WO2016158700A1 - Instrument médical - Google Patents

Instrument médical Download PDF

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Publication number
WO2016158700A1
WO2016158700A1 PCT/JP2016/059486 JP2016059486W WO2016158700A1 WO 2016158700 A1 WO2016158700 A1 WO 2016158700A1 JP 2016059486 W JP2016059486 W JP 2016059486W WO 2016158700 A1 WO2016158700 A1 WO 2016158700A1
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monomer
polymer
film thickness
base material
group
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PCT/JP2016/059486
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English (en)
Japanese (ja)
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政則 倉本
崇王 安齊
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テルモ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices

Definitions

  • the present invention relates to a medical device.
  • the present invention relates to a medical device having a surface having lubricity and blood compatibility.
  • Medical devices such as catheters are required to have lubricity in order to reduce tissue damage such as blood vessels and improve the operability of the operator.
  • a medical device inserted into a blood vessel such as a catheter is required to have blood compatibility.
  • a lesion in a peripheral blood vessel is treated, and a reduction in the diameter of the catheter is required. Accordingly, a technique for reducing the film thickness such as a lubricious coating is also required.
  • Patent Document 1 describes that a polymer chain is grown on the surface of a medical device by radical polymerization of a deliquescent monomer, thereby imparting lubricity while reducing the film thickness.
  • an alkali metal-containing monomer and a zwitterionic monomer are disclosed as deliquescent monomers.
  • JP 2014-214226 A (equivalent to US 2014/0322468 A1)
  • the polymer brush may be charged too negatively. In such a case, due to the negative charge of the polymer brush, the hydration between the polymer brush and water may be significantly disturbed, and blood compatibility may be reduced.
  • the polymer brush is not charged negatively or positively (neutral), so there is no repulsive force between the polymer brushes, and the polymer brushes Tend to grow together and form aggregates. For this reason, when a polymer brush peels, there exists a possibility of having a bad influence on a human body by the magnitude
  • the present invention has been made in view of the above circumstances, and an object thereof is to provide a medical device having a lubricating layer in which association between polymer brushes is reduced while ensuring blood compatibility.
  • the object is a medical device having a base material layer, wherein the polymer chain has a lubricating layer in which polymer chains having a length of less than 10 ⁇ m are present in a brush shape on the base material layer.
  • a medical device which is formed from a copolymer of a zwitterionic monomer and an anionic monomer having blood compatibility and has a negative charge when contacting a body fluid.
  • FIG. 1 indicates a medical device; 2 indicates a polymer chain (polymer brush); 3 indicates a lubricating layer; and 4 indicates a base material layer.
  • 2 indicates a polymer chain (polymer brush); 3 indicates a lubricating layer; and 4 indicates a base material layer.
  • the medical device of the present invention is a medical device having a base material layer, and has a lubricating layer in which polymer chains having a length of less than 10 ⁇ m are present in a brush shape on the base material layer, and the polymer
  • the chain is formed from a copolymer of a zwitterionic monomer having an affinity for blood and an anionic monomer, and is negatively charged when contacting a body fluid.
  • a polymer chain having a length of less than 10 ⁇ m and existing in a brush shape on the base material layer is also simply referred to as “polymer brush according to the present invention” or “polymer brush”.
  • zwitterionic monomer having blood compatibility is also simply referred to as “zwitterionic monomer according to the present invention” or “zwitterionic monomer”.
  • the polymer chain constituting the lubricating layer is formed from a copolymer of a zwitterionic monomer and an anionic monomer having blood compatibility; and (b) the lubricating layer has a length of less than 10 ⁇ m. And having a polymer chain existing in a brush shape.
  • the medical device having the above configuration can reduce the association between polymer chains with an anionic monomer while ensuring blood compatibility with a zwitterionic monomer.
  • the polymer chain has a structural unit derived from a zwitterionic monomer.
  • the constituent unit derived from this zwitterionic monomer has blood compatibility and hydrophilicity.
  • the lubricating layer can exhibit excellent blood compatibility and lubricity.
  • the polymer chain has a structural unit derived from an anionic monomer in addition to a structural unit derived from a zwitterionic monomer.
  • the structural unit derived from the anionic monomer is negatively charged when contacting a body fluid (for example, an aqueous liquid such as blood). That is, as shown in FIG.
  • each polymer chain 2 constituting the lubricating layer 3 is negatively charged when contacting a body fluid and repels adjacent polymer chains due to this negative charge.
  • Ah electrostatic repulsion
  • adjacent polymer chains do not associate with each other due to electrostatic repulsion, but rather extend in parallel on the base material layer 4 in a brush shape (perpendicular to the surface of the base material layer 4) and are oriented. Therefore, the lubricating layer according to the present invention can effectively exhibit the original characteristics (blood compatibility, lubricity) of the polymer brush when contacting body fluid.
  • “association” means that polymer brushes (polymer chains) according to the present invention are bonded to each other.
  • the polymer chain according to the present invention has a structural unit derived from an anionic monomer.
  • an anionic monomer By using an anionic monomer in this way, even if the polymer is peeled off, it is difficult for the polymers to associate with each other due to electrostatic repulsion. Even when the medical device of the present invention is used in blood, the anion on the blood cell surface repels the anion of the anionic monomer of the polymer chain, so that the induction of blood cell aggregation can be suppressed / prevented.
  • “aggregation” or “aggregation of blood cells” means that blood cells bind to each other via a polymer chain.
  • blood compatibility and lubricity can be exhibited by the zwitterionic monomer.
  • the charge amount of the polymer brush is appropriately adjusted by the anionic monomer to effectively suppress / prevent disturbance of the hydration structure of the polymer brush with water, and further decrease in blood compatibility and lubricity of the polymer brush. it can.
  • the lubricating layer can be a thin film of less than 10 ⁇ m.
  • the medical device can exhibit excellent blood compatibility and lubricity even with such a thin film. Therefore, the diameter of the catheter can be reduced and it can be suitably used for the treatment of a lesion in a peripheral blood vessel.
  • the polymer brush is peeled off from the base material layer, the polymer brush is negative, so the polymer brushes hardly meet each other. The same. For this reason, the peeled material is in the form of fine particles of less than 10 ⁇ m, and has a size with little or no influence on the human body. Therefore, the medical device of the present invention can be safely applied in vivo.
  • the said mechanism is estimation and this invention is not limited to the said estimation.
  • X to Y indicating a range includes X and Y, and means “X or more and Y or less”. Unless otherwise specified, measurement of operation and physical properties is performed under conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50%.
  • FIG. 1 is a schematic partial cross-sectional view for explaining the surface of the medical device of the present invention.
  • the medical device 1 of the present invention has a structure in which a lubricating layer 3 is formed on a base material layer 4.
  • the lubricating layer 3 has the polymer chain 2 in a brush shape.
  • the polymer chain 2 is negatively charged with an anionic monomer in a body fluid (for example, an aqueous liquid such as blood).
  • a body fluid for example, an aqueous liquid such as blood.
  • the adjacent polymer chains 2 are appropriately separated from each other by electrostatic repulsion and are oriented substantially perpendicularly (in a brush shape) to the surface of the base material layer 4.
  • the lubricating layer according to the present invention can exhibit higher effects (blood compatibility, lubricity) when contacting body fluid.
  • the “polymer brush” is intended to indicate a state in which the polymer chain exists in a brush shape, and the polymer brush and the polymer chain are treated as synonymous unless otherwise specified.
  • the polymer chain is negatively charged when contacting body fluid means that it is only required to be negatively charged at least when contacting body fluid, and not negatively charged when not contacting body fluid. Also good.
  • the base material layer constitutes a medical device.
  • the material of the base material layer is not particularly limited and can be appropriately selected depending on the application. It is preferable that at least the surface of the base material layer is made of a polymer material.
  • the “base layer is made of a polymeric material” means that at least the surface of the base layer is made of a polymeric material, and the entire base layer (all) is made of a polymeric material. It is not limited to what is configured (formed). Therefore, on the surface of the base material core portion formed of a hard reinforcing material such as a metal material or a ceramic material, a polymer material that is more flexible than a reinforcing material such as a metal material is applied by an appropriate method (dipping or spraying).
  • the base material core portion may be a multilayer structure in which different materials are laminated in multiple layers, or a structure (composite) in which members formed of different materials for each part of the medical device are connected. . Further, a different intermediate layer may be formed between the base material core portion and the surface polymer layer.
  • the surface polymer layer a multilayer structure in which different polymer materials are laminated in multiple layers, or a structure (composite) in which members made of different polymer materials are connected to each part of a medical device, etc. There may be.
  • various stainless steels such as SUS304, SUS316L, SUS420J2, SUS630, gold, platinum, tantalum, silver, copper, nickel, cobalt, titanium, iron, aluminum, tin, magnesium, zinc and nickel-titanium alloy, cobalt
  • metal materials such as chromium alloys and zinc-tungsten alloys, inorganic materials such as various ceramic materials, and metal-ceramic composites, but are not limited thereto.
  • the polymer material that can be used for the base material layer or the surface polymer layer is not particularly limited, and examples thereof include nylon 6, nylon 11, nylon 12, and nylon 66 (all are registered trademarks).
  • Polyolefin resins such as polyamide resin, linear low density polyethylene (LLDPE), low density polyethylene (LDPE), high density polyethylene (HDPE), and polypropylene resin, epoxy resin, urethane resin, diallyl phthalate resin (allyl resin) ), Polycarbonate resin, fluorine resin, amino resin (urea resin, melamine resin, benzoguanamine resin), polyester resin, styrene resin, acrylic resin, polyacetal resin, vinyl acetate resin, phenol resin, polyvinyl chloride (PVC) (vinyl chloride) Block copolymer having a hard segment made of nylon resin, silicone resin (silicon resin), nylon 6, nylon 66, nylon 11 or nylon 12, and soft segment made of polyalkylene glycol, polyether or aliphatic polyester.
  • nylon elastomer etc. are mentioned. These may be used individually by 1 type and may use 2 or more types together. What is necessary is just to select the polymeric material optimal as polymeric base materials, such as a catheter, a guide wire, and an indwelling needle which are use applications, as said polymeric material suitably.
  • the material that can be used for the intermediate layer is not particularly limited, and may be appropriately selected depending on the intended use. Examples include various metal materials, various ceramic materials, and organic-inorganic composites, but are not limited thereto.
  • the lubrication layer has a polymer chain in a brush shape.
  • the lubricating layer is composed of a polymer brush (polymer chain).
  • the polymer chain is a copolymer of a zwitterionic monomer and an anionic monomer having blood compatibility.
  • the polymer chain has a length of less than 10 ⁇ m.
  • the length of the polymer chain corresponds to the thickness of the lubricating layer. That is, the lubricating layer can be a thin film of less than 10 ⁇ m.
  • the medical device can exhibit excellent blood compatibility and lubricity even with such a thin lubrication layer, and the diameter of the catheter is reduced. It can also be used suitably for the treatment of lesions in peripheral blood vessels. Even when the polymer chain (polymer brush) is peeled off from the base material layer, the polymer brush is negative and the polymer brushes are hardly associated with each other.
  • the length of the polymer chain is less than 10 ⁇ m, and in consideration of a further reduction effect on the influence on the human body, it is preferably 9.999 ⁇ m or less, more preferably 8.000 ⁇ m or less, and particularly preferably 7.000 ⁇ m or less.
  • the lower limit of the polymer chain length is not particularly limited and is a measurement limit.
  • the length of the polymer chain is preferably 0.001 ⁇ m or more, more preferably 0.0051 ⁇ m or more, and particularly preferably 0.0101 ⁇ m or more. With such a length, the polymer chain can reduce the influence on the human body while ensuring high blood compatibility and lubricity. According to a preferred embodiment, the length of the polymer chain is 0.001 to 9.999 ⁇ m, more preferably 0.005 to 8.000 ⁇ m, particularly preferably 0.010 to 7.000 ⁇ m.
  • the length of the polymer chain is defined as the length of the polymer brush and the film thickness of the polymer brush being approximately the same. Further, the film thickness of the polymer brush and the film thickness of the lubricating layer are considered to be approximately the same.
  • the film thickness of the polymer brush on the base material layer can be calculated from an optical measurement method using an ellipsometry or an optical interference film thickness meter, or from a micrograph. Consider it a length.
  • a value measured using an optical interference film thickness meter FILMETRIX, F40
  • the polymer chain (polymer brush) according to the present invention is formed from a copolymer of a zwitterionic monomer and an anionic monomer having blood compatibility and lubricity.
  • zwitterionic monomers are compounds having both a cationic group and an anionic group in one molecule.
  • Such zwitterionic monomers are not particularly limited, and examples thereof include those having a carboxybetaine skeleton, a sulfobetaine skeleton, a phosphobetaine skeleton, and those having an amino acid skeleton.
  • the zwitterionic monomer preferably has a betaine skeleton such as a carboxybetaine skeleton, a sulfobetaine skeleton, or a phosphobetaine skeleton. That is, according to a preferred embodiment of the present invention, the zwitterionic monomer has a betaine skeleton.
  • a carboxybetaine type, sulfobetaine type, or phosphobetaine type zwitterionic monomer having the following structure is preferably used.
  • R 1 is a hydrogen atom or a methyl group, and is preferably a methyl group from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity.
  • Z is an oxygen atom or —NH—, and preferably an oxygen atom from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity.
  • R 2 is a linear or branched alkylene group having 1 to 6 carbon atoms.
  • the linear or branched alkylene group having 1 to 6 carbon atoms is not limited to the following, and examples thereof include a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Can be mentioned.
  • it is preferably a linear or branched alkylene group having 1 to 3 carbon atoms, preferably a methylene group or an ethylene group. More preferably, it is particularly preferably an ethylene group.
  • R 3 and R 4 are each independently an alkyl group having 1 to 4 carbon atoms.
  • R 3 and R 4 may be the same or different.
  • the alkyl group having 1 to 4 carbon atoms is not limited to the following, but for example, a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group linear or Examples include branched alkyl groups.
  • a linear or branched alkyl group having 1 to 3 carbon atoms is preferable, and 1 or 2 carbon atoms are preferable.
  • an alkyl group (methyl group, ethyl group) and particularly preferably a methyl group.
  • R 5 is a methylene group, ethylene group, trimethylene group, propylene group, butylene group, isobutylene group, sec-butylene group, or tert-butylene group.
  • a methylene group, an ethylene group, a trimethylene group, and a propylene group are preferable from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or improving lubricity.
  • an alkylene group having 1 carbon atom is particularly preferred
  • an alkylene group having 3 carbon atoms is particularly preferred.
  • X is —COO ⁇ (carboxybetaine type zwitterionic monomer), —SO 3 ⁇ (sulfobetaine type zwitterionic monomer).
  • a zwitterionic monomer having a carboxybetaine skeleton includes N- (meth) acryloyloxymethyl- N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine, N- (meth) acryloyloxyethyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine, N- (meth) acryloyloxypropyl-N, N-dimethylammonium- ⁇ -N-methylcarboxybetaine, N- (meth) acryloyloleoxymethyl-N, N-diethylammonium- ⁇ -N-methylcarboxybetaine, N- (meth) acryloyloxyethyl-N, N-diethylammonium- ⁇ -N-methylcarboxybeta And N- (
  • a phosphobetaine-type zwitterionic monomer having the following structure is preferably used.
  • R 11 is a hydrogen atom or a methyl group, and preferably a methyl group from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity.
  • Z ′ is an oxygen atom or —NH—, and preferably an oxygen atom from the viewpoint of improving blood compatibility (for example, antithrombogenicity) and / or lubricity.
  • R 12 and R 13 are linear or branched alkylene groups having 1 to 6 carbon atoms.
  • R 12 and R 13 may be the same or different.
  • the linear or branched alkylene group having 1 to 6 carbon atoms is not limited to the following, and examples thereof include a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Can be mentioned.
  • it is preferably a linear or branched alkylene group having 1 to 3 carbon atoms, preferably a methylene group or an ethylene group. More preferably, it is particularly preferably an ethylene group.
  • R 14 to R 16 are each independently an alkyl group having 1 to 4 carbon atoms.
  • R 14 to R 16 may be the same or different.
  • the alkyl group having 1 to 4 carbon atoms is not limited to the following, but for example, a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group linear or Examples include branched alkyl groups.
  • a linear or branched alkyl group having 1 to 3 carbon atoms is preferable, and 1 or 2 carbon atoms are preferable.
  • an alkyl group (methyl group, ethyl group) and particularly preferably a methyl group.
  • zwitterionic monomers having a phosphobetaine skeleton include 2- (meth) acryloyloxyethyl phosphorylcholine, 4- (meth) acryloyloxybutylphosphorylcholine, Examples include 6- (meth) acryloyloxyhexyl phosphorylcholine, ⁇ - (meth) acryloyloxyethylene phosphorylcholine, 4-styryloxybutyl phosphorylcholine, and the like. Of these, 2- (meth) acryloyloxyethyl phosphorylcholine is preferred.
  • Zwitterionic monomers having an amino acid skeleton include, for example, (meth) acryloyl-L-lysine, (meth) acryloyl-L-serine, (meth) acryloyl-L-threonine, (meta And acryloyl-L-tyrosine.
  • the zwitterionic monomers may be used alone or in combination of two or more. By using such a zwitterionic monomer, high blood compatibility (for example, antithrombogenicity) can be imparted to the lubricating layer of the medical device.
  • high blood compatibility for example, antithrombogenicity
  • (meth) acryl means “acryl and / or methacryl”.
  • (meth) acryloyl” means “acryloyl and / or methacryloyl”.
  • R 1 is a methyl group
  • Z is an oxygen atom
  • R 2 is an alkylene group having 1 to 3 carbon atoms
  • R 3 and R 4 are each independently And an alkyl group having 1 or 2 carbon atoms
  • X is preferably —COO 2 — or —SO 3 —
  • R 11 is a methyl group
  • Z ′ is an oxygen atom
  • R 12 and R 13 are alkylene groups having 1 to 3 carbon atoms
  • R 14 to R 16 are respectively Independently, an alkyl group having 1 or 2 carbon atoms is preferable.
  • the zwitterionic monomer is represented by the formula (1), wherein R 1 is a methyl group, Z is an oxygen atom, R 2 is an ethylene group (—CH 2 CH 2 —), R 3 and R [2- (methacryloyloxy) ethyl] dimethyl- (3-sulfopropyl) ammonium hydroxide (SPB)) in which 4 is a methyl group, R 5 is a trimethylene group, and X is —SO 3 — ;
  • R 1 is a methyl group
  • Z is an oxygen atom
  • R 2 is an ethylene group (—CH 2 CH 2 —)
  • R 3 and R 4 are methyl groups
  • R 5 is methylene group
  • X is -COO - a is N- methacryloyloxyethyl -N, N- dimethylammonium-.alpha.-N- methyl carboxy betaine (CMB); and the above formula (2), R 11 is a methyl group Yes, Z
  • An anionic monomer is a compound that is negatively charged when contacting a body fluid.
  • “having a negative charge when contacting a body fluid” means having a minus charge enough to repel an anionic group (minus) present in the body fluid.
  • Such an anionic monomer is not particularly limited, but includes a carboxyl group (—COOH), a sulfonic acid group (—SO 3 H), a sulfuric acid group (—OSO 3 H), and a phosphonic acid group (—PO 3 H 2 ). And compounds having an anionic group such as a phosphate group (—PO 4 H 2 ).
  • a negative charge is appropriately charged when contacting the body fluid, repelling the anionic group (minus) on the surface of the body fluid component (for example, blood cells), and more effectively suppressing the aggregation of the body fluid component ⁇ Can be prevented.
  • anionic monomers are appropriately negatively charged when contacting body fluids, and also exhibit blood compatibility (for example, antithrombogenicity) due to negative charges derived from these functional groups (blood of medical devices) Compatibility can be further improved).
  • the anionic monomer may contain the said functional group independently, and may contain both of these.
  • anionic monomers include (meth) acrylic acid, ⁇ -carboxyethyl acrylate, 2- (meth) acrylamide-2-methyl-propanesulfonic acid (AMPS), vinyl sulfate, allyl sulfate, 4-vinylphenyl sulfate, styrene sulfonic acid, sulfoethyl (meth) acrylate, sulfopropyl (meth) acrylate, 2-methyl-2-propene-1-sulfonic acid, 2-propene-1-sulfonic acid, 2-hydroxy-3 -((Meth) acryloyloxy) propane-1-sulfonic acid, 2-acrylamido-2-methyl-1-propanesulfonic acid, 3-((meth) acryloylamino) propane-1-sulfonic acid, phosphoric acid (meth) 2-hydroxyethyl acrylate, 2- (meth) acryloyl phosphate 2-phosphoric acid (
  • the salt of the anionic monomer is not particularly limited, and examples thereof include inorganic cation salts and organic cation salts.
  • the salt of the inorganic cation alkali metal salts, alkaline earth metal salts, and ammonium salts are preferable, and among them, sodium salts, potassium salts, and lithium salts are more preferable.
  • the organic cation salt is preferably a primary to tertiary amine salt.
  • the anionic monomers may be used alone or in combination of two or more.
  • anionic monomers By using these anionic monomers, a negative charge is appropriately charged when contacting the body fluid, repelling the anionic group (minus) on the surface of the body fluid component (for example, blood cells), and more effectively suppressing the aggregation of the body fluid component ⁇ Can be prevented.
  • these anionic monomers are appropriately negatively charged when contacting body fluids, and also exhibit particularly excellent blood compatibility (for example, antithrombogenicity) due to the negative charge derived from these functional groups (medical treatment) The blood compatibility of the device can be further improved).
  • an anionic monomer even if the polymer is peeled off, it is difficult for the polymers to associate with each other due to electrostatic repulsion.
  • the copolymer according to the present invention has a repeating unit derived from a zwitterionic monomer and a repeating unit derived from an anionic monomer, but the composition of the copolymer is not particularly limited. Specifically, from the viewpoint of blood compatibility, it is preferable that the proportion of zwitterionic monomers is higher than the proportion of anionic monomers. Further, from the viewpoint of the effect of suppressing association and / or aggregation due to the anionic monomer, the proportion of the anionic monomer is preferably more than 0.5 mol% with respect to the copolymer.
  • the composition of the copolymer (molar ratio of zwitterionic monomer: anionic monomer) is such that the copolymer contains more zwitterionic monomer than anionic monomer (molar ratio of zwitterionic monomer> anion).
  • the composition of the copolymer (molar ratio of zwitterionic monomer: anionic monomer) is 60 to 99:40 to 1, more preferably 60 to 97:40 to 3, particularly preferably. 70-97: 30-3.
  • the sum of the molar ratio of zwitterionic monomer: anionic monomer is 100.
  • the copolymer (polymer brush) can more effectively achieve both the high blood compatibility and lubricity due to the zwitterionic monomer and the inhibitory effect on association and / or aggregation due to the anionic monomer.
  • it can confirm with a well-known method that the copolymer is negatively charged. For example, using a Zetasizer (MALVERN), 1 mL of the polymer solution is put into a cell with an electrode, and the potential of the polymer surface (zeta potential) is measured by passing an electric current. You can confirm that it is tinged.
  • MALVERN Zetasizer
  • the copolymer constituting the polymer chain according to the present invention essentially contains a repeating unit derived from a zwitterionic monomer and a repeating unit derived from an anionic monomer, but may contain other repeating units.
  • the copolymer constituting the polymer chain according to the present invention is composed only of a repeating unit derived from a zwitterionic monomer and a repeating unit derived from an anionic monomer.
  • the copolymer constituting the polymer chain according to the present invention comprises only a repeating unit derived from a zwitterionic monomer and a repeating unit derived from an anionic monomer.
  • the form of the copolymer according to the present invention is not particularly limited, and may take any form such as a random copolymer, an alternating copolymer, a graft copolymer, and a block copolymer.
  • a method for forming a lubricating layer is 2006-523128 (US 2004) except that a polymer chain having a length of less than 10 ⁇ m can be formed from a zwitterionic monomer and an anionic monomer.
  • / 0191538 (corresponding to A1)
  • Japanese Patent Application Laid-Open No. 2014-214226 (corresponding to US 2014/0322468 A1) and the like can be applied similarly or appropriately modified.
  • this invention is not limited to the following form.
  • a radical starting point is formed in the base material layer.
  • the method for forming the radical start point on the base material layer is not particularly limited, but the method for immobilizing the polymerization initiator on the base material surface, plasma treatment, ultraviolet irradiation, laser light irradiation, corona discharge, radiation (electron) Line, gamma ray) irradiation, microwave, etc.
  • a method of immobilizing the polymerization initiator on the substrate surface is preferable.
  • radiation irradiation is preferable, and electron beam irradiation (particularly atmospheric pressure electron beam irradiation) is preferable.
  • the radiation graft polymerization method in which the starting point of radicals is formed in the base material layer by electron beam irradiation has a wide range of base material shapes and materials that can be selected; use an initiator. Without the use of a catalyst, and the graft polymerization can be carried out under mild conditions.
  • the processing conditions in this case are not particularly limited.
  • the dose of the electron beam is not particularly limited, but strongly relates to the control of the density of the polymer brush formed on the base material layer. Therefore, the electron beam dose is preferably 10 to 1000 kGy, and more preferably 50 to 500 kGy.
  • a polymer brush can be formed on a base material with a suitable density, and lubricity and blood compatibility can further be improved. Moreover, if it is the above conditions, a polymer brush will be formed on a base material with a suitable density, and the association
  • the pressure conditions for electron beam irradiation are not particularly limited, and can be under reduced pressure or atmospheric pressure. However, it is possible to realize a system configuration with low space and low cost, and it is economically superior. Therefore, it is good to carry out under atmospheric pressure.
  • the irradiation atmosphere is not particularly limited, and examples thereof include an inert gas atmosphere such as nitrogen and helium.
  • the electron beam irradiation time is, for example, in the range of 0.1 second to 1 hour, more preferably 0.5 second to 10 minutes.
  • the polymer brush can be formed on the substrate with an appropriate density, and the lubricity and blood compatibility can be further improved.
  • a polymer brush will be formed on a base material with a suitable density, and the association
  • radical initiation points may be formed in the base material layer by adsorbing a polymerization initiator on the base material layer.
  • a polymerization initiator it does not restrict
  • Specific examples include carbonyl compounds such as benzophenone compounds and photoreducible dyes. Of these, carbonyl compounds, particularly benzophenone compounds, are preferred.
  • the benzophenone compound is not limited to the following, but includes benzophenone, xanthone, 9-fluorenone, 2,4-dichlorobenzophenone, methyl o-benzoylbenzoate, 4,4′-bis (dimethylamino) benzophenone, 4, Examples thereof include 4′-bis (diethylamino) benzophenone; fluorinated benzophenones such as 2,3,4,5,6-pentafluorobenzophenone and decafluorobenzophenone. Of these, benzophenone, xanthone, thioxanthone, fluorenone, acetophenone, and anthraquinone are preferable in consideration of ease of adjustment of the formation density and length of the polymer brush.
  • the method for forming the radical starting point on the base material layer using the polymerization initiator is not particularly limited, and a known method can be applied in the same manner or appropriately modified. Specifically, a method in which a polymerization initiator is dissolved in an appropriate solvent to obtain a polymerization initiator solution, and the substrate layer is treated with this polymerization initiator solution to adsorb the polymerization initiator to the substrate layer is preferable. Can be used.
  • the solvent that can be used for preparing the polymerization initiator solution is not particularly limited as long as the polymerization initiator can be dissolved, and is appropriately selected according to the polymerization initiator to be used.
  • the usage-amount of a solvent will not be restrict
  • the amount is such that the concentration of the polymerization initiator in the polymerization initiator solution is preferably about 75 to 0.1 g / 100 mL solvent.
  • the method for treating the base material layer with the polymerization initiator solution is not particularly limited as long as the polymerization initiator can be present on the surface of the base material layer.
  • conventionally known methods such as coating / printing method, dipping method (dipping method, dip coating method), spraying method (spray method), spin coating method, mixed solution-impregnated sponge coating method, and the like can be applied.
  • the dipping method (dipping method, dip coating method) is preferably used.
  • it is not necessary to process the whole base material layer with a polymerization initiator solution and you may process a part of base material layer surface with a polymerization initiator solution.
  • a coating / printing method and a spraying method can be preferably used.
  • the base material layer may be dried to remove the solvent if necessary. Thereby, a polymerization initiator can adsorb
  • the conditions for treating the base material layer with the polymerization initiator solution are not particularly limited as long as the polymerization initiator can be present on the surface of the base material layer.
  • the contact temperature of the base material layer with the polymerization initiator solution is preferably 10 to 100 ° C., more preferably Is 20 to 80 ° C.
  • the immersion time is preferably 0.5 minutes to 30 minutes, more preferably 1 minute to 10 minutes.
  • a zwitterionic monomer and an anionic monomer are supplied to the radical generated as described above to perform polymerization (radical polymerization).
  • the supply form of the monomer is not particularly limited.
  • a method of polymerizing a monomer by immersing a base material layer having a radical start point formed on the surface thereof in a monomer solution containing a zwitterionic monomer and an anionic monomer, and, if necessary, another monomer, and a radical A method of polymerizing the monomer by supplying a zwitterionic monomer and an anionic monomer and, if necessary, other monomers in a gaseous form to the base material layer having the starting point of the surface formed on the surface is preferred.
  • the solvent used for the preparation of the monomer solution is not particularly limited as long as it can dissolve the zwitterionic monomer and the anionic monomer.
  • water, methanol, ethanol, propanol, n-butanol and the like can be used.
  • Alcohols such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, acetic acid, tetrahydrofuran (THF), 1,4-dioxane, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, hexamethylphosphoric triamide, triethylamine ,
  • a solvent miscible with water such as pyridine and dimethyl sulfoxide, or a solvent soluble in water such as diethyl ether and ethyl acetate. These solvents may be used alone or in the form of a mixture of two or more.
  • the mixing ratio of the zwitterionic monomer and the anionic monomer in the monomer solution is not particularly limited, but the preferred composition of the copolymer (molar amounts of zwitterionic monomer and anionic monomer, and other monomers if necessary). Ratio) is preferably adjusted.
  • the concentration of the zwitterionic monomer and the anionic monomer in the monomer solution and, if necessary, the concentration of other monomers (monomer concentration) are not particularly limited, but the density of the polymer brush on the base material layer, the polymer Considering the length of the brush and the like, the total monomer concentration is preferably 0.01 to 20 mol, more preferably 0.05 to 10 mol, per liter of the monomer solution.
  • the monomer concentration is the total concentration of zwitterionic monomer and anionic monomer and, if necessary, other monomers.
  • the monomer solution may be bubbled with an inert gas such as nitrogen or helium when the base material layer is immersed.
  • the conditions for immersing the base material layer in the monomer solution are also not particularly limited.
  • the immersion temperature liquid temperature of the monomer solution
  • the immersion time is preferably 1 minute to 24 hours, more preferably 5 minutes to 12 hours. Under such conditions, a polymer brush having a predetermined length can be efficiently formed.
  • the immersion time of the base material layer in the monomer solution is strongly related to the length of the polymer brush formed on the base material layer, the polymer brush having a predetermined length can be obtained by adjusting the immersion time as described above. It can be formed efficiently.
  • the radical starting point is formed on the base material layer by adsorbing the polymerization initiator, after the base material layer adsorbed with the polymerization initiator is immersed in the monomer solution, the starting point of the base material layer surface is set. It is preferable to radically polymerize monomers (zwitterionic monomers and anionic monomers and, if necessary, other monomers) as a starting point. Thereby, a polymer brush is formed on the substrate layer surface.
  • the solvent used for the preparation of the monomer solution and the concentration of the monomer (monomer concentration) are not particularly limited and are the same as those in the above-described radiation graft polymerization method, and thus the description thereof is omitted here.
  • the monomer solution may be bubbled with an inert gas such as nitrogen or helium when the base material layer is immersed.
  • the conditions for immersing the base material layer in the monomer solution are also not particularly limited.
  • the radical polymerization method is not particularly limited, and known radical polymerization methods can be applied in the same manner or appropriately modified. Specifically, a method of irradiating ultraviolet rays (200 to 400 nm, particularly a high pressure mercury lamp having a wavelength of 300 to 400 nm) is preferable. Thereby, radical polymerization (photo radical polymerization) proceeds more efficiently, and a polymer brush having a desired length can be grown on the base material layer.
  • the radical polymerization conditions are not particularly limited as long as a polymer brush having a desired length can be grown on the base material layer.
  • the illuminance of the ultraviolet rays is preferably 70 ⁇ 0.1mW / cm 2, more preferably 30 ⁇ 0.5mW / cm 2.
  • the irradiation time is preferably 0.1 to 12 hours, more preferably 0.5 to 6 hours. Under such conditions, radical polymerization (photo radical polymerization) proceeds more efficiently, and a polymer brush having a desired length can be grown on the base material layer.
  • a lubricating layer in which the polymer chain according to the present invention is present in a brush shape can be formed on the base material layer.
  • the base material layer on which the lubricating layer is formed may be washed (for example, washed with water).
  • the density of the polymer brush is not particularly limited, but is preferably about 0.1 to 1 ⁇ g / cm 2 in consideration of lubricity and the like.
  • divided the weight difference before and behind the polymerization measured by the ultramicro balance (Sartorius) by the area is used for the density of the polymer brush.
  • the molecular weight of the copolymer (polymer chain, polymer brush) of the zwitterionic monomer and the anionic monomer is not particularly limited, but the length of the polymer is not limited from the viewpoint of lubricity and safety of the peeled fine particles. It is preferable that the length is adjusted so as to be as described above.
  • Examples of the medical device according to the present invention include, for example, an implantable artificial organ and a therapeutic instrument, an extracorporeal circulation artificial organ, a catheter, a guide wire, and the like.
  • an artificial blood vessel, an artificial trachea, a stent, or an implantable medical device such as an artificial skin or an artificial pericardium, or an artificial heart system, an artificial lung system, an artificial heart lung or the like inserted into or replaced into a blood vessel or a lumen.
  • the medical device according to the present invention is excellent in blood compatibility and can suppress the formation of thrombus on the surface of the medical device, so that the medical device to be inserted into a blood vessel, specifically, cardiovascular, cerebral blood vessel, etc. It is preferably applied to various catheters used for endovascular treatment.
  • a blood vessel specifically, cardiovascular, cerebral blood vessel, etc.
  • It is preferably applied to various catheters used for endovascular treatment.
  • medical devices in these fields are particularly required to have lubricity and blood compatibility (antithrombogenicity to prevent thrombus formation) for improving operability.
  • blood compatibility can be evaluated by, for example, a blood coagulation test or a protein adsorption test.
  • Example 1 A base material 1 was prepared by irradiating the surface of a polypropylene (PP) film (thickness: 60 ⁇ m) with an electron beam of 70 kGy / sec for 5 seconds in a nitrogen atmosphere.
  • PP polypropylene
  • the monomer solution (1) was prepared by dissolving in water so that the molar ratio was 5.
  • the total monomer concentration (molar concentration) of the monomer solution was adjusted to be 1 mol / L monomer solution.
  • the base material 1 prepared above is immersed in the monomer solution (1) prepared above while nitrogen bubbling, and a polymerization reaction is performed at 50 ° C. (monomer solution temperature) for 1 hour, thereby forming a lubrication comprising a polymer brush.
  • a layer was formed on substrate 1 (substrate 2).
  • This base material 2 was washed with water to produce a medical device 1.
  • the film thickness (dry film thickness) was measured using an optical interference type film thickness meter (F40 manufactured by FILMETRIX). As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured.
  • the film thickness of the lubricating layer is regarded as the average length of the polymer brush.
  • the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm.
  • the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm.
  • the obtained medical device 1 When the obtained medical device 1 was rubbed with a finger, it exhibited excellent lubricity and durability.
  • Example 2 A medical device 2 was produced in the same manner as in Example 1 except that a nylon elastomer sheet (thickness: 1 mm) was used instead of the polypropylene film (thickness: 60 ⁇ m). With respect to the lubricating layer thus formed, the film thickness (dry film thickness) was measured in the same manner as in Example 1. As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured. Here, the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm.
  • the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm.
  • Example 1 When the obtained medical device 2 was rubbed strongly with a finger, as in Example 1, excellent lubricity and durability were exhibited.
  • the HDPE sheet (base material 3) adsorbed with benzophenone thus obtained was immersed in the monomer aqueous solution and subjected to nitrogen bubbling for 1 minute, and then sealed and irradiated with ultraviolet rays (illuminance 2.5 mW / cm 2 , (Wavelength 365 nm) was irradiated for 2 hours, a copolymer of SPB and AAc was grafted onto the surface of the HDPE sheet, and a lubricating layer composed of a polymer brush was formed on the substrate 3 (substrate 4). This base material 4 was washed with water to produce a medical device 3.
  • the film thickness (dry film thickness) was measured in the same manner as in Example 1. As a result, the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured.
  • the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm. On the other hand, since it showed slipperiness when touched with a finger, the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more.
  • the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm.
  • Example 4 2.91 g (10.4 mmol) of SPB, 0.19 g (2.6 mmol) of AAc, and water were added to prepare 13 mL of an aqueous monomer solution (4). At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 80:20.
  • Example 3 the medical device 4 was produced in the same manner as in Example 3 except that the monomer aqueous solution (4) thus prepared was used instead of the monomer aqueous solution (3).
  • the film thickness (dry film thickness) was measured in the same manner as in Example 1.
  • the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured.
  • the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm.
  • the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm.
  • Example 5 SPB 2.54 g (9.1 mmol), AAc 0.28 g (3.9 mmol), and water were added to prepare 13 mL of an aqueous monomer solution (5). At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 70:30.
  • Example 3 the medical device 5 was produced in the same manner as in Example 3 except that the monomer aqueous solution (5) thus prepared was used instead of the monomer aqueous solution (3).
  • the film thickness (dry film thickness) was measured in the same manner as in Example 1.
  • the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured.
  • the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm.
  • the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm.
  • the obtained medical device 5 was rubbed strongly with a finger, it exhibited excellent lubricity and durability.
  • Example 6 SPB 2.18 g (7.8 mmol), AAc 0.37 g (5.2 mmol), and water were added to prepare 13 mL aqueous monomer solution (6). At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 60:40.
  • Example 3 a medical device 6 was produced in the same manner as in Example 3 except that the monomer aqueous solution (6) thus prepared was used instead of the monomer aqueous solution (3).
  • the film thickness (dry film thickness) was measured in the same manner as in Example 1.
  • the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured.
  • the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm.
  • the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm.
  • the obtained medical device 6 was rubbed with a finger, it exhibited excellent lubricity and durability.
  • Example 7 SPB 1.82 g (6.5 mmol), AAc 0.47 g (6.5 mmol), and water were added to prepare a 13 mL aqueous monomer solution (7). At this time, the charging ratio of SPB and AAc (SPB: AAc (molar ratio)) is 50:50.
  • Example 3 the medical device 7 was produced in the same manner as in Example 3 except that the monomer aqueous solution (7) thus prepared was used instead of the monomer aqueous solution (3).
  • the film thickness (dry film thickness) was measured in the same manner as in Example 1.
  • the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured.
  • the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm.
  • the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this example is presumed to be in the range of 10 nm to 100 nm.
  • the obtained medical device 7 was rubbed strongly with a finger, it exhibited excellent lubricity and durability.
  • Example 3 the medical device 8 was produced in the same manner as in Example 3 except that the monomer aqueous solution (8) thus prepared was used instead of the monomer aqueous solution (3).
  • the film thickness (dry film thickness) was measured in the same manner as in Example 1.
  • the film thickness (dry film thickness) was less than the detection limit (100 nm) and could not be measured.
  • the film thickness of the lubricating layer is regarded as the average length of the polymer brush. For this reason, the film thickness (dry film thickness) (hence, the length of the polymer brush) is estimated to be less than 100 nm.
  • the film thickness (dry film thickness) (and hence the length of the polymer brush) is estimated to be 10 nm or more. Therefore, the film thickness (dry film thickness) (and hence the length of the polymer brush) of the lubricating layer formed in this comparative example is estimated to be in the range of 10 nm to 100 nm.
  • the obtained medical device 8 When the obtained medical device 8 was rubbed with a finger, it exhibited excellent lubricity and durability.
  • Example 3 a medical device 9 was produced in the same manner as in the above Example 3 except that this water was used in place of the monomer aqueous solution (3).
  • the obtained medical device 9 was strongly rubbed with a finger, but no lubricity was exhibited.
  • the medical devices 3 to 9 are immersed in a 1% glutaraldehyde PBS solution and allowed to stand at room temperature (25 ° C.) for 3 hours, and then the medical devices 3 to 9 are pulled up from the glutaraldehyde PBS solution and washed three times with RO water. Washed and dried under reduced pressure for 48 hours.
  • the amount of thrombus attached was calculated from the change in weight before and after contact with blood.
  • the results are shown in Table 1 below.
  • the evaluation of blood compatibility is regarded as one point for every 0.0001 g of increased weight of clot adhesion, and the smaller the score, the better the blood compatibility. Further, if the score is 1.5 points or less, it is determined to be acceptable, if the score is 1.0 points or less, it is determined that the blood compatibility is excellent, and if the score is 0.5 points or less, Judged to be very excellent in blood compatibility.
  • the medical device of the present invention exhibits blood compatibility.
  • the introduction rate of acrylic acid, which is an anionic monomer is 30 mol% or less in the copolymer, it is suggested that particularly excellent blood compatibility can be exhibited.
  • the lubrication layer made of the polymer brush according to the present invention exhibits excellent blood compatibility and lubricity, and the association between the polymer chains does not occur or hardly occurs. .

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
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Abstract

La présente invention concerne un instrument médical ayant une couche de lubrification qui réduit l'association de brosses polymères tout en garantissant l'hémocompatibilité. Cet instrument médical comporte une couche de matériau de base et une couche lubrifiante comprenant des chaînes polymères qui ont une longueur inférieure à 10 μm présente sous la forme de brosses sur la couche de matériau de base, les chaînes polymères étant formées à partir d'un copolymère hémocompatible de monomères zwittérioniques et de monomères anioniques, et portant une charge négative pendant le contact avec des fluides corporels.
PCT/JP2016/059486 2015-03-30 2016-03-24 Instrument médical WO2016158700A1 (fr)

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Cited By (1)

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WO2019163764A1 (fr) * 2018-02-20 2019-08-29 テルモ株式会社 Instrument médical

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JPH07502053A (ja) * 1991-07-05 1995-03-02 バイオコンパテイブルズ・リミテツド ポリマーの表面コーティング
JP2002538897A (ja) * 1999-03-13 2002-11-19 バイオインターラクションズ リミテッド 生体適合性内部プロテーゼ
JP2014214226A (ja) * 2013-04-25 2014-11-17 住友ゴム工業株式会社 表面改質方法及び表面改質弾性体

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JPH07502053A (ja) * 1991-07-05 1995-03-02 バイオコンパテイブルズ・リミテツド ポリマーの表面コーティング
JP2002538897A (ja) * 1999-03-13 2002-11-19 バイオインターラクションズ リミテッド 生体適合性内部プロテーゼ
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KUO, WEI-HSUAN ET AL.: "Surface Modification with Poly(sulfobetaine methacrylate-co-acrylic acid) To Reduce Fibrinogen Adsorption, Platelet Adhesion, and Plasma Coagulation", BIOMACROMOLECULES, vol. 12, 2011, pages 4348 - 4356, XP055315720, ISSN: 1525-7797 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019163764A1 (fr) * 2018-02-20 2019-08-29 テルモ株式会社 Instrument médical
CN111565768A (zh) * 2018-02-20 2020-08-21 泰尔茂株式会社 医疗器械
JPWO2019163764A1 (ja) * 2018-02-20 2021-02-12 テルモ株式会社 医療用具
CN111565768B (zh) * 2018-02-20 2022-09-02 泰尔茂株式会社 医疗器械
JP7267988B2 (ja) 2018-02-20 2023-05-02 テルモ株式会社 医療用具
US11872326B2 (en) 2018-02-20 2024-01-16 Terumo Kabushiki Kaisha Medical instrument

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