) acrylate, 3-hydroxybutyl (meth) acrylate, 4-hydroxybutyl (meth) acrylate In general, these are preferably used, and 2-hydroxyethyl (meth) acrylate is most preferable among them.

  Also, styrene, methylstyrene, ethylene, propylene, vinyl chloride, butyl (meth) acrylate, isobutyl (meth) acrylate, t-butyl (meth) acrylate, propyl (meth) acrylate, isopropyl (meth) acrylate, ethyl (meth) Acrylate, methyl (meth) acrylate, phenyl (meth) acrylate, ethylhexyl (meth) acrylate, cyclohexyl (meth) acrylate, benzyl (meth) acrylate, neopentyl (meth) acrylate, octyl (meth) acrylate, lauryl (meth) acrylate, Stearyl (meth) acrylate, methoxyethyl (meth) acrylate, ethoxyethyl (meth) acrylate, methoxybutyl (meth) acrylate, diethylaminoethyl ( A) Phosphoric acid group-containing methacrylates having a phospholipid-like structure such as acrylate, vinyl acetate, methyl itaconate, ethyl itaconate, vinyl acetate, vinyl propionate, 2-methacryloxyethyl phosphorylcholine, etc. Can be mentioned. Among them, alkyl (meth) acrylates such as butyl (meth) acrylate, isobutyl (meth) acrylate, propyl (meth) acrylate, isopropyl (meth) acrylate, ethyl (meth) acrylate, and methyl (meth) acrylate are moderately hydrophobic. It is preferably used because of its properties and easy polymerization. Furthermore, methyl (meth) acrylate is most preferable in terms of high safety to living bodies.

Specific examples of the comonomer having an amide group may be any vinyl monomer having methacrylamide or acrylamide. N-methylacrylamide, N-ethylacrylamide, N-cyclopropylacrylamide, N-isopropylacrylamide, methacrylamide, N-methylmethacrylamide, N-cyclopropylmethacrylamide, N-isopropylmethacrylamide, N, N-dimethylacrylamide, Methacrylamide such as N, N-dimethylaminopropylacrylamide, N-methyl-N-ethylacrylamide, N-methyl-N-isopropylacrylamide, N-methyl-Nn-propylacrylamide, N, N-diethylacrylamide, acrylamide Kind.

  Examples of the polymerizable monomer having a polyalkylene oxide chain include methoxydiethylene glycol (meth) acrylate, ethoxydiethylene glycol (meth) acrylate, methoxydipropylene glycol (meth) acrylate, ethoxydipropylene glycol (meth) acrylate, and methoxytriethylene glycol. (Meth) acrylate, methoxytripropylene glycol (meth) acrylate, methoxypolyethylene glycol (meth) acrylate, ethoxytriethylene glycol (meth) acrylate, ethoxytripropylene glycol (meth) acrylate, methoxytetraethylene glycol (meth) acrylate, methoxy Tetrapropylene glycol (meth) acrylate, ethoxytetraethylene group Call (meth) acrylate, ethoxy tetrapropylene glycol (meth) acrylate, methoxy diethylene glycol vinyl ether, ethoxydiethylene glycol vinyl ether, methoxy triethylene glycol ether, but an ethoxy triethylene glycol vinyl ether, but is not limited thereto. Among them, (meth) acrylate having a polyethylene glycol chain is preferably used.

  Other hydrophilic monomers that can be used in the present invention include N-vinyl pyrrolidone, methyl vinyl ether, alkyl vinyl ether, vinyl alcohol, methacrylic acid, acrylic acid, N-vinyl caprolactam, dimethylaminoethyl (meth) acrylate, allylamine, and the like. And amino group-containing monomers.

  Among the comonomers, 2-hydroxyethyl (meth) acrylate, methoxyethyl (meth) acrylate, (meth) acrylate having a polyethylene glycol chain, and the like are preferable from the viewpoint of improving biocompatibility.

  The use ratio of 4-chloromethylstyrene and comonomer is 5:95 to 95: to 5, preferably 20:80 to 80: to 20, more preferably 30:70 to 70:30 in molar ratio. Can be.

  The cross-linking composition according to the present invention is typically in the form of or present as a coating film fixed on the support surface. Such a support can be a medical material made from a material selected from the group consisting of woven fabrics, non-woven fabrics, metals, ceramics, and plastics. The cross-linking composition can be firmly fixed to the surface of any material of the support, for example, when the material is a plastic such as polypropylene, the structure or mechanism is unknown, The atmospheric pressure low temperature plasma treatment provides some means for strengthening the bonding between the surface and the crosslinked composition, and can provide a crosslinked composition coating film that is extremely stably fixed to the support surface.

  The support may be a medical material or medical device itself or the like or a part thereof that is in direct contact with living biological tissue, or in direct contact with isolated or separated biological tissue, body fluid, etc. Yes, but not limited to such medical materials include syringes, blood bags, infusion sets, prostheses, catheters, osteosynthesis, endoscopes, stents, dialysis hollow fibers, drug release for embedding Examples include devices, sutures, culture dishes for testing, and hemostatic materials.

Since the atmospheric pressure microplasma jet apparatus used in the present invention can generate plasma jets in various forms, it can easily treat the inner surface of the tube having a very small inner diameter. Because it is a plasma generation method by electrostatic coupling method that generates plasma by applying an electric field from the outside, by placing a movable electrode near the tube, that is, by sending out the tube near the electrode, the tube It is also possible to perform the plasma treatment of the inner surface continuously.

  According to the present invention, as described above, a method for producing a support subjected to surface treatment is also provided. In providing this, the step of applying the coating film-forming copolymer is conveniently performed by dissolving or suspending the copolymer in an appropriate organic solvent or a mixture of water and a water-miscible organic solvent. It is applied to the surface of a desired support using a dipping method in a solution or a spin coating method. The coating film thus formed can be cross-linked (or insolubilized) at least part of the coating film by irradiating a predetermined region with atmospheric pressure and low-temperature plasma in the presence of the solvent or evaporating the solvent. it can. Irradiation time cannot be limited because the optimum value varies depending on the type of copolymer used, the intensity of plasma generation output, and the degree of crosslinking or modification of interest, but it is not limited, but He is 40 L / min to 100 L / min. In the case of irradiating the atmospheric pressure low temperature plasma under the condition of applying a low frequency high voltage (10 KHz, 60 V) to the gas flow electrode, it can be about 5 minutes to 60 minutes. It is possible to reduce the gas flow required for plasma generation by constructing a closed reactor. Although it does not limit as an organic solvent at the time of coating, toluene, benzene, and tetrahydrofuran can be used.

  Further, the method for modifying the cross-linked composition includes an amino group-containing organic compound that can be covalently bonded via a chloromethyl group in a residual chlorobenzyl (or chloromethylphenyl) group of the cross-linked copolymer. It is carried out by contacting with. Although contact is not limited, it can be performed by immersing the composition in an organic solvent in which an amino group-containing organic compound is dissolved, for example, dimethyl sulfoxide, N, N-dimethylformamide, for an appropriate time. As such an amino group-containing organic compound, a wide variety of compounds may be used depending on the purpose as long as the compound does not adversely affect the covalent bonding of the compound with the chloromethyl group with a hydrogen chloride elimination reaction. it can. Although it is not limited, ammonia, triethylenetetramine, ethylenediamine, 1,3-propanediamine, and diethylenetriamine can be exemplified, and among these, ammonia and triethylenetetramine are preferable. By modifying the cross-linking composition with such an amino group-containing organic compound, the surface of the medical material can be precisely controlled by improving the immobilization of specific biomolecules and cell adhesiveness while having biocompatibility. Could provide a convenient composition for the patient.

  Hereinafter, the present invention will be specifically described with reference to specific examples. However, the present invention is not intended to be limited to these embodiments.

(1) Used apparatus or equipment, and usage conditions thereof 1-1. Low frequency dielectric barrier discharge plasma jet (LF plasma jet)
A schematic diagram of a plasma jet generator is shown in FIG. He gas was flowed using a glass tube. As a high voltage electrode, a Cu film provided with a conductive adhesive tape was placed outside the glass tube. The plasma used in the present invention was generated by applying a low frequency high voltage (10 KHz, 10 kV) to an electrode disposed in the vicinity of a He gas flow of 40 L / min to 100 L / min.
1-2. Size Exclusion Chromatography Size Exclusion Chromatography (SEC) measurements were performed using TOSOH HLC-8120 equipped with TSK gel columns (Super HZ4000 and Super HZ3000), internal refractive index (RI) and ultraviolet (UV) detectors. As eluent, tetrahydrofuran (THF) containing 5% (v / v) triethylamine at a flow rate of 0.35 mL / min was used at 40 ° C.
1-3. ¹ H NMR
¹ H NMR spectra were obtained on a 270 MHz JEOLEX 270 spectrometer using CDCl ₃ .
1-4. The glass transition temperature (Tg) was measured by a differential scanning calorimeter (DSC; Seiko Instruments Inc. EXSTRAR6000 DSC / TG / DTA).
1-5. Contact angle The contact angle of water on the prepared surface was measured using a contact angle analyzer (CA-X, Kyowa Interface).
Science Co. , Ltd.,. , Asaka, Japan). The droplet was slowly placed on the surface, and after installation, the contact angle was measured by the θ / 2 method for 10 seconds. The net surface charge on the surface was measured using a zeta (ζ) potential analyzer (He-Ne laser, Zetasizer Nano ZZS, Malvem, UK) at 25 ° C.

(2) Production Example: Polymerization of 4-methylstyrene (CMS) and 2-methoxyethyl acrylate as comonomer and (MEA)

Under a nitrogen atmosphere, a predetermined ratio of CMS, MEA (total 100 mmol) and azobisisobutyronitrile (AIBN) (1 mmol) were added to dioxane (50 mL) in a 100 mL round bottom flask equipped with a three-way stopcock. The mixture was reacted at 65 ° C. After the reaction, the purification process was repeated three times by pouring the reaction solution into isopropanol (2 L) to precipitate the product, re-dissolving the precipitate in dioxane and then precipitating. For the precipitation, centrifugation at 5000 rpm for 30 minutes was used. The obtained polymer was freeze-dried with benzene to obtain a white powder. After purification, benzene freeze-drying was performed, and gel permeation chromatography (GPC) and ¹ HNMR measurement were performed using CDCl ₃ as a solvent. The polymerization conditions and yield are summarized in Table 1 below.

<Other results>
The polymerization reaction between the CMS and MEA proceeded smoothly, and gel formation was not observed.

The measurement result of the size exclusion chromatography (SEC) of the random copolymer (PCM (45)) which shows the weight fraction of CMS45% in a polymer is shown in FIG. It was confirmed by ¹ HNMR measurement that it was a random copolymer. The weight average molecular weight and distribution of the copolymer obtained above were 1.8-3.0 × 10 ⁴ and 1.5-2.1, respectively.

  The Tg increased in proportion to the increase in the CMS content in the copolymer (see FIG. 3).

  The above result shows that the PCM random copolymer shown by the said reaction scheme was obtained.

(3) Coating of polymer having plasma reaction activity on substrate (or support) A toluene solution (5 wt%) of the polymer (Product No. 5) produced above was prepared. 200 μL was dropped onto a 2 cm × 3 cm polypropylene (PP) substrate, spin-coated at 500 rpm for 5 seconds, and spin-coated at 2000 rpm for 25 seconds. It was dried overnight at room temperature and normal pressure. These substrates were evaluated by contact angle measurement and zeta potential measurement, scanning electron microscope (SEM), X-ray photoelectron spectrometer (XPS) and the like.

(4) Plasma surface treatment of polymer coated substrate.
Under various conditions (irradiation conditions: He gas flow rate 40 L / min, voltage 10 kV, frequency: 10 kHz, irradiation distance: 12.5 mm, irradiation time: 5, 15, 30, 60, irradiation temperature: room temperature) Plasma irradiation was performed. After irradiation, contact angle measurement and zeta potential measurement, a scanning electron microscope (SEM), an X-ray photoelectron spectrometer (XPS) and the like were evaluated.

<Result>
After coating with PMC, plasma treatment was performed, and the contact angles before and after that were measured. As shown in FIG. 4, the contact angle on the surface of the PMC coating before plasma irradiation returned to the pre-coating by washing with toluene and washed away, but after the plasma, the contact angle did not change even with toluene washing and was stably immobilized. I understand that. In addition, when the contact angle was measured by changing the CMS weight fraction in PMC, the contact angle before and after plasma irradiation did not change at the low CMS content as shown in FIG. On the other hand, when the CMS content is increased, the contact angle of the plasma-treated surface is lower than that of the untreated surface, and it is confirmed that the reaction occurs.

  Thus, according to the atmospheric pressure low temperature plasma irradiation treatment, it is clear that the PMEA part does not react and the CMS part selectively reacts.

(5) Introduction of functional group to plasma-treated surface Examination of amination method for surface functionalization is carried out by using a coating substrate and a plasma-irradiated substrate as a 10 mM solution of 20 mL of a mixed solvent of water: dimethylsulfoxide (DMSO) = 1: 1. After being immersed in an ethylenetetramine (N4) solution for 24 hours, introduction of triethylenetetramine accompanied by elimination of hydrogen chloride from the remaining chlorobenzyl group was performed. After thoroughly washing with distilled water, the contact angle measurement and zeta potential measurement, a scanning electron microscope (SEM), an X-ray photoelectron spectrometer (XPS) and the like were evaluated.

<Result>
As shown in FIG. 6, when the surface before the plasma treatment was reacted with N4, the zeta potential before and after the reaction did not change at about -10 mV. Since this is not fixed to the substrate surface and is not crosslinked, it is considered that it was solubilized and peeled by the reaction of the chlorobenzyl group and N4. On the other hand, when N4 was reacted with the plasma-treated surface, the zeta potential was greatly increased by amination, and efficient introduction of N4 was achieved. This surface is expected to be a biocompatible and highly cell-adhesive surface.

  According to the present invention, functionality (biocompatibility, biocompatibility, hydrophilicity control, functional group introduction, etc.) can be easily imparted to the support surface, and a stable material surface can be provided. Therefore, the present invention can be used in industries related to surface treatment of medical materials or medical instruments, surface treatment of industrial materials, and the like.

Schematic diagram of plasma jet generator The figure which shows the measurement result of the size exclusion chromatography (SEC) of a random copolymer (PMC (45)). The graph which shows the change of the glass transition temperature of the polymer accompanying the change of CMS content in PMC Graph showing the results of contact angle measurement before and after toluene cleaning on the surface of a polypropylene (PP) substrate coated with PMC and plasma-irradiated Graph showing change in contact angle with and without plasma treatment (treatment time 5 minutes) on the surface of a PP substrate coated with PCM polymer Graph showing change in zeta potential before and after amination treatment on the surface of a PP substrate coated with PMC polymer

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Gas supply glass tube 2 Derivative pipe tube for gas supply 3 Electrode 4 Voltage application apparatus 5 Non-equilibrium plasma jet

Claims (17)

  A homopolymer or copolymer derived from a monomer that forms a polymer having a functional group that is cross-linked by irradiation with atmospheric-pressure low-temperature plasma on the side chain of the repeating unit, and the coating-forming polymer is subjected to atmospheric-pressure low-temperature plasma. A crosslinked polymer composition comprising a crosslinked polymer obtainable by irradiation. The cross-linked polymer composition according to claim 1, wherein the monomer forming the homopolymer or copolymer having a functional group that is cross-linked by atmospheric pressure and low-temperature plasma irradiation is halogen from chlorine, bromine, iodine and fluorine. halogenated methylstyrene selected from the group consisting of divinyl benzene, 1,3-butadiene, aryl alcohol alkyl ethers _(a CH _{2 =} CHCH ₂ Oalk, alk is _C 1 -C ₆ alkyl), vinyl acetate, methacrylic The above composition which is methyl acid or acrylonitrile. (1) halogenated methylstyrene selected from the group consisting of chlorine, bromine, iodine and fluorine;
(2) _{CH 2 = C (R) -X} -A-B (I)
Wherein (a) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) O—, and A represents linear or branched C ₁ -C ₆ alkylene, and B represents hydroxyl, C ₁ -C ₄ alkyloxy, mono-C ₁ -C ₄ alkylamino, di _-C 1 -C _{4 alkylamino,} C 1 -C ₄ alkyloxycarbonyl, or represents phosphorylcholine,
(B) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) O—, and AB represents a linear or branched C ₁ -C ₂₀ alkyl, C ₃ -C ₆ cycloalkyl, which may be fluorinated with one or more fluorine atoms. C ₁ -C ₄ alkylene-C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkylenephenyl or phenyl,
(C) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) O—, and AB represents the formula — (CH ₂ CH ₂ O) _p R ^a , — (CH ₂ CH (CH ₃ ) O) _q R ^b or — (CH ₂ CH ₂ CH ₂ CH ₂ O) _r R ^c , where R ^a , R ^b and R ^c independently represent C ₁ -C ₄ alkyl, and p, q and r are independently 2-200 Represents an integer, or
(D) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) N (R ¹ ) —, wherein R ¹ represents a hydrogen atom or C ₁ -C ₄ alkyl;
A represents linear or branched C ₁ -C ₆ alkylene or C ₃ -C ₆ cycloalkyl, and B represents a hydrogen atom or amino, mono-C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ Represents alkylamino, carboxy,
(E) R represents the formula —CH ₂ C (O) R ₂ , where R ₂ represents a hydrogen atom or C ₁ -C ₄ alkyl;
X represents -C (O) O-,
Or A-B represents a hydrogen atom or a _C 1 -C ₄ alkyl,
(F) R represents a hydrogen atom,
X represents —O—C (O) — and A—B represents C ₁ -C ₄ alkyl;
(G) R represents a hydrogen atom, or X-A-B represents a hydrogen atom, _methyl, C 1 -C ₄ phenyl optionally substituted by alkyl, 2-pyrrolidone -1-yl,
A cross-linked copolymer obtainable by irradiating a film-forming copolymer produced by copolymerization of one or more ethylenically unsaturated polymerizable comonomers represented by A crosslinked polymer composition comprising:   4. The crosslinked polymer composition according to claim 3, wherein the halogenated methylstyrene is 4-chloromethylstyrene. The cross-linked polymer composition according to claim 3, wherein in the ethylenically unsaturated copolymerizable comonomer, R in the formula (I) represents a hydrogen atom or methyl, and X represents -C (O) O-. And A represents linear or branched C ₁ -C ₆ alkylene and B represents hydroxyl or C ₁ -C ₄ alkyloxy, or A-B is fluorinated with one or more fluorine atoms also represents a good straight or _C 1 _{-C 20} alkyl branched chain, the composition.   The coating film by which the crosslinked polymer composition of any one of Claims 1-5 was fixed on the support surface.   The coating film by which the crosslinked polymer composition of any one of Claims 3-5 was fixed on the support surface.   The coating film according to claim 6 or 7, wherein the support is a medical material made from a material selected from the group consisting of woven fabric, non-woven fabric, metal, ceramic, and plastic.   The coating film according to claim 8, wherein the medical material is selected from the group consisting of a prosthesis, a catheter, a syringe, a blood bag, a culture dish for examination, a suture, a hemostatic agent, and an internal fixation device.   The medical material which has the coating film derived from the crosslinked polymer composition of any one of Claims 1-5 in at least 1 part of the surface.   The medical material which has a coating film derived from the crosslinked polymer composition of any one of Claims 3-5 in at least 1 part of the surface. A polymer derived from a monomer that forms a homopolymer or copolymer having a functional group that is cross-linked by irradiation with atmospheric pressure and low-temperature plasma on the side chain of the repeating unit on the surface of the support, and has a coating film-forming property. A surface-treated support comprising: a step of applying a polymer; and a step of crosslinking at least a part of the polymer component of the coating film by irradiating the coating film thus formed with atmospheric pressure and low-temperature plasma. Production method. 11. The production method according to claim 10, wherein the monomer forming the homopolymer or copolymer having a functional group capable of crosslinking by atmospheric pressure low temperature plasma irradiation is selected from the group consisting of halogen, chlorine, bromine, iodine and fluorine. halogenated methylstyrene, divinylbenzene, 1,3-butadiene, aryl alcohol alkyl ethers _(a CH _{2 =} CHCH ₂ Oalk, alk is _C 1 -C ₆ alkyl), vinyl acetate, methacrylic acid methyl or acrylonitrile A manufacturing method as described above. (1) halogenated methylstyrene selected from the group consisting of chlorine, bromine, iodine and fluorine,
(2) _{CH 2 = C (R) -X} -A-B (I)
Wherein (a) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) O—, and A represents linear or branched C ₁ -C ₆ alkylene, and B represents hydroxyl, C ₁ -C ₄ alkyloxy, mono-C ₁ -C ₄ alkylamino, di _-C 1 -C _{4 alkylamino,} C 1 -C ₄ alkyloxycarbonyl, or represents phosphorylcholine,
(B) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) O—, and AB represents a linear or branched C ₁ -C ₂₀ alkyl, C ₃ -C ₆ cycloalkyl, which may be fluorinated with one or more fluorine atoms. C ₁ -C ₄ alkylene-C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkylenephenyl or phenyl,
(C) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) O—, and AB represents the formula — (CH ₂ CH ₂ O) _p R ^a , — (CH ₂ CH (CH ₃ ) O) _q R ^b or — (CH ₂ CH ₂ CH ₂ CH ₂ O) _r R ^c , where R ^a , R ^b and R ^c independently represent C ₁ -C ₄ alkyl, and p, q and r are independently 2-200 Represents an integer, or
(D) R represents a hydrogen atom or a _C 1 -C ₄ alkyl,
X represents —C (O) N (R ¹ ) —, wherein R ¹ represents a hydrogen atom or C ₁ -C ₄ alkyl;
A represents linear or branched C ₁ -C ₆ alkylene or C ₃ -C ₆ cycloalkyl, and B represents a hydrogen atom or amino, mono-C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ Represents alkylamino, carboxy,
(E) R represents the formula —CH ₂ C (O) R ₂ , where R ₂ represents a hydrogen atom or C ₁ -C ₄ alkyl;
X represents -C (O) O-,
Or A-B represents a hydrogen atom or a _C 1 -C ₄ alkyl,
(F) R represents a hydrogen atom,
X represents —O—C (O) — and A—B represents C ₁ -C ₄ alkyl;
(G) R represents a hydrogen atom, or X-A-B represents a hydrogen atom, _methyl, C 1 -C ₄ phenyl optionally substituted by alkyl, 2-pyrrolidone -1-yl,
A step of applying a coating film-forming copolymer produced by copolymerization of one or more ethylenically unsaturated polymerizable comonomers shown in FIG. A method for producing a surface-treated support comprising a step of crosslinking at least a part of a polymer component of a membrane.   The manufacturing method according to any one of claims 12 to 14, wherein the support is a medical material. By bringing the crosslinked polymer composition according to any one of claims 3 to 5 or the crosslinked polymer composition forming the coating film according to any one of claims 7 to 8 into contact with an amino group-containing organic compound in a solvent, Of the cross-linked polymer composition comprising reacting a methyl halide group remaining in the cross-linked copolymer in the composition with an amino group-containing compound and thus introducing the amino compound into the composition. Modification method.   The modification method according to claim 16, wherein the amino group-containing compound is an organic diamine compound.