WO2016093231A1 - Article pour culture cellulaire, et polymère biocompatible - Google Patents

Article pour culture cellulaire, et polymère biocompatible Download PDF

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Publication number
WO2016093231A1
WO2016093231A1 PCT/JP2015/084404 JP2015084404W WO2016093231A1 WO 2016093231 A1 WO2016093231 A1 WO 2016093231A1 JP 2015084404 W JP2015084404 W JP 2015084404W WO 2016093231 A1 WO2016093231 A1 WO 2016093231A1
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block
polymer
cell culture
acrylic
polyethylene oxide
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PCT/JP2015/084404
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English (en)
Japanese (ja)
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直人 荻原
岳 柏村
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東洋インキＳｃホールディングス株式会社
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Publication of WO2016093231A1 publication Critical patent/WO2016093231A1/fr

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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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • 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
    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M3/00—Tissue, human, animal or plant cell, or virus culture apparatus

Definitions

  • Embodiments of the present invention relate to an article for cell culture and a biocompatible polymer used for the article for cell culture.
  • the surface of the biocompatible polymer effectiveness such as a microphase-separated surface, a hydrophilic surface, and a surface structure similar to a cell membrane containing a zwitterionic molecule has been reported.
  • a polymer having 2-methacryloyloxyethyl phosphorylcholine (MPC) having a phospholipid polar group which is a phosphobetaine type as a component can be applied to a substrate surface to obtain a superhydrophilic surface. Since cells such as lymphocytes do not adhere at all, they are used as surface treatment agents for various medical products such as heart-lung machines, stents, contact lenses, and cell culture substrates.
  • MPC 2-methacryloyloxyethyl phosphorylcholine
  • 2-methoxyethyl acrylate has a simple chemical structure, it is a polymer material that exhibits biocompatibility similar to MPC polymer, so it is a product as a surface treatment agent for many medical devices such as heart-lung machines. It has become.
  • PEG polyethylene oxide moiety
  • PEO polyethylene oxide moiety
  • Patent Document 1 discloses the use of a PEG-containing polyester
  • Patent Document 2 discloses the use of a PEG-containing liquid crystalline polyester
  • Patent Document 3 discloses the use of PEG-containing polyamide
  • Patent Document 4 discloses the use of PEG-containing polyimide
  • Patent Document 5 discloses a PEG copolymer having an alkyl chain as a side chain.
  • Patent Document 6 an acrylic resin as disclosed in Patent Document 6 has been proposed.
  • Patent Document 7 discloses an acrylic resin in which a PEG chain is incorporated in the main chain, but there is no description regarding biocompatibility.
  • An embodiment of the present invention is an article for cell culture having a coating film on the surface, the coating film comprising an acrylic monomer having an average value of water / 1-octanol partition coefficient (LogP) of 0 or more and 2 or less.
  • the present invention relates to an article for cell culture comprising a block polymer having an acrylic polymer block to be formed and a polyethylene oxide block.
  • Another embodiment of the present invention is a method for producing an article for cell culture having a coating film on the surface, wherein the average value of water / 1-octanol partition coefficient (LogP) is 0 or more on the surface of the article for cell culture.
  • it is related with the manufacturing method of the article for cell cultures including the process of hardening.
  • Another embodiment of the present invention provides a cell having an acrylic polymer block formed from an acrylic monomer having an average water / 1-octanol partition coefficient (LogP) of 0 or more and 2 or less, and a polyethylene oxide block
  • LogP 1-octanol partition coefficient
  • the present invention relates to a biocompatible block polymer for culture articles.
  • Still another embodiment of the present invention relates to a polyethylene oxide having an acrylic monomer having an average value of water / 1-octanol partition coefficient (LogP) of 0 or more and 2 or less and having a moiety represented by the following general formula (II):
  • An acrylic polymer block and a polyethylene oxide block comprising a step of polymerizing using a polymer azo polymerization initiator having a block and a weight average molecular weight of 5,000 to 100,000 has the structure of the following formula (IA) It is related with the manufacturing method of the biocompatible block polymer for articles
  • the coating film (cell culture coating film) in the cell culture article of this embodiment is formed from a coating agent containing a block polymer mainly composed of polyethylene oxide and a specific acrylic polymer portion, It has low cytotoxicity and can promote the formation of cell aggregates. Moreover, the coating agent has good processability when applied.
  • FIG. 1 is a perspective view schematically showing an article for cell culture (microwell plate) according to an embodiment of the present invention.
  • FIG. 2 is a partial cross-sectional view schematically showing an enlarged part of a cell culture article (microwell plate) according to an embodiment of the present invention.
  • the cell culture article of this embodiment is characterized by having a cell culture coating film (hereinafter, also simply referred to as “coating film”) containing a specific block polymer on the surface that comes into contact with the cells. That is, this coating film is a block polymer having an acrylic polymer block formed from an acrylic monomer having an average value of water / 1-octanol partition coefficient (LogP) of 0 or more and 2 or less, and a polyethylene oxide block. Is included.
  • the coating film is a biocompatible coating film, and the block polymer is a biocompatible block polymer.
  • the cell culture member of this embodiment is referred to as “cell culture member comprising a cell culture member (3) and a cell culture coating film positioned on the surface of the cell culture member (3). Also referred to as “member (4)”.
  • the block polymer constituting the coating film is “block polymer (A)”
  • the acrylic polymer block also referred to as “acrylic polymer portion”
  • Part (A1)” and polyethylene oxide block also referred to as “polyethylene oxide part” are also referred to as “polyethylene oxide block (A2)” or “polyethylene oxide part (A2)", respectively.
  • polyethylene oxide may be abbreviated as “PEG” (or “PEO”).
  • PEG is considered to cause thrombus formation by promoting fibrin formation by inducing complement activation at the time of blood contact due to high motility and free hydroxyl group that interacts strongly with polar groups in the living body. It is not appropriate for use in medical materials where importance is placed on sex. Therefore, the present inventors reduced the number of hydroxyl groups present at the end of PEG and excessive mobility by incorporating PEG into the main chain of the block polymer, thereby improving the hydrophilicity and flexibility of PEG. We have developed a polymer with excellent biocompatibility that has improved the problem of thrombus formation while maintaining it.
  • the block polymer having an acrylic polymer portion (A1) and a polyethylene oxide portion (A2) using an acrylic monomer having an average water / 1-octanol partition coefficient (LogP) of 0 or more and 2 or less.
  • LogP 1-octanol partition coefficient
  • this block polymer has low cytotoxicity, and can promote the formation of cell aggregates (spheroids) of uniform size during cell culture.
  • the cell culture article of the present embodiment is an article (apparatus) that has a surface in contact with cells and is widely used in the field of cell culture, which is one of the tools for drug discovery research and regenerative medicine research.
  • Specific examples include a flask, a petri dish, a test tube, a plate, a microwell plate, a pipette tip, a pipette, a microtube, a tube, a centrifuge tube, and a plate seal.
  • materials for cell culture articles include polyester, polystyrene, silicone, polyamide, polyimide, polyolefin, polysulfone, polyethersulfone, polyethylene, polypropylene, polyacrylonitrile, polymethyl methacrylate, ethylene-vinyl alcohol copolymer, poly Various resins such as vinyl chloride, polyvinylidene chloride, polyvinylidene fluoride, polytetrafluoroethylene, halogenated polyolefin, polycarbonate, and polyvinylidene fluoride; polysaccharides such as cellulose and cellulose derivatives (eg, nitrocellulose, regenerated cellulose) Synthetic polymer; and the like.
  • metal materials such as stainless steel, titanium, and titanium alloys, ceramics such as hydroxyapatite, graphite, and titanium nitride can be used.
  • the form of the article for cell culture may be a three-dimensional molded body, a sheet form, or a thread form.
  • the sheet-like material include a film, a nonwoven fabric, and paper.
  • the film include various plastic films such as silicone, PET, cellulose ester, polyethylene, polypropylene, ethylene / vinyl acetate copolymer, polyvinyl chloride, and polyurethane.
  • silicone film or a nonwoven fabric from the viewpoint of oxygen permeability.
  • the block polymer (A) is an acrylic formed from a monomer having an average value of water / 1-octanol partition coefficient (cLogPow: hereinafter referred to as “LogP”) of 0 or more and 2 or less (hereinafter also referred to as “0 to 2”). It has a system polymer part (A1) and a polyethylene oxide part (A2). Each of the blocks (A1) and (A2) only needs to be included in one or more.
  • This block polymer is a biocompatible block polymer having biocompatibility, and has a low plasma protein adsorptivity and low platelet adhesion, and thus is preferably used for the above-mentioned cell culture article. It is a biocompatible block polymer for articles for medical use.
  • block polymer is synonymous with “block copolymer”.
  • the acrylic polymer portion is a polymer block of an acrylic monomer, and this block portion may be either a homopolymer of an acrylic monomer or a copolymer of an acrylic monomer. In the case of a copolymer, any form of alternating copolymerization, random copolymerization, or block copolymerization may be used.
  • Log P is one of the numerical values representing the properties of chemical substances, and is a constant value independent of the amount added.
  • concentration of each phase is shown in the common logarithm. .
  • LogP The measurement of LogP can be generally performed by a flask soaking method described in JIS Japanese Industrial Standard Z7260-107 (2000).
  • LogP can be estimated by a computational chemical method or an empirical method instead of actual measurement.
  • known methods can be used, but in this embodiment, LogP is obtained by using a program built in the system: ChemdrawPro 11.0 of CambridgeSoft.
  • the block polymer of this embodiment has an acrylic polymer portion formed from a monomer having an average value of LogP of 0 to 2 as compared with a conventional PEG polymer, it has solubility in water. Is controlled and fat solubility is improved. As a result, when applied to a cell culture article, coating on the cell culture article proceeds rapidly. Furthermore, a crosslinked coating film can also be formed by copolymerizing a monomer having a functional group capable of reacting with a crosslinking agent described later on the acrylic polymer portion in the block polymer. By forming the crosslinked coating film, peeling of the coating film from the substrate (cell culture article) and elution of the block polymer from the coating film can be suppressed. Examples of the functional group that the acrylic polymer portion may have include a carboxyl group, a hydroxyl group, an epoxy group, an amino group, and an isocyanate group.
  • the block polymer of the present embodiment has a low antigenicity due to a change in the surface aggregation structure induced by microphase separation because the PEG portion is incorporated in the main chain with respect to the conventional acrylic polymer. can do.
  • the block polymer of the present embodiment has a molecular weight and a side chain so that plasma protein adsorption, hemolysis, and cytotoxicity can be suppressed, and the effects of biological safety can be maximized. It is possible to optimize the functional group type and the side chain functional group introduction amount according to the purpose of use.
  • the hydrophilic PEG part (A2) and the hydrophobic acrylic polymer part (A1) constituting the block polymer (A) Due to the balance between the hydrophilic PEG part (A2) and the hydrophobic acrylic polymer part (A1) constituting the block polymer (A), plasma protein adsorptivity, hemolysis and cytotoxicity are suppressed. Can be controlled effectively.
  • the biocompatible block polymer of this embodiment is used as a coating material, the amount and physical properties of the acrylic polymer portion (A1) are controlled in order to improve the wettability to a substrate, that is, an article for cell culture. It is possible.
  • the acrylic polymer part (A1) suitable for the properties of the base material it is possible to sufficiently exhibit the respective effects of plasma protein adsorption, hemolysis, and cytotoxicity suppression. .
  • the block polymer (A) preferably contains a large amount of an acrylic polymer portion relative to the PEG portion, and the mass of the PEG portion (A2) / [total of the acrylic polymer portion (A1) and the PEG portion (A2)
  • the mass of the PEG moiety (A2) / [total mass of the acrylic polymer moiety (A1) and the PEG moiety (A2)] can be calculated from the mass of the monomer used in the synthesis. As will be described later, when a polymer azo polymerization initiator having a PEG moiety is used, strictly speaking, when calculating the mass of the PEG moiety (A2), only the weight of PEG in the azo polymerization initiator is calculated. However, in this embodiment, the weight of the polymer azo polymerization initiator having the PEG moiety (A2) is applied as it is.
  • the mass of the acrylic polymer portion (A1) is the total amount of acrylic monomers used for polymerization.
  • the mass of the PEG part (A2) / [acrylic polymer part (A1) and PEG The total mass of the portion (A2)] is 0.1.
  • the mass average molecular weight of the block polymer (A) is preferably from 3,000 to 1,000,000, more preferably from 5,000 to 500, from the viewpoint of handling and application to a cell culture article or the like. , 000.
  • the glass transition temperature of the block polymer (A) is preferably ⁇ 70 ° C. to 50 ° C., more preferably ⁇ 60 ° C. to 40 ° C.
  • the glass transition temperature of the block polymer (A) is preferably ⁇ 70 ° C. to 50 ° C., more preferably ⁇ 60 ° C. to 40 ° C.
  • the glass transition temperature is in the above range, so that it is easily impregnated.
  • the glass transition temperature can be adjusted by appropriately preparing the monomer constituting the acrylic polymer part (A1). For example, by increasing the ratio of polyalkoxyalkyl (meth) acrylates such as 2-methoxyethyl (meth) acrylate, flexibility unique to the side chain ether bond can be imparted, so that the glass transition temperature is ⁇ 50 ° C. Can be adjusted within a range close to.
  • an acrylic polymer block and a PEG block are bonded via a structure (bonding structure) of any of the following formulas (IA), (IB), or (IC).
  • the synthesis method will be described later, it is not particularly limited.
  • the block polymer preferably includes one or more of the following bond structures (IA) to (IC), but may include a bond structure other than these.
  • the acrylic polymer block and the PEG block are bonded by the above formula (IA).
  • the cell culturing member comprises a cell culturing member (3) and a cell culturing member (3) and a cell culturing coating film located on the surface of the cell culturing member (3) 4) wherein the coating film for cell culture is
  • An acrylic polymer portion (A1) formed from an acrylic monomer having an average value of water / 1-octanol partition coefficient (LogP) of 0 or more and 2 or less, and a polyethylene oxide portion (A2) are represented by the following formula (IA) ) In the form of a block polymer (A).
  • the acrylic monomer that is a raw material for the acrylic polymer portion (A1) of the block polymer (A) will be described.
  • the acrylic monomer means both an acrylic monomer and a methacrylic monomer.
  • Acrylic and methacrylic are sometimes collectively referred to as “(meth) acrylic”.
  • the average value of water / 1-octanol partition coefficient (LogP) of the acrylic monomer is preferably 0-2. .
  • the average value of LogP is a value obtained by averaging LogP of each monomer to be used by weight percent of each monomer. That is, when a monomer having LogP of 0 and a monomer having LogP of 2 is charged at a ratio of 50:50 wt%, the average value of LogP is 1.
  • the acrylic monomer used has a Log P in the range of 0 to 2, it can be used as a raw material for the homopolymer portion.
  • the log P of the acrylic monomer used is outside the range of 0 to 2, if the average value of Log P including other acrylic monomers is in the range of 0 to 2, it is used as a raw material for the copolymer portion. be able to.
  • Examples of the monomer having a water / 1-octanol partition coefficient (Log P) of 0 or more and 2 or less are divided into a monomer having no functional group that serves as a crosslinking point and a monomer that includes a functional group that serves as a crosslinking point. be able to.
  • the monomer having a functional group serving as a crosslinking point a carboxyl group-containing monomer, a hydroxyl group-containing monomer, an epoxy group-containing monomer, an amino group-containing monomer, an isocyanate group-containing monomer, and the like can be used.
  • a crosslinking agent By using these monomers and crosslinking the crosslinkable functional group with a crosslinking agent, peeling of the coating film and elution of the block polymer from the coating film can be suppressed.
  • a copolymer having a carboxyl group introduced therein can be crosslinked with an epoxy compound, an aziridine compound, a carbodiimide compound, a metal chelate compound, or an N-hydroxyethylacrylamide compound.
  • a copolymer into which a hydroxyl group has been introduced can be crosslinked with an isocyanate compound or a carbodiimide compound.
  • a copolymer having an amino group introduced therein can be crosslinked with an epoxy compound.
  • a copolymer having an isocyanate group introduced therein can be crosslinked with a hydroxyl group-containing compound.
  • the carboxyl group-containing monomer is not particularly limited as long as it has a carboxyl group in its structure.
  • alkylene oxide-added succinic acid (meth) acrylate having a carboxyl group at the terminal where oxide is repeatedly added examples include alkylene oxide-added succinic acid (meth) acrylate having a carboxyl group at the terminal where oxide is repeatedly added.
  • the hydroxyl group-containing monomer is not particularly limited as long as it has a hydroxyl group in its structure.
  • An alkylene oxide addition system (meth) acrylic acid ester having a hydroxyl group at the terminal to which an alkylene oxide such as an acrylic acid ester, ethylene oxide or propylene oxide is repeatedly added, and a glucose ring system (meth) acrylic acid ester are included.
  • the epoxy group-containing monomer is not particularly limited as long as it has an epoxy group in its structure, and examples thereof include glycidyl (meth) acrylate and 3,4-epoxycyclohexylmethyl (meth) acrylate. It is done.
  • the amino group-containing monomer is not particularly limited as long as it has an amino group in its structure.
  • monomethylaminopropyl acid and monoethylaminopropyl (meth) acrylate examples thereof include monomethylaminopropyl acid and monoethylaminopropyl (meth) acrylate.
  • each may be used alone or in combination of two or more.
  • different monomers having the same functional group may be combined, or multiple types of compounds having different functional groups may be combined.
  • the functional group which can react with the crosslinking agent mentioned later can be introduce
  • the amount of the monomer having a functional group that becomes a crosslinking point is preferably 10% by mass or less in a total of 100% by mass of all monomers. By using it at 10 mass% or less, when a crosslinking agent is used together, a coating film having an appropriate crosslinking density can be obtained.
  • the acrylic polymer portion (A1) has a water / 1-octanol distribution coefficient (LogP). More preferably, it is a homopolymer portion formed only of monomers having a 0 to 2 or a copolymer portion consisting of a plurality of types of monomers having a water / 1-octanol partition coefficient (LogP) of 0 to 2. That is, in a preferred embodiment, only one type of monomer having the partition coefficient LogP of 0 to 2 may be used, or a block polymer may be obtained using a plurality of types of monomers having the partition coefficient LogP of 0 to 2. May be.
  • examples of the monomer having a log P outside the range of 0 to 2 include acrylates having an alkyl group having 5 to 20 carbon atoms, and alkyl groups having 4 to 4 carbon atoms. 20 methacrylates and vinyl group-containing monomers such as styrene.
  • examples of the monomer having a functional group serving as a crosslinking point include carboxyl group-containing monomers such as maleic acid, 4-hydroxystyrene, and N-hydroxyethyl (meth).
  • examples include hydroxyl group-containing monomers such as acrylamide.
  • a polyfunctional monomer may be further copolymerized in order to partially introduce a crosslinked structure into the block polymer (A).
  • the crosslinking ratio increases as the amount of the polyfunctional monomer used increases, and the possibility of gelation during the reaction increases. Therefore, the amount of the polyfunctional monomer is preferably in the range of 0.01 to 10% by mass, more preferably 0.1 to 5% by mass, based on 100% by mass of the total monomers.
  • the polyfunctional monomer is not particularly limited as long as it has two or more ethylenically unsaturated groups in its structure.
  • the method for synthesizing the block polymer using the monomer is not particularly limited, and can be synthesized by a known method. For example, solution polymerization, bulk polymerization, emulsion polymerization, and dispersion (precipitation) polymerization are preferable, and solution polymerization and dispersion (precipitation) polymerization are more preferable.
  • the solvent used for the synthesis is not particularly limited, and hydrocarbon solvents, alcohol solvents, ketone solvents, ester solvents, and the like can be used, but those that can also be used as a solvent for a coating agent described later are used. You may make it prepare a coating agent, without isolating a polymer after a synthesis
  • An example of a method for synthesizing a block polymer having a bond structure represented by the above formula (IA) will be given.
  • an acrylic polymer is synthesized using 4,4′-azobis (4-cyanovaleric acid) (for example, a commercial product “V-501” manufactured by Wako Pure Chemical Industries, Ltd.) as a radical polymerization initiator
  • An acrylic resin having a carboxyl group is obtained.
  • a block polymer in which an acrylic polymer portion and a PEG portion are bonded by the above formula (IA) can be obtained by adding polyethylene glycol as a raw material constituting the PEG portion and carrying out an esterification reaction thereto. it can.
  • the block polymer having a bond structure represented by the above formula (IA) can be used as a radical polymerization initiator for synthesizing an acrylic polymer, with a PEG moiety (A2) and an azo moiety represented by the following formula (II). It can be preferably synthesized using a polymer azo polymerization initiator having a structural unit containing a group. In the formula, m and n are each independently an integer of 1 or more.
  • the polymer azo polymerization initiator has a structure in which a polymer segment and an azo group (—N ⁇ N—) are repeatedly bonded. In this embodiment, the polymer azo initiator includes a PEG block as the polymer segment. By using this, the block polymer (A) can be easily synthesized.
  • the mass average molecular weight of the block polymer (A) is appropriately changed by appropriately changing the ratio of the total number of moles of the acrylic monomer to the number of moles of the azo group contained in the initiator. Can be adjusted. For example, if the ratio of the total number of moles of acrylic monomers to the number of moles of azo groups contained in the polymer azo polymerization initiator is 200, 200-mer acrylic polymers are incorporated between PEG chains. Thus, a high cohesive force due to the entanglement of the polymer can be imparted.
  • the mass average molecular weight of the polymer azo polymerization initiator is preferably about 5,000 to 100,000, more preferably about 10,000 to 50,000.
  • the molecular weight of the PEG moiety of the initiator is preferably about 800 to 10,000, and more preferably about 1,000 to 8,000.
  • m is 15 to 200, more preferably m is 20 to 100, preferably n is 3 to 50, and more preferably n is 4 to 30.
  • the polymer azo polymerization initiator has a PEG moiety (A2), it is soluble in water, alcohol, and organic solvent, and the block polymer (A) is obtained by solution polymerization, emulsion polymerization, or dispersion polymerization. Can be synthesized.
  • the high molecular azo polymerization initiator includes: C (CH 3 ) CN— (CH 2 ) 2 —COO— (CH 2 CH 2 O) m —CO— (CH 2 ) 2 —C (CH 3 ) CN
  • the radicals shown below are generated, and the acrylic monomer is polymerized. And the main chain which the acrylic polymer part (A1) formed from an acrylic monomer and the part derived from the said radical couple
  • the PEG moiety (A2) is derived from a part of the radical.
  • Specific examples of the polymer azo polymerization initiator include a polymer azo initiator VPE0201 manufactured by Wako Pure Chemical Industries, Ltd. (the molecular weight of the (CH 2 CH 2 O) m portion of the above formula (II) is about 2000, and n is about 6) And the like.
  • the biocompatible block polymer (A) is a monomer having an average value of water / 1-octanol partition coefficient (LogP) of 0 or more and 2 or less represented by the general formula (II). And a block polymer obtained by polymerization using a high molecular azo polymerization initiator having a PEG moiety (A2) and having a mass average molecular weight of 5,000 to 100,000.
  • the method for producing the biocompatible block polymer (A) includes a monomer having a water / 1-octanol partition coefficient (LogP) of 0 or more and 2 or less represented by the general formula (II).
  • Acrylic polymer part (A1) and PEG part, characterized by being polymerized using a polymer azo polymerization initiator having a PEG part (A2) and a weight average molecular weight of 5,000 to 100,000 (A2) is the manufacturing method which has couple
  • the molecular weight and the terminal structure may be controlled by using a mercaptan such as lauryl mercaptan or n-dodecyl mercaptan, or a chain transfer agent such as ⁇ -methylstyrene dimer or limonene depending on the application.
  • a mercaptan such as lauryl mercaptan or n-dodecyl mercaptan
  • a chain transfer agent such as ⁇ -methylstyrene dimer or limonene depending on the application.
  • the block polymer (A) in which the acrylic polymer portion (A1) and the PEG portion (A2) are bonded via the structure of the above formula (IB) has a water / 1-octanol partition coefficient (LogP).
  • 2,2′-azobis [N- (2-hydroxyethyl) -2-methylpropanamide] for example, commercially available product “VA-086” from Wako Pure Chemical Industries, Ltd.
  • VA-086 commercially available product “VA-086” from Wako Pure Chemical Industries, Ltd.
  • polyethylene glycol is added as a raw material constituting the PEG portion, and a urethanization reaction is performed using a bifunctional isocyanate compound, thereby obtaining a block polymer in which an acrylic polymer portion and a PEG portion are bonded. it can.
  • Examples of the bifunctional isocyanate compound used in the urethanization reaction include 2,2′-diphenylmethane diisocyanate, 2,4′-diphenylmethane diisocyanate, 4,4′-diphenylmethane diisocyanate, 2,4-tolylene diisocyanate, 2, Examples include 6-tolylene diisocyanate, hexamethylene diisocyanate, and isophorone diisocyanate.
  • the block polymer (A) in which the acrylic polymer portion (A1) and the PEG portion (A2) are bonded via the structure of the above formula (IC) will be described.
  • the block polymer (A) in which an acrylic polymer block and a polyethylene oxide block are bonded by the structure of the above formula (IC) has an average value of water / 1-octanol partition coefficient (LogP).
  • 2,2′-azobis [N- (2-carboxyethyl) -2-methylpropionamidine] tetrahydrate as a radical polymerization initiator for example, “VA-057” commercially available from Wako Pure Chemical Industries, Ltd.) Etc.
  • a radical polymerization initiator for example, “VA-057” commercially available from Wako Pure Chemical Industries, Ltd.) Etc.
  • VA-057 commercially available from Wako Pure Chemical Industries, Ltd.
  • a block polymer in which an acrylic polymer portion and a PEG portion are bonded to each other can be obtained by adding polyethylene glycol as a raw material constituting the PEG portion and carrying out an esterification reaction.
  • the method for producing a cell culture article according to this embodiment forms a coating film by coating the surface of the cell culture article with the coating agent containing the block polymer (A). And a step of drying or curing the obtained coating film.
  • the coating agent preferably contains the block polymer (A) and a solvent for dissolving or dispersing the block polymer (A).
  • the solvent is not particularly limited, and examples thereof include water or organic solvents such as methanol, ethanol, acetone, and methyl ethyl ketone (hereinafter referred to as MEK), and two or more solvents that are miscible with each other may be used in combination. .
  • MEK methyl ethyl ketone
  • Content of the block polymer in a coating agent is not specifically limited, For example, it can adjust suitably so that it may become a viscosity according to the coating method, or it may become a desirable film thickness.
  • the content of the block copolymer is preferably about 0.5 to 10% by mass, and more preferably about 1 to 3% by mass.
  • the coating agent can contain a crosslinking agent.
  • the block polymer in the coating film can contain a crosslinked structure formed by the crosslinking agent.
  • a crosslinking agent For example, a metal chelate compound, a carbodiimide group containing compound, etc. other than what has at least 1 type of functional group chosen from an epoxy group, an isocyanate group, and an aziridinyl group are mentioned.
  • These crosslinking agents can be used for the purpose of increasing the elastic modulus and resistance of the coating film, or for adjusting the adhesive force.
  • the crosslinking agent having an epoxy group is not particularly limited as long as it has two or more epoxy groups in one molecule.
  • Examples of the crosslinking agent having a bifunctional epoxy group include ethylene glycol diglycidyl ether, polyethylene oxide diglycidyl ether, propylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, tetramethylene glycol diglycidyl ether, and polytetramethylene glycol diglycidyl.
  • Aliphatic epoxy compounds such as ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether, and polybutadiene diglycidyl ether; bisphenol A type epoxy resin, bisphenol F type epoxy resin, bisphenol S type epoxy resin, biphenol Epoxy resin, dihydroxybenzophenone diglycidyl ether, resorcinol diglycidyl Aromatic epoxy compounds such as ether, hydroquinone diglycidyl ether, dihydroxyanthracene type epoxy resin, bisphenol fluorenediglycidyl ether, and N, N-diglycidyl aniline; hydrogenated aromatic epoxy compounds as described above, hexahydrophthalic acid Examples include alicyclic epoxy compounds such as diglycidyl esters. Examples of the crosslinking agent having three or more epoxy groups include triglycidyl isocyanurate, trisphenol type epoxy compound, tetrakisphenol type epoxy compound, and
  • the crosslinking agent having an isocyanate group may be a compound having two or more isocyanate groups in one molecule, and is not particularly limited.
  • the bifunctional isocyanate compound include 2,2′-diphenylmethane diisocyanate, 2,4′-diphenylmethane diisocyanate, 4,4′-diphenylmethane diisocyanate, 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate, hexa
  • Examples include methylene diisocyanate and isophorone diisocyanate.
  • Examples of the trifunctional isocyanate compound include a trimethylolpropane adduct of diisocyanate described above, a burette reacted with water, and a trimer having an isocyanurate ring.
  • the isocyanate group in the crosslinking agent having an isocyanate group may be blocked or may not be blocked.
  • the blocked isocyanate crosslinking agent is not particularly limited as long as the isocyanate group in the isocyanate compound is blocked with ⁇ -caprolactam, MEK oxime, cyclohexanone oxime, pyrazole, phenol or the like. Absent.
  • the cross-linking agent (aziridine compound) having an aziridinyl group is not particularly limited as long as it is a compound having two or more aziridine groups in one molecule.
  • the aziridine compound include 2,2′-bishydroxymethylbutanol tris [3- (1-aziridinyl) propionate], 4,4-bis (ethyleneiminocarbonylamino) diphenylmethane, and the like.
  • Metal chelate compounds examples include organoaluminum compounds such as aluminum chelate compounds, aluminum alkoxide compounds, and aluminum acylate compounds; organotitanium compounds such as titanium chelate compounds, titanium alkoxide compounds, and titanium acylate compounds; zirconium chelate compounds; Examples include zirconium alkoxide compounds and organic zirconium compounds such as zirconium acylate compounds.
  • Carbodiimide group-containing compound Nisshinbo's Carbodilite series can be used, and water-based types such as V-02, V-04, and V-06, V-01, V-03, and V-05. , V-07, and V-09.
  • a ⁇ -hydroxyalkylamide group-containing compound can also be used as a crosslinking agent.
  • the ⁇ -hydroxyalkylamide group-containing compound is not particularly limited as long as it is a compound containing a ⁇ -hydroxyalkylamide group in the molecule. Examples thereof include various compounds including N, N, N ′, N′-tetrakis (hydroxyethyl) adipamide (PrimidXL-552 manufactured by Ems Chemie).
  • the crosslinking agent may be used alone or in combination.
  • the amount of the crosslinking agent used may be determined in consideration of the type and number of moles of the functional group contained in the block polymer (A), and is not particularly limited.
  • the block polymer (A) It is used in the range of 0.1 to 10 parts by mass with respect to 100 parts by mass.
  • the concern that the unreacted crosslinking agent is liberated can be eliminated.
  • particularly excellent performance is exhibited in each of the effects of blood compatibility, biological tissue compatibility, biological tissue adhesion suppression, and plasma protein adsorption, hemolysis, and cytotoxicity suppression. Is done.
  • the coating agent can contain other optional components used in general paints.
  • a colorant may be included to form a colored coating film, and one or more known components such as a surfactant, a thickener, an antioxidant, a pH adjuster, and a pigment are blended. Can do.
  • the coating method of the coating agent is not particularly limited, and various coating methods such as brush, dipping, roller, spraying, pouring, and coating machine can be applied to the molded body or the substrate.
  • the coating method for the film include dip coating, comma coating, gravure coating, curtain coating, die coating, lip coating, micro gravure coating, slot die coating, reverse coating, and kiss coating.
  • the coating film is preferably formed on all the cell contact surfaces of the cell culture article, but may be formed only on a part depending on the actual state of use.
  • the coating film is dried or cured. Drying and curing are preferably performed by heating, and the conditions (temperature and time) are appropriately set according to the characteristics of the block polymer (A) to be used and the characteristics of the crosslinking agent when a crosslinking agent is included. That's fine.
  • the temperature is preferably in the range of 100 to 200 ° C.
  • the thickness of the coating film is not particularly limited, but the thickness after drying is preferably 1 mm or less, preferably 0.05 ⁇ m to 20 ⁇ m, and more preferably 0.1 ⁇ m to 10 ⁇ m.
  • a molded body of cell culture parts may be formed by an injection molding process using a mold.
  • the block polymer (A) may be added to a thermoplastic resin such as polyethylene, polypropylene, polystyrene, polycarbonate, polyethylene terephthalate, or cyclic polyolefin resin and kneaded and molded.
  • the block polymer (A) may be extruded together and then molded into a desired shape by using a mold.
  • the sheet-like block polymer (A) is laminated via an adhesive layer, and then molded into a desired shape using a mold or the like. May be.
  • FIG. 1 is a perspective view schematically showing an example of the manufactured cell culture article.
  • the cell culture article (4) is a cell culture article (microwell plate) (3).
  • the cell contact surface, that is, the inner surface thereof has a coating film (10).
  • the block polymer (A) is suitable for use as a biocompatible material because it has low plasma protein adsorption and platelet adhesion, and is particularly cytotoxic. And the formation of cell aggregates can be promoted, and therefore it can be suitably used as a coating film for cell culture articles.
  • the coating agent containing the block polymer (A) is excellent in coatability, it is applied to the surface (cell contact surface) of the article for cell culture (3), and then dried and / or cured. An article (4) for cell culture with a coating film can be provided.
  • the block polymer (A) Since the block polymer (A) has low cytotoxicity and low plasma protein adsorptivity, a coating film for cell culture is formed on the surface of the article for cell culture (3) by using this, thereby conducting drug discovery research. And a cell culture article (4) which is one of research materials for regenerative medicine research.
  • the coating film for cell culture is not a medium for cells to be cultured, but supports and promotes rapid growth and proliferation of cells.
  • the block polymer (A) has low plasma protein adsorption and platelet adhesion, it can be suitably used as a coating film for various medical devices for body fluid contact.
  • the medical device for contacting body fluid is an article widely used in the medical field having a surface that comes into contact with body fluid, and includes various medical devices and medical devices that are preferably used for examination or treatment.
  • Examples of medical devices for contact with body fluids include all disposable medical devices used in combination with anticoagulants such as vacuum blood collection tubes, blood bags, extracorporeal circulation circuits; medical devices such as heart-lung machines and stents; Medical devices that come into contact with blood, such as artificial organs (for example, a hollow fiber or hollow fiber membrane of a dialysis machine (dialyzer) used in hemodialysis); a membrane or non-woven fabric used in immunochromatography, or a test chip that comes into contact with body fluids Etc .; Among these, a vacuum blood collection tube and a blood bag are suitable. It is only necessary that a coating film is formed on the surface of these tools that comes into contact with the body fluid.
  • the coating film can be provided around the electrode that contacts the body fluid.
  • the body fluid include blood, lymph fluid, tissue fluid, body fluid, digestive fluid, sweat, tears, runny nose, urine, semen, vaginal fluid, water for use, milk, etc., especially for medical devices that come into contact with blood.
  • the coating film of an embodiment can be used conveniently.
  • Examples of the material for the medical device for contacting body fluid include the same resins (including polysaccharides and semi-synthetic polymers), metal materials, ceramics, and the like as the material for the above-described cell culture article.
  • the form of the medical device for body fluid contact may be in the form of a sheet or thread in addition to the three-dimensional molded body, as in the case of the above-described cell culture article.
  • another embodiment of the present invention provides an acrylic polymer block formed from an acrylic monomer having an average value of water / 1-octanol partition coefficient (LogP) of 0 or more and 2 or less, and a polyethylene oxide block.
  • the present invention relates to the use of a block polymer having a medical device for contacting a body fluid or an article for cell culture.
  • the biocompatible polymer of this embodiment may be stably present at the interface that contacts blood, biological tissue, protein, and cells when applied to the substrate, molded body, or film. And there is very little risk that the biocompatible polymer will elute from the coating. As a result of holding the polymer at the interface, effects such as inhibition of protein and cell adsorption and inhibition of platelet adhesion and activation are exhibited.
  • the biocompatible polymer of the present embodiment can be used not only by being applied to a medical device or a cell culture article, but also the biocompatible polymer can be in the form of a sheet or thread.
  • a structural material such as a hollow fiber for dialysis or artificial heart lung can be obtained from the biocompatible polymer of the present embodiment.
  • the column temperature was 40 ° C., and the mass average molecular weight (Mw) was determined in terms of polystyrene.
  • Mw mass average molecular weight
  • a calibration curve, molecular weight, and peak area were calculated using software built in the manufacturer, and a mass average molecular weight was determined with a retention time of 15 to 30 minutes as an analysis target.
  • Tg glass transition temperature
  • DSC-1 manufactured by METTLER TOLEDO
  • the glass transition temperature was measured from ⁇ 80 to 200 ° C. under a temperature rising rate of 2 ° C./min, and the glass transition temperature was determined from the differential heat curve of the reversible component.
  • the mixture was aged for 1 hour, and then a solution prepared by dissolving 0.0125 part of 2,2′-azobis (isobutyric acid) dimethyl in 2 parts of MEK was added and aged for 1 hour. Thereafter, a solution obtained by dissolving 0.0125 part of 2,2′-azobis (isobutyric acid) dimethyl in 2 parts of MEK was further added and aged for 1 hour, and then cooled to room temperature to stop the reaction. Then, after removing MEK with a diaphragm pump, a block polymer solution having a solid content of 10% was obtained by adding ethanol and diluting. The resulting block polymer had an Mw of 281,000, a Tg of ⁇ 45 ° C., and a PEG ratio of 4.8%.
  • the mixture was aged for 5 hours, and then cooled to stop the reaction. After removing methanol with a diaphragm pump, ion exchange water was added and diluted to obtain a block polymer aqueous dispersion having a solid content of 10%.
  • the obtained block polymer had a Tg of ⁇ 50 ° C. and a PEG ratio of 15.0%. Mw was not measured because the resin was insoluble in THF.
  • a block polymer solution having a solid content of 10% was obtained by adding ethanol and diluting when the internal temperature decreased to 100 ° C.
  • the obtained block polymer had Mw of 102,000, Tg of ⁇ 42 ° C., and the proportion of PEG was 25.5%.
  • the mixture was aged for 1 hour, and then a solution prepared by dissolving 0.0125 part of 2,2′-azobis (isobutyric acid) dimethyl in 2 parts of MEK was added and aged for 1 hour. Thereafter, a solution obtained by dissolving 0.0125 part of 2,2′-azobis (isobutyric acid) dimethyl in 2 parts of MEK was further added and aged for 1 hour, and then cooled to room temperature to stop the reaction. Then, after removing MEK with a diaphragm pump, ethanol was added and diluted to obtain an acrylic resin solution having a solid content of 10%.
  • the obtained acrylic resin had an Mw of 62,000, a Tg of ⁇ 18 ° C., and a PEG ratio of 0%.
  • Example 11 and 12 Ion exchange water was added to each of the block polymers described in Production Examples 7 and 8 so that the solid content was 5% to obtain a coating agent. The evaluation was made in the same manner as in Example 1.
  • Examples 13 and 14 With the solid content ratio shown in Table 2, the block polymer described in Production Example 8 and a crosslinking agent were blended, and the solid content was adjusted to 5% with ion-exchanged water to obtain a coating agent. The evaluation was made in the same manner as in Example 1.
  • Examples 2 to 5 [Comparative Examples 6 to 7]
  • the block polymer described in Production Example 1 or the comparative polymer described in Comparative Production Example 5 and a crosslinking agent were blended at the solid content ratio shown in Table 2, and the solid content was adjusted to 5% with ethanol. A coating agent was obtained. The evaluation was made in the same manner as in Example 1.
  • Solubility in water 100 ⁇ [(z ⁇ x) / (y ⁇ x)] ⁇ 100 (X: mass of shallow metal container, y: mass before treatment with ion exchange water, z: mass after treatment with ion exchange water) a: Solubility in water ⁇ 5% b: 5% ⁇ solubility in water ⁇ 50% c: 50% ⁇ solubility in water
  • Spheroid formation is a well plate prepared by the same method as in (2) above, and the cell culture state after 5 days is photographed with a transmission optical microscope 40 times to observe the cell morphology.
  • c Among 96 wells, there were wells that did not form spheroids.
  • the absorbance at 576 nm was measured for the supernatant after centrifuging the test solution after incubation at about 750 ⁇ g for 5 minutes. Absorbance was measured in the same manner using 10 mL of physiological saline as a negative control and 10 mL of distilled water as a positive control, each with 0.2 mL of rabbit defibrinated blood. The hemolysis rate was calculated by the following formula, and hemolysis (hemolysis toxicity) was evaluated.
  • Hemolysis rate (%) (absorbance of specimen ⁇ absorbance of negative control) / (absorbance of positive control ⁇ absorbance of negative control) ⁇ 100 a: hemolysis rate ⁇ 2 b: 2 ⁇ hemolysis rate ⁇ 20 c: 20 ⁇ hemolysis rate
  • the block polymer (A) having the acrylic polymer part (A1) and the PEG part (A2) used in Examples 1 to 15 is a comparative example.
  • the comparative polymer having the PEG portion used in 2 to 7 has an acrylic polymer portion composed of a monomer having an average value of LogP of 0 to 2 in the main chain, so that it is soluble in water. Therefore, physical properties satisfying all of cytotoxicity, protein adsorption and hemolysis were obtained.
  • Comparative Example 1 even if the main chain has an acrylic polymer portion composed of monomers having an average value of LogP of 0 to 2, if the PEG portion (A2) is not present, Adsorption is significant.
  • the block polymer (A) of the example was excellent in spheroid-forming property, and could form one spheroid having almost the same size.
  • the biocompatible polymer of this embodiment can be used for blood, a part that comes into contact with living tissue, and a part that comes in contact with cells and proteins. Moreover, it can be applied not only to the application to the molded body but also in the form of a film or a sheet. Furthermore, it can be applied and developed to structural materials such as hollow fibers for dialysis or cardiopulmonary bypass. .

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Abstract

Cette invention concerne un article pour culture cellulaire portant un film de revêtement formé sur sa surface. Le film de revêtement comprend un polymère séquencé comprenant : une séquence polymère acrylique formée à partir d'un monomère acrylique ayant un coefficient moyen de distribution eau/1-octanol (LogP) dans la plage de 0 à 2, bornes incluses; et une séquence oxyde de polyéthylène.
PCT/JP2015/084404 2014-12-12 2015-12-08 Article pour culture cellulaire, et polymère biocompatible WO2016093231A1 (fr)

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CN113166580A (zh) * 2019-05-15 2021-07-23 积水化学工业株式会社 由细胞培养用支架材料形成的树脂膜、细胞培养用载体和细胞培养用容器

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JP6578919B2 (ja) * 2015-12-07 2019-09-25 東洋インキＳｃホールディングス株式会社 細胞培養用部材
JP6569690B2 (ja) * 2017-01-23 2019-09-04 東洋インキＳｃホールディングス株式会社 細胞培養用物品
JP6952340B2 (ja) * 2017-01-30 2021-10-20 東京都公立大学法人 表面処理剤
JP6874447B2 (ja) * 2017-03-17 2021-05-19 東洋インキＳｃホールディングス株式会社 生化学分析用ブロッキング剤。
JP2019183021A (ja) * 2018-04-12 2019-10-24 東洋インキＳｃホールディングス株式会社 バイオフィルム形成抑制コート剤及びバイオフィルム形成抑制積層体
WO2020130033A1 (fr) * 2018-12-20 2020-06-25 Terumo Kabushiki Kaisha Substrat de culture cellulaire
JP7110973B2 (ja) * 2018-12-26 2022-08-02 東洋インキＳｃホールディングス株式会社 メディカルデバイス用基材、メディカルデバイス積層体、及びメディカルデバイス用基材の製造方法

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CN113166580A (zh) * 2019-05-15 2021-07-23 积水化学工业株式会社 由细胞培养用支架材料形成的树脂膜、细胞培养用载体和细胞培养用容器

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