WO2010143646A1 - Structure de fibre - Google Patents

Structure de fibre Download PDF

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Publication number
WO2010143646A1
WO2010143646A1 PCT/JP2010/059745 JP2010059745W WO2010143646A1 WO 2010143646 A1 WO2010143646 A1 WO 2010143646A1 JP 2010059745 W JP2010059745 W JP 2010059745W WO 2010143646 A1 WO2010143646 A1 WO 2010143646A1
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Prior art keywords
fiber structure
acid
group
amino acid
structure according
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PCT/JP2010/059745
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English (en)
Japanese (ja)
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WO2010143646A8 (fr
Inventor
浩作 大川
賢 大橋
学 北澤
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味の素株式会社
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Publication of WO2010143646A8 publication Critical patent/WO2010143646A8/fr

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    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F6/00—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof
    • D01F6/58—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products
    • D01F6/68—Monocomponent artificial filaments or the like of synthetic polymers; Manufacture thereof from homopolycondensation products from polyaminoacids or polypeptides
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning

Definitions

  • the present invention relates to a specific fiber structure, a manufacturing method thereof, and a medical material containing the obtained fiber structure.
  • a fiber structure such as a sponge body, a honeycomb body, or a nonwoven fabric in which fibers are layered is known, and as a fiber among these, a conventionally known fiber diameter is used.
  • a fiber diameter is used as a fiber among these.
  • microfibers micrometer order fibers
  • nanofibers thinner nanometer order fibers (nanofibers) are being developed and put to practical use. Since nanofibers have a remarkably large specific surface area compared to conventional microfibers, they are advantageous in that a more porous fiber structure can be produced.
  • nanofibers have an average fiber diameter of several tens to several hundreds of nanometers, and have a fiber diameter comparable to that of an extracellular matrix in vivo, so that they can be easily decomposed in vivo. For this reason, a fiber structure in which nanofibers are integrated is being studied for application as a medical material that is desired to disappear quickly after tissue and cells are repaired and regenerated in vivo.
  • Nanofibers can be formed by a method called electrospinning (electrospinning). After the polymer compound is dissolved in a solvent to form a solution, the polymer compound solution is discharged while applying a high voltage to form nanofibers, which are then accumulated on the substrate (collector). This is a method for obtaining a fiber structure in which fibers are accumulated.
  • Patent Document 1 discloses a method of electrospinning polysaccharides such as chitosan, chondroitin sulfate, and pectin.
  • Patent Document 2 discloses a method of electrospinning after dissolving chitosan in water to which a solubilizing agent such as an organic acid is added. Although the obtained fiber diameter is controlled, since water is volatilized in the stage of forming the fiber, the discharge speed cannot be increased sufficiently.
  • Patent Document 3 discloses a method in which chitosan or cellulose is dissolved in an organic acid solvent, a volatile organic solvent is mixed therein, and then electrospinning is performed. However, since the dissolution of chitosan or cellulose in the solution is not complete, a satisfactory fiber structure has not been obtained.
  • Non-Patent Document 1 discloses that when poly- ⁇ -benzyl-L-glutamic acid is dissolved in an organic solvent having low polarity, the fiber diameter is controlled by suppressing the interaction between molecules by reducing the concentration thereof. A method for obtaining a fibrous structure is disclosed. However, if the solution concentration is too low, fiber formation becomes difficult, and the fiber diameter has not been reduced to a satisfactory fineness.
  • Patent Document 4 discloses an adhesion preventing material composed of a fiber structure of biodegradable and absorbable polymer, and specifically uses polylactic acid.
  • polylactic acid lacks flexibility, its compatibility with soft tissues is poor, and it has also been suggested that it causes an inflammatory response to the living body, and a sufficiently safe biodegradable material has not yet been obtained.
  • the problem to be solved by the present invention is a medical material that is safe for the living body, has high biocompatibility, and has a high effect of suppressing adhesion of cells and tissues (the medical material is particularly useful as a scaffold material). ) To provide a fiber structure that can be used.
  • the present invention is as follows.
  • [1] A fiber structure containing a polyamino acid as a main component and having an average fiber diameter of 50 nm or more and less than 500 nm.
  • [2] The fiber structure according to [1], wherein the amino acid is one or more selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine and proline.
  • [4] The fiber structure according to any one of [1] to [3], wherein the polyamino acid is composed of one amino acid.
  • the protective group is one or more selected from the group consisting of a methyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, and a trifluoroacetyl group, 12].
  • a method for producing a fiber structure comprising the following steps; Step 1) Step of dissolving a polyamino acid in a solvent to form a solution, Step 2) A step of continuously discharging the solution put in the syringe from a nozzle attached to the tip of the syringe, Step 3) A step of applying a high voltage between the nozzle and the collector with a high voltage generator in the discharge, Step 4) changing the discharged solution into a fiber shape between the nozzle and the collector, Step 5) A step of collecting the fiber on a collector.
  • the polyamino acid solution concentration in step 1 is 1 to 20% by weight
  • the polyamino acid solution discharge speed in step 2 is 1 to 20 ml / hour, and is applied between the nozzle and collector in step 3.
  • the solvent in Step 1 is trifluoroacetic acid, acetic acid, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1,3,3,3-hexafluoro-2-propanol, 2,2,2- [14] or [15], wherein the production method is one or more selected from the group consisting of trifluoroethanol, N, N-dimethylformamide and water.
  • a medical material comprising the fiber structure according to any one of [1] to [13].
  • the medical material according to [17] which is an adhesion preventing material.
  • the fiber structure of the present invention has a nanometer-order fiber diameter that is uniformly controlled and is therefore excellent in degradability in vivo, and the material used as the main component is composed of amino acids widely present in the living body. Therefore, it is safe for the living body.
  • the fiber structure of the present invention is excellent in flexibility in addition to biodegradability because the fibers are not bound to each other, and is highly compatible with living bodies. Furthermore, since the fiber structure of the present invention has low adhesion to cells derived from living tissue, it can be used as a medical material having a high effect of suppressing adhesion of cells and tissues.
  • the medical material is particularly used as a scaffold material. Useful.
  • FIG. 3 is a photograph of a surface of a fiber structure composed of poly-L-alanine obtained by the operation of Production Example 1 taken with a scanning electron microscope (SEM).
  • the polyamino acid used in the present invention is composed of an amino acid or a derivative thereof, and is usually prepared using a neutral amino acid, an acidic amino acid, a basic amino acid, an aromatic amino acid, etc.
  • Nonpolar neutral amino acids and polar neutral amino acids are used.
  • the polyamino acid one composed of one or more amino acids can be used, but in the present invention, a polyamino acid composed of one or two amino acids is preferable.
  • the amino acid residue used contains an asymmetric carbon atom, either an optically active substance or a racemic substance may be used.
  • the amino acid or derivative thereof is not particularly limited as long as it forms a polymer that can constitute the fiber structure of the present invention.
  • Amino acid residues with a small number of carbon atoms in the amino acid side chain are likely to form a dense molecular packing structure, and can be expected to give fibers with a small fiber diameter, so that glycine, sarcosine, alanine, N-methylalanine, ⁇ -alanine, ⁇ -aminobutyric acid, valine, norvaline, leucine, isoleucine, norleucine, cysteine, glutamine, asparagine, aspartic acid, aspartic acid- ⁇ -methyl ester, lysine, proline, hydroxyproline, serine, O-acetyl-serine Threonine is preferable, and glycine, alanine, valine, leucine, isoleucine, proline, glutamine, and lysine are more preferable. These may be used alone or in combination of two or more.
  • phenylglycine Phenylalanine, aspartic acid- ⁇ -benzyl ester, N ⁇ -benzyloxycarbonyl-lysine, N ⁇ -benzyloxycarbonyl-ornithine, histidine, N (Im) -methyl-histidine, O-benzyl-serine, O-benzyl-threonine, tryptophan N (In) -methyl-tryptophan, tyrosine, O-benzyl-tyrosine, O-methyl-tyrosine, O-acetyl-tyrosine, phenylalanine, aspartic acid- ⁇ -benzyl ester, N ⁇ -benzyloxycarbonyl-lysine, Tryptophan, Chiro Syn and O-acetyl-ty
  • amino acids exemplified above can be used as appropriate, but when the polyamino acid contained in the fiber structure is composed of one kind of amino acid, such amino acids are glycine, alanine, valine, leucine. , Isoleucine, phenylalanine, proline, aspartic acid- ⁇ -benzyl ester, N ⁇ -benzyloxycarbonyl-lysine, tryptophan, O-acetyl-tyrosine are preferred, glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline are more preferred, Alanine, valine and leucine are even more preferred, and alanine is most preferred.
  • the polyamino acid when the polyamino acid is composed of two kinds of amino acids, it is a combination of an acidic amino acid or basic amino acid and a nonpolar neutral amino acid, or a combination of an acidic amino acid or basic amino acid and an aromatic amino acid. Is preferred.
  • glutamic acid is preferable as the acidic amino acid
  • lysine is preferable as the basic amino acid.
  • a nonpolar neutral amino acid alanine, valine, leucine, and isoleucine are preferable, and as an aromatic amino acid, phenylalanine is preferable.
  • the polyamino acid used in the present invention may have a structure in which a salt is coordinated to a part or all of the polar groups in the structure.
  • the ratio of the salt to the polar group is such that, when a fiber structure composed of a polyamino acid is produced by an electrospinning method, for example, the solubility of the polyamino acid in a solvent and / or the average fiber diameter of the resulting fiber structure is It is determined from the viewpoint of being optimal.
  • the salt examples include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium and calcium; inorganic bases such as ammonia; monoethanolamine, diethanolamine, triethanolamine, 2-amino-2-methyl-1 Organic amine salts such as propanol, 2-amino-2-methyl-1,3-propanediol, lysine, ornithine, arginine; inorganic acid salts such as hydrochloride, sulfate, carbonate, phosphate; acetate, Examples thereof include organic acid salts such as tartrate, citrate, p-toluenesulfonate, glycolate, malate, lactate, fatty acid salt, acidic amino acid salt and pyroglutamate. These may be used alone or in combination of two or more.
  • the method for preparing the polyamino acid used in the present invention is not particularly limited as long as it is a method in which an amino acid or a derivative thereof is prepared into a polymerized structure.
  • N-carboxy- ⁇ -amino acid anhydride or N-carboxy- An example is a method in which an ⁇ -amino acid derivative anhydride is dissolved or suspended in an organic solvent or water, and a polymerization initiator is added thereto if necessary.
  • organic solvent examples include acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, tetrahydrofuran, diethyl ether, diisopropyl ether, petroleum ether, 1,4-dioxane, benzene, toluene, xylene, hexane, cyclohexane, ethyl acetate, butyl acetate.
  • Trifluoroacetic acid Trifluoroacetic acid, acetic acid, formic acid, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, trichloroethylene, trifluoroethane, 1,1,1,3,3,3-hexafluoro-2-propanol, 2,2,2-trifluoroethanol, hexafluoroacetone, methanol, ethanol, 1-propanol, 2-propanol, formamide, N, N-dimethylformamide, N, N-dimethyl Acetamide, N- methylpyrrolidone, dimethyl sulfoxide, pyridine, acetonitrile, may be mentioned trimethylamine, triethylamine, tributylamine and the like. These may be used alone or in combination of two or more.
  • polymerization initiator examples include ethylenediamine, propylenediamine, hexamethylenediamine, 1,4-cyclohexanediamine, 1,2-cyclohexanediamine, o-phenylenediamine, m-phenylenediamine, p-phenylenediamine, and toluene-2.
  • Primary amines such as methylamine, ethylamine and 1-propylamine; Alcohol amines such as methanolamine, ethanolamine and diethanolamine; Dimethylamine and diethylamine Secondary amines such as dipropylamine; primary tertiary diamines such as N, N-dimethylethylenediamine and N, N-dimethyl-1,3-propanediamine; trimethylamine and triethylamine Tertiary amines such as tributylamine; amino group-containing polymers such as polyether diamine and polyester diamine; primary alcohols such as methanol and ethanol; secondary alcohols such as isopropanol; ethylene glycol, propylene glycol, 1,4-butanediol, hexa Examples include glycols such as methylene glycol; hydroxyl group-containing polymers such as polyether diol and polyester diol; thiols. These may be used alone or in combination of two or more.
  • N-carboxy- ⁇ -amino acids (including derivatives) anhydrides corresponding to various amino acids are mixed appropriately and dissolved or suspended in an organic solvent.
  • a polymerization initiator can be added to this to form a copolymer.
  • the mixing ratio of amino acids is, for example, 95: 5 to 5:95, preferably 90:10 to 10:90, more preferably 70:30 to 30:70 in terms of molar ratio for two types of amino acids. it can.
  • the mixing ratio can be calculated based on the molar ratio of the N-carboxy- ⁇ -amino acid anhydride to be used.
  • N-carboxy- ⁇ -aliphatic amino acid anhydride which is different from any of the N-carboxy- ⁇ -aliphatic amino acid anhydride and the N-carboxy- ⁇ -aromatic amino acid anhydride, By mixing and / or polymerizing with an N-carboxy- ⁇ -aromatic amino acid anhydride to form a copolymer, the solubility in an organic solvent can be increased.
  • N-carboxy- ⁇ -amino acid anhydrides include aspartic acid- ⁇ -methyl ester, aspartic acid- ⁇ -benzyl ester, glutamic acid- ⁇ -methyl ester, N ⁇ -benzyloxycarbonyl-lysine, N ⁇ -benzyloxycarbonyl- N-carboxy- ⁇ -amino acid (including derivatives) anhydrides corresponding to ornithine, O-benzyl-serine or O-benzyl-threonine are preferred, corresponding to glutamic acid- ⁇ -methyl ester or N ⁇ -benzyloxycarbonyl-lysine N-carboxy- ⁇ -amino acid anhydride is more preferred. These may be used alone or in combination of two or more.
  • a method for preparing the polyamino acid used in the present invention includes ⁇ -polyglutamic acid using a microorganism. Examples thereof include a method for preparing ( ⁇ -PGA) and a method for preparing ⁇ -polylysine using a microorganism.
  • a protecting group can be bonded to the side chain of an amino acid residue serving as a structural unit.
  • the protecting group refers to an atomic group used for the purpose of protecting a highly reactive characteristic group in the side chain of an amino acid so as not to react with other compounds.
  • the protecting group may be bonded during the preparation of the polyamino acid as described above, or may be bonded after the preparation. Further, the protecting group may be bonded to the side chains of all amino acid residues constituting the polyamino acid, or may be bonded only to the side chains of some amino acid residues.
  • it is preferable that a protective group is bonded to the polyamino acid because the adhesion suppressing effect of living tissue or cells in the fiber structure can be enhanced.
  • the protecting group is not particularly limited as long as it can convert a highly reactive characteristic group in the side chain of an amino acid residue into an inactive functional group.
  • amino-protecting groups include substituted benzyloxycarbonyl groups such as benzyloxycarbonyl group and p-methoxybenzyloxycarbonyl group; tert-butoxycarbonyl group, p-biphenylisopropyloxycarbonyl group, 9-fluorenylmethyl Urethane-type protecting groups such as oxycarbonyl group; acyl-type protecting groups such as formyl group, phthaloyl group, trifluoroacetyl group, p-toluenesulfonyl group, o-nitrophenylsulfenyl group; trityl group, benzyl group, 2-benzoyl Examples thereof include alkyl-type protecting groups such as -1-methylvinyl group; and arylidene-type protecting groups such as 2-hydroxyaryliden
  • Examples of the protecting group for the carboxyl group include substituted benzyl esters such as methyl group, ethyl group, benzyl group, tert-butyl group, and p-nitrobenzyl group; phenacyl group; trichloroethyl group; cyclohexyl group and the like.
  • Protected in the form of Examples of protecting groups for guanidino groups include nitro groups, p-toluenesulfonyl groups, benzyloxycarbonyl groups, and the like.
  • Examples of the protecting group for the imidazolyl group include a benzyl group, a benzyloxycarbonyl group, a p-toluenesulfonyl group, a trityl group, a diphenylmethyl group, a dinitrofluorobenzene group, and a tert-butoxycarbonyl group.
  • Examples of the protecting group for the carbamide group include a xanthyl group, a bis-2,4-dimethoxybenzyl group, and a 4,4'-dimethoxybenzhydryl group.
  • Examples of the protective group for the hydroxy group include ether-type protective groups such as a benzyl group, a substituted benzyl group, and a tert-butyl group; and acyl-type protective groups such as an acetyl group, a trifluoroacetyl group, and a benzyloxycarbonyl group.
  • Examples of the protecting group for the mercapto group include substituted benzyl groups such as a benzyl group and a p-methoxybenzyl group; a trityl group; a benzhydryl group; an acetamidomethyl group; and a carbomethoxysulfenyl group.
  • Examples of the protecting group for the indolyl group include a formyl group.
  • a methyl group, a benzyloxycarbonyl group, a 9-fluorenylmethylcarbonyl group, and a trifluoroacetyl group are preferable.
  • the polyamino acid used in the present invention can be further chemically modified after being prepared as described above.
  • poly- ⁇ -methyl-glutamic acid it can be converted to a polyamino acid having a structure in which part or all of the methyl ester group is saponified by allowing alkali to act on this, or reactive.
  • a polyamino acid having a structure in which a nucleophilic functional group such as an amino compound is reacted to convert part or all of the methyl ester group into an amide group can be obtained.
  • polyglutamic acid a polyamino acid having a structure in which an alkylamine is reacted with this to convert a part or all of the carboxyl group into an alkylamide group can be obtained.
  • the weight average molecular weight of the polyamino acid in the present invention is not particularly limited, but is usually 1,000 or more. In the present invention, it is preferably 10,000 or more, more preferably 100,000 or more, from the viewpoint of increasing the degree of entanglement between polymers in the solution and improving the productivity of the nanofiber.
  • the polyamino acid used in the present invention may have a structure in which a compound other than an amino acid or a derivative thereof is polymerized in addition to the amino acid or a derivative thereof.
  • a compound other than an amino acid or a derivative thereof is polymerized in addition to the amino acid or a derivative thereof.
  • N-carboxy- ⁇ -amino acid anhydride and urethane examples thereof include a copolymer obtained by polymerizing a prepolymer.
  • the fiber structure of the present invention containing the polyamino acid is composed of nanofibers having an average fiber diameter (diameter) of 5 nm or more and less than 1,500 nm, preferably 10 nm or more and less than 1,000 nm, more preferably 50 nm or more and less than 500 nm.
  • the average fiber diameter of the fiber structure can be measured using a method known to those skilled in the art. Specifically, from a photograph of the surface of the fiber structure taken at random with a scanning electron microscope, 10 positions are arbitrarily selected, the fiber diameter is measured, and the average value is obtained as the average fiber diameter. be able to. For the photograph of the fiber structure, a photograph taken at a magnification of 500 to 200,000 times can be used. In the present invention, more specifically, the average fiber diameter of the fiber structure can be measured according to Examples described later.
  • the fiber structure refers to a structure formed of one or a plurality of fibers, and examples of the form thereof include a filament, a stable, a filament yarn, a spun yarn, a woven fabric, a knitted fabric, Nonwoven fabric, paper, sheet-like material, tube, mesh, thread-like material and the like can be mentioned.
  • a preferred form of the fiber structure in the present invention is a nonwoven fabric.
  • the fiber structure of the present invention is manufactured by electrospinning using an electrospinning apparatus.
  • the electrospinning apparatus include a nanofiber electrospinning unit (NEU) manufactured by Kato Tech Co., Ltd., which includes a syringe, a nozzle (needle), a syringe pump, a high voltage generator, and a collector.
  • NEU nanofiber electrospinning unit
  • the manufacturing method of the fiber structure containing the polyamino acid of the present invention comprises the following steps. Step 1) Step of dissolving a polyamino acid in a solvent to form a solution, Step 2) A step of continuously discharging the solution put in the syringe from a nozzle attached to the tip of the syringe, Step 3) A step of applying a high voltage between the nozzle and the collector with a high voltage generator in the discharge, Step 4) changing the discharged solution into a fiber shape between the nozzle and the collector, Step 5) A step of collecting the fiber on a collector.
  • the concentration of the polyamino acid in the solution in Step 1 is appropriately set depending on the type of polyamino acid to be used, the type of solvent for dissolving the polyamino acid, etc., but is generally 0.1 to 60% by weight, preferably 1 It can be made -45 wt%, more preferably 1-20 wt%. If the polyamino acid concentration is higher than the above range, the viscosity of the solution tends to increase and the spinnability tends to be poor. If the concentration is lower than the above range, it takes a long time to produce the fiber structure. When two or more polyamino acids are used, a solution in which various polyamino acids are appropriately mixed and dissolved may be prepared.
  • the mixing ratio of the polyamino acids can be, for example, 95: 5 to 5:95, preferably 90:10 to 10:90 as a weight ratio in the case of two kinds of polyamino acids.
  • the solvent for dissolving the polyamino acid used in the present invention in Step 1 is not particularly limited as long as it is a solvent that dissolves the polyamino acid and is easily removed by evaporation or the like at the stage of forming the fiber.
  • trifluoroacetic acid, acetic acid, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, trichloroethylene, trifluoroethane, 1,1,1,1 3,3,3-hexafluoro-2-propanol, 2,2,2-trifluoroethanol, N, N-dimethylformamide, water are preferred, trifluoroacetic acid, acetic acid, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1,3,3,3-hexafluoro-2-propanol, 2,2,2-trifluoroethanol, N, N-dimethylformamide, and water are more preferable. These may be used alone or in combination of two or more.
  • solubilizing agents include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, inorganic bases such as ammonia, monoethanolamine, diethanolamine, and triethanolamine.
  • Organic amines such as 2-amino-2-methyl-1-propanol, 2-amino-2-methyl-1,3-propanediol, lysine, ornithine and arginine, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, tartaric acid And organic acids such as citric acid, p-toluenesulfonic acid, glycolic acid, malic acid, lactic acid, fatty acid, acidic amino acid, pyroglutamic acid. These may be used alone or in combination of two or more.
  • the rate at which the polyamino acid solution is discharged in step 2 is appropriately set according to the viscosity of the solution to be discharged, the scale of the electrospinning apparatus, etc., but is generally 0.1 to 60 ml / hour, preferably 1 to 20 ml / hour. It can be.
  • the discharge speed is made faster than the above range, the discharged solution tends to reach the collector in the form of droplets and cause fusion of fibers and the like.
  • the discharge speed is slower than the above range, it takes a long time to produce the fiber structure.
  • the number of nozzles from which the solution is discharged may be one or two or more. Therefore, the discharge of the solution may be performed at one or two or more locations.
  • the discharge of the nozzle in the step 2 is blocked by the adhesion of the fibers formed in the step 4, the precipitation of solids from the discharged solution in the step 2, etc., it is appropriate. By discharging while removing these deposits, precipitates, etc., by the method, it is possible to prevent the discharge of the solution from being hindered.
  • the voltage applied between the nozzle and the collector in step 3 is appropriately set depending on the viscosity of the solution to be discharged, the scale of the electrospinning apparatus, etc., but is generally 5 to 50 kV, preferably 11 to 45 kV. it can.
  • the voltage can be 11 kV or more, preferably 13 kV or more, more preferably 15 kV or more, further preferably 17 kV or more, particularly preferably 19 kV or more, and the voltage can be 45 kV or less, preferably 40 kV or less, More preferably, it can be 35 kV or less, more preferably 30 kV or less, and particularly preferably 25 kV or less. If the applied voltage is higher than the above range, there is a risk of discharge between the nozzle and the collector. On the other hand, when the applied voltage is lower than the above range, the fiber diameter is not reduced and the spinnability tends to be poor.
  • the interval between the nozzle and the collector in step 4 is appropriately set depending on the scale of the electrospinning apparatus, but can be generally 5 to 50 cm, preferably 10 to 40 cm.
  • the interval can be 10 cm or more, preferably 12 cm or more, more preferably 14 cm or more, still more preferably 16 cm or more, and particularly preferably 18 cm or more, and the interval can be 40 cm or less, preferably 35 cm or less, More preferably, it is 30 cm or less, More preferably, it is 25 cm or less, Most preferably, it can be 20 cm or less.
  • the interval is longer than the above range, the formed fiber does not reach the collector and adheres to the portion between the nozzle and the collector. If the interval is shorter than the above range, the discharged solution tends to reach the collector in the form of droplets and cause fusion of fibers.
  • the fiber structure formed on the collector in step 5 can be subjected to operations such as neutralization and drying as necessary.
  • an organic acid is used as a solvent or a solubilizing agent for dissolving the polyamino acid used in the present invention
  • an alkaline aqueous solution immersed in an alkaline aqueous solution such as sodium hydroxide, potassium hydroxide, or sodium bicarbonate is used.
  • the organic acid remaining in the fiber structure can be neutralized by a method such as spraying or leaving it in ammonia saturated vapor.
  • the polyamino acid used in the present invention is dissolved in a solvent having low volatility, it remains in the fiber structure by a method such as heating, blowing dry air, or leaving it under vacuum or reduced pressure. Solvent to be removed.
  • the thickness of the fiber structure formed on the collector in step 5 is arbitrary depending on the application. For example, it is about 1 to 30 ⁇ m when used as a scaffold for tissue or cells, and 50 when used as artificial skin. About 100 ⁇ m.
  • the temperature and humidity at which the electrospinning in Steps 1 to 5 is performed are appropriately set depending on the type of the solvent that dissolves the polyamino acid used in the present invention, but generally 5 to 30 ° C. and relative humidity 10 to 80. % Adjusted.
  • the nozzle used in steps 1 to 5 may have any shape and size as long as it can discharge a solution in step 2 and can serve as an electrode when a high voltage is applied in step 3.
  • an injection needle can be mentioned.
  • the diameter of the injection needle used for electrospinning including the steps 1 to 5 is generally 0.01 to 2.0 mm, preferably 0.1 to 1.5 mm.
  • the diameter of the injection needle is larger than the above range, the discharged solution tends to reach the collector in the form of droplets.
  • the diameter is smaller than the above range, the amount of discharge per hour is small, so that it takes a lot of time to manufacture the fiber structure.
  • the collector used in steps 1 to 5 may have any shape and size as long as it comprises a metal having good conductivity such as copper, aluminum, or stainless steel and can serve as an electrode when a high voltage is applied in step 3. .
  • a membrane-like, tubular, or hollow fiber structure can be obtained by using a collector as a cylindrical rotating body.
  • a material that does not impair the function of the collector electrode such as aluminum foil, spunbond nonwoven fabric, gauze, micro-nanofiber sheet, etc., is laid on the collector.
  • the fiber structure of the present invention may be formed on these.
  • the fiber structure of the present invention is characterized by containing a polyamino acid as a main component.
  • the main component means a main component contained as a raw material of the fiber structure, and the content thereof is usually 80% by weight or more, preferably 90% by weight with respect to the total weight of the fiber structure. As mentioned above, More preferably, it is 95 weight% or more.
  • the fiber structure containing the polyamino acid of the present invention can further contain a polymer compound other than the polyamino acid in addition to the polyamino acid.
  • a polymer compound include polyvinyl chloride, polyacrylonitrile, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, polybutylene succinate, polyethylene succinate, polystyrene, polycarbonate, Polyhexamethylene carbonate, polyarylate, polyvinyl isocyanate, polybutyl isocyanate, polymethyl methacrylate, polyethyl methacrylate, polypropyl methacrylate, polybutyl methacrylate, polymethyl acrylate, polyethyl acrylate, polybutyl acrylate, polyethylene terephthalate, polytrimethylene terephthalate , Polyethylene naphthalate, polyparaphenylene terephthalamide, polyparaphenylene terephthal Luamide-3
  • polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer are preferable from the viewpoint of maintaining or improving the strength or / and shape of the fiber structure containing a polyamino acid.
  • Polycaprolactone carboxymethylcellulose, oxidized regenerated cellulose, hyaluronic acid, sodium hyaluronate, polyvinyl alcohol, collagen, atelocollagen, gelatin, laminin, fibronectin, sericin, chitin, chitosan, cellulose, more preferably polylactic acid Polyglycolic acid, polylactic acid-glycolic acid copolymer, carboxymethyl cellulose, oxidized regenerated cellulose, sodium hyaluronate, polyvinyl alcohol, collagen, and gelatin can be used. These may be used alone or in combination of two or more.
  • the ratio of the polymer compound to the polyamino acid is appropriately set depending on the function of the fiber structure to be obtained, and can be generally 1 to 80% by weight, preferably 5 to 50% by weight.
  • the ratio with respect to the polyamino acid is higher than the upper limit range, the function of the fiber structure based on the polyamino acid tends to be impaired, and when the ratio with respect to the polyamino acid is lower than the lower limit range, the effect of containing the polymer compound is obtained. It becomes difficult to be recognized.
  • the polymer compound may be electrospun in a state of being mixed with a polyamino acid to form a fiber structure, or may be combined after electrospinning separately from the polyamino acid to form a fiber structure.
  • the fiber structure of the present invention can be widely used for medical materials. Specifically, it can be used for medical materials such as scaffolds for regenerative medicine, surgical sutures, wound dressings, artificial blood vessels, and drug-supporting substrates.
  • medical materials such as scaffolds for regenerative medicine, surgical sutures, wound dressings, artificial blood vessels, and drug-supporting substrates.
  • the fiber structure of the present invention is used in various applications such as a cell-supporting substrate in a cell culture apparatus, a supporting substrate such as a living organism in a bioreactor, various filters, a catalyst-supporting substrate, a clothing substrate, and a cosmetic substrate. Can also be used.
  • the scaffold or scaffold is a biological tissue culture substrate in the field of regenerative medicine, and refers to a molded body that functions as a biological material for the purpose of defect, repair, regeneration, and treatment of biological tissue,
  • a three-dimensional cell culture substrate, a cell aggregate (spheroid) formation substrate, an adhesion prevention material, and the like are included in this.
  • the fiber structure of the present invention has a fiber diameter comparable to that of an extracellular matrix in vivo, it can be easily decomposed in vivo. Therefore, the fibrous structure is suitable for a scaffold material that is desired to disappear quickly after a living tissue or cell is repaired and regenerated in a living body.
  • the fiber structure of the present invention is particularly suitable as a scaffold material that is required to have an effect of suppressing the adhesion of cells and living tissues, and is useful as, for example, a cell aggregate formation base (spheroid) formation material or an adhesion prevention material.
  • a cell aggregate formation base spheroid
  • it can be used for wound dressings, hemostatic materials, etc. due to such effects, as well as artificial organs (artificial blood vessels, artificial lungs, artificial kidneys, artificial hearts) that need to avoid thrombus formation, or medical devices (catheters, It is also useful as a surface covering material for cannulas, artificial dialyzers, dialysis membranes, injection needles, syringes, blood storage containers, shunts, blood circuits).
  • the fiber structure of the present invention is formed into a shape and structure corresponding to a part of a living tissue, and the defect, repair, regeneration, etc. of living tissue such as skin, blood vessel, nerve, bone, cartilage, esophagus, valve, other organs, It can be used directly or indirectly for treatment.
  • various agents such as an anti-inflammatory agent, an antiallergic agent, an antitumor agent, vitamins, can also be contained in a fiber structure or its fiber.
  • Fiber structure of poly-L-alanine / ⁇ -methyl-L-glutamic acid copolymer (9/1) N-carboxy-L-alanine anhydride and N-carboxy- ⁇ -methyl-
  • a poly-L-alanine / ⁇ -methyl-L-glutamic acid copolymer was prepared by adding L-glutamic anhydride in a molar ratio of 9: 1 to a total of 1.4% by weight and stirring for 2 to 3 days. (9/1) was obtained.
  • Fiber structures of various polyamino acid copolymers In the same manner as in Production Example 8, two types of N-carboxy-L-amino acid anhydrides were added to the polymerization solvent, and polymerization was started as necessary. The agent was added and stirred for 2 to 3 days to obtain various polyamino acid copolymers. Each was carried out under the materials and conditions shown in Table 1. Various polyamino acid copolymers were made into solutions using the solvents shown in Table 1, and fiber structures composed of various polyamino acid copolymers were obtained from these solutions by the same method as in Production Example 1.
  • Poly- ⁇ -methyl / (polyethylene glycol) -L-glutamic acid copolymer fiber structure Polyethylene glycol methyl ether (Sigma-Aldrich) was added to poly- ⁇ -methyl-L-glutamic acid obtained in Production Example 23. , Average molecular weight 350) and p-toluenesulfonic acid monohydrate are added in an amount of 2 equivalents and 0.2 equivalents relative to the number of moles of N-carboxy- ⁇ -methyl-L-glutamic anhydride and reacted at 75 ° C. A - ⁇ -methyl / (polyethylene glycol) -L-glutamic acid copolymer was obtained.
  • the weight average molecular weight measured by the method described in Measurement 1 was 1.4 ⁇ 10 6 . This was dissolved in 2,2,2-trifluoroethanol to obtain a 10% by weight poly- ⁇ -methyl / (polyethylene glycol) -L-glutamic acid copolymer solution. From this solution, a fiber structure comprising a poly- ⁇ -methyl / (polyethylene glycol) -L-glutamic acid copolymer was obtained in the same manner as in Production Example 1.
  • Poly-L-alanine / L-lysine copolymer fiber structure Poly-L-alanine / ⁇ -benzyloxycarbonyl-L-lysine copolymer (9/1) obtained in Production Example 16 Trifluoroacetic acid (Tokyo Chemical Industry Co., Ltd.) and thioanisole (Tokyo Chemical Industry Co., Ltd.) were added at 270 equivalents and 5 equivalents, respectively, with respect to the number of moles of N-carboxy- ⁇ -benzyloxycarbonyl-L-lysine anhydride. To obtain a poly-L-alanine / L-lysine copolymer.
  • Fiber structure of poly-L-alanine-poly-L-lysine mixture Poly-L-alanine and poly-L-lysine hydrobromide obtained in Production Example 1 (Sigma Aldrich, weight average molecular weight) 300,000) in a ratio of 9: 1 by weight in a dichloromethane-trifluoroacetic acid-N, N-dimethylformamide mixed solvent (50: 50: 12.5 (v / v)).
  • An L-alanine-L-lysine mixture solution was obtained. From this solution, a fiber structure comprising a poly-L-alanine-L-lysine mixture was obtained in the same manner as in Production Example 1.
  • Fiber structure of poly-L-alanine-poly- ⁇ -benzyloxycarbonyl-L-lysine mixture (6/4) Poly-L-alanine obtained in Production Example 1 and obtained in Production Example 5 Poly- ⁇ -benzyloxycarbonyl-L-lysine was dissolved in a dichloromethane-trifluoroacetic acid mixed solvent (50:50 (v / v)) at a molar ratio of 6: 4 in terms of monomer, and 5.3 wt. % Poly-L-alanine-poly- ⁇ -benzyloxycarbonyl-L-lysine mixture (6/4) solution. From this solution, a fiber structure comprising a poly-L-alanine-poly- ⁇ -benzyloxycarbonyl-L-lysine mixture (6/4) was obtained in the same manner as in Production Example 1.
  • the obtained photograph was placed horizontally and divided into 10 equal area sections by dividing the horizontal direction and the vertical direction into 5 equal parts and 2 equal parts, respectively.
  • the fibers in focus at the center of each section or the fibers closest to the center were selected and their diameters were measured, and the average value of them was obtained to obtain the average fiber diameter.
  • the evaluation criteria are as follows. A: Average fiber diameter is less than 150 nm B: Average fiber diameter is 150 nm or more and less than 500 nm ⁇ : Average fiber diameter is 500 nm or more and less than 1 ⁇ m X: Average fiber diameter is 1 ⁇ m or more
  • Human bone marrow mesenchymal stem cells (Lonza, Human Mesenchymal Stem Cell) or mesenchymal stem cell medium (Lonza, MSCGM), or inactivated fetal bovine serum (Invitrogen, GIBCO FBS) and penicillin-streptomycin (Sigma- Aldrich Co.) laden Dulbecco's modified Eagle's medium (Invitrogen Corp., was suspended in GIBCO DMEM), was seeded by 20,000Cell / well, 5% CO 2/37 °C conditions incubator (Thermo Scientific, Inc., former incubator ) For 3 days.
  • GIBCO FBS inactivated fetal bovine serum
  • penicillin-streptomycin Sigma- Aldrich Co.
  • the evaluation criteria are as follows. A: The amount of intracellular DNA is less than 15% of that of the comparison control. ⁇ : The amount of intracellular DNA is 15% or more and less than 30% of that of the comparison control. Less than 50% ⁇ : The amount of intracellular DNA is 50% or more of that of the control
  • the evaluation criteria are as follows. A: Absorbance is less than 15% relative to that of the comparison control. O: Absorbance is not less than 15% and less than 30% relative to that of the comparison control. More than 50% of that of the control
  • Evaluations 5 and 6 are all general-purpose methods for measuring the number of cells from the viewpoint of ease of operation, measurement accuracy, and the like.
  • poly-L-valine was produced in the same manner as in Production Example 22 except that the voltage applied to the poly-L-valine / L-phenylalanine (1/1) solution shown in Production Example 22 was changed to 10 kV. An attempt was made to produce a fiber structure composed of / L-phenylalanine (1/1). Further, the voltage applied to the poly-L-valine / L-phenylalanine (1/1) solution shown in Production Example 22 was changed to 19 to 20 kV, and the distance between the nozzle containing the solution and the collector was changed to 5 cm. Except for this, an attempt was made to produce a fiber structure composed of poly-L-valine / L-phenylalanine (1/1) by the same method as in Production Example 22.
  • the surface of the obtained fiber structure was visually evaluated. Specifically, the number of visible granular materials was measured.
  • the evaluation criteria for the granular materials are as follows, and the results are shown in Table 4. ⁇ : The number of granular materials is 0 per 1 cm square ⁇ : The number of granular materials is 1 or more and 9 or less per 1 cm square ⁇ : The number of granular materials is 10 or more and 49 or less per 1 cm square ⁇ : Number of granular materials 50 or more per 1 cm square-: Impossible to measure
  • fibers that can be used for medical materials (particularly scaffold materials) that are safe for the living body, high in biocompatibility, and highly effective in suppressing adhesion of cells and tissues, It is significant that we can now provide medical materials or scaffolds.

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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
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  • Spinning Methods And Devices For Manufacturing Artificial Fibers (AREA)
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Abstract

L'invention porte sur une structure de fibre qui est sûre pour les organismes vivants, a une biocompatibilité élevée, et peut être utilisée dans un matériau médical (en particulier un matériau d'échafaudage), ayant un effet élevé d'inhibition de l'adhésion de cellules ou de tissus. La structure de fibre comprend un acide polyamique spécifique en tant que composant principal.
PCT/JP2010/059745 2009-06-09 2010-06-09 Structure de fibre WO2010143646A1 (fr)

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WO2012077691A1 (fr) * 2010-12-06 2012-06-14 味の素株式会社 Équipement médical et son procédé de fabrication
JP2017507001A (ja) * 2014-01-30 2017-03-16 ポリ−メッド インコーポレイテッド 時間依存性の合成生物学的バリア材料
WO2019089944A1 (fr) * 2017-11-03 2019-05-09 Kci Usa, Inc. Pansement enrichi en nutriments
WO2020116552A1 (fr) * 2018-12-07 2020-06-11 国立大学法人 東京大学 Acide polyaminé, copolymère bloc et composition de particules de polymères
US11891727B2 (en) 2014-01-30 2024-02-06 Poly-Med, Inc. Thermally and dimensionally stabilized electrospun compositions and methods of making same

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JP2004321484A (ja) * 2003-04-24 2004-11-18 Sangaku Renkei Kiko Kyushu:Kk 医療用高分子ナノ・マイクロファイバー
JP2006283241A (ja) * 2005-04-01 2006-10-19 Kanai Hiroaki ナノ繊維ウェブの製造方法、ナノ繊維ウェブまたは積層体、コレクタ電極並びにナノ繊維ウェブ製造装置
JP2008502376A (ja) * 2004-05-25 2008-01-31 バイオインターアクションズ リミテッド 吸収性生物適合性材料
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JP2004321484A (ja) * 2003-04-24 2004-11-18 Sangaku Renkei Kiko Kyushu:Kk 医療用高分子ナノ・マイクロファイバー
JP2008502376A (ja) * 2004-05-25 2008-01-31 バイオインターアクションズ リミテッド 吸収性生物適合性材料
JP2006283241A (ja) * 2005-04-01 2006-10-19 Kanai Hiroaki ナノ繊維ウェブの製造方法、ナノ繊維ウェブまたは積層体、コレクタ電極並びにナノ繊維ウェブ製造装置
JP2009091682A (ja) * 2007-10-05 2009-04-30 Idemitsu Technofine Co Ltd 繊維架橋体および繊維架橋体の製造方法

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012077691A1 (fr) * 2010-12-06 2012-06-14 味の素株式会社 Équipement médical et son procédé de fabrication
US9192624B2 (en) 2010-12-06 2015-11-24 Ajinomoto Co., Inc. Medical material and method for manufacturing same
JP2017507001A (ja) * 2014-01-30 2017-03-16 ポリ−メッド インコーポレイテッド 時間依存性の合成生物学的バリア材料
US11739452B2 (en) 2014-01-30 2023-08-29 Poly-Med, Inc. Time-dependent synthetic biological barrier material
US11891727B2 (en) 2014-01-30 2024-02-06 Poly-Med, Inc. Thermally and dimensionally stabilized electrospun compositions and methods of making same
WO2019089944A1 (fr) * 2017-11-03 2019-05-09 Kci Usa, Inc. Pansement enrichi en nutriments
US11877910B2 (en) 2017-11-03 2024-01-23 Systagenix Wound Management, Limited Nutrient-enriched dressing
WO2020116552A1 (fr) * 2018-12-07 2020-06-11 国立大学法人 東京大学 Acide polyaminé, copolymère bloc et composition de particules de polymères

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