WO2015020192A1 - 骨再生材料キット、ペースト状骨再生材料、骨再生材料及び骨接合材 - Google Patents
骨再生材料キット、ペースト状骨再生材料、骨再生材料及び骨接合材 Download PDFInfo
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- WO2015020192A1 WO2015020192A1 PCT/JP2014/071007 JP2014071007W WO2015020192A1 WO 2015020192 A1 WO2015020192 A1 WO 2015020192A1 JP 2014071007 W JP2014071007 W JP 2014071007W WO 2015020192 A1 WO2015020192 A1 WO 2015020192A1
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- bone
- fine particles
- bone regeneration
- regeneration material
- salt
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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
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/104—Gelatin
-
- 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
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/222—Gelatin
-
- 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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
- A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
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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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- the present invention includes microparticles made of bioabsorbable polymers, which can secure bone mechanical strength by compensating for bone defects or injuries in the short term and can regenerate the patient's own bone in the long term.
- the present invention relates to a bone regeneration material kit, a paste-like bone regeneration material, a bone regeneration material, and an osteosynthesis material that can be promoted and can exhibit a non-disintegration property that does not disintegrate even after contact with moisture such as blood or body fluid after filling.
- Artificial bones are used to treat bone defects or damaged parts.
- conventional artificial bones dense and porous artificial bones made of calcium phosphate have been known.
- Such an artificial bone needs to be shaped in accordance with the condition of the bone to be treated.
- it has been difficult to cut or cut the artificial bone at the surgical site, and there is a problem that it is difficult to use.
- paste-like bone filling materials in which calcium phosphate granules are suspended in an aqueous medium have been proposed (for example, Patent Documents 1 to 3).
- the paste-like bone filling material can be filled into a bone defect or damage using an injector or the like.
- the paste-like bone filling material hardens after filling and is fixed to a bone defect or damaged part. If a paste-like bone filling material is used, even a complicated defect or damage can be easily treated.
- Patent Document 4 discloses a bone regeneration material kit composed of fine particles made of a calcium phosphate compound, fine particles made of a bioabsorbable polymer, and an aqueous medium.
- a fine hole made of a bioabsorbable polymer is bioabsorbed to form a continuous hole in the filling part. Osteoblasts can enter and proliferate. That is, the bone regeneration material kit described in Patent Document 4 can serve as a scaffold material for osteoblast proliferation, as well as supplementing the bone defect.
- a paste-like bone regeneration material that mixes the fine particles of the calcium phosphate compound, the fine particles of the bioabsorbable polymer, and the aqueous medium constituting the kit is prepared at the surgical site.
- the paste-like bone regeneration material thus filled is filled into a bone defect or damaged part with an injector or the like, and then closed to complete the surgical procedure.
- the part filled with paste-like bone regeneration material is a part with a lot of water such as blood and body fluid, and once filled, the paste-like bone regeneration material absorbs moisture and collapses, thereby compensating the bone defect part. There was a problem that it may become impossible to fulfill.
- the present invention includes fine particles composed of a bioabsorbable polymer, and in the short term, can compensate for a bone defect or damaged portion to ensure the mechanical strength of the bone.
- Bone regeneration material kit, paste-like bone regeneration material, bone regeneration material, and bone joint that can promote bone regeneration and can exhibit non-disintegration that does not disintegrate after contact with water such as blood or body fluid after filling The purpose is to provide materials.
- the present invention is a bone regeneration material kit including fine particles made of calcium salt adsorbed on the surface of inositol phosphate or a salt thereof, fine particles made of a bioabsorbable polymer, and an aqueous medium.
- the present invention is described in detail below.
- the bone regeneration material kit of the present invention comprises fine particles comprising calcium salt adsorbed on its surface with inositol phosphate or a salt thereof (hereinafter also referred to as “inositol phosphate-adsorbed calcium salt fine particles”) and a bioabsorbable polymer. It consists of fine particles and an aqueous medium.
- the inositol phosphate or the salt thereof adsorbed on the surface of the fine particles of calcium salt adsorbed on the surface is formed into a paste when mixed with an aqueous medium and hardens in the body to supplement the mechanical strength of the bone.
- the phosphoric acid or salt thereof interacts with the fine particles comprising the bioabsorbable polymer, so that the paste-like bone regeneration material obtained can exhibit sufficient non-disintegrating properties in a relatively short period of time. Can be granted.
- the inositol phosphate-adsorbed calcium salt fine particles can be prepared, for example, by immersing and pulverizing the fine particles comprising the calcium salt in an aqueous solution in which the inositol phosphate or a salt thereof is dissolved.
- the inositol phosphate or salt thereof is considered to be chemically adsorbed on the surface of fine particles made of calcium salt.
- Examples of the calcium salt include calcium phosphate and calcium carbonate. These calcium salts may be used alone or in combination of two or more. Of these, calcium phosphate is preferred. Examples of the calcium phosphate include hydroxyapatite, ⁇ -tricalcium phosphate, ⁇ -tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, amorphous calcium phosphate, etc. Is mentioned. These calcium phosphates may be used alone or in combination of two or more. Of these, hydroxyapatite, ⁇ -tricalcium phosphate or ⁇ -tricalcium phosphate are preferable, and hydroxyapatite is more preferable.
- the preferable lower limit of the specific surface area of the fine particles comprising the calcium salt is 0.1 m 2 / g, and the preferable upper limit is 120 m 2 / g. When the specific surface area is within this range, a sufficient amount of the inositol phosphate or salt thereof can be adsorbed on the surface of the fine particles comprising the calcium salt.
- a more preferable lower limit of the specific surface area is 20 m 2 / g, and a still more preferable lower limit is 40 m 2 / g.
- the specific surface area of the fine particles comprising the calcium salt can be measured by the BET method using, for example, a micromeritics automatic specific surface area measuring apparatus Flowsorb III2305 (manufactured by Shimadzu Corporation).
- inositol phosphate examples include inositol monophosphate, inositol diphosphate, inositol triphosphate, inositol tetraphosphate, inositol pentaphosphate, phytic acid (inositol hexaphosphate), and the like.
- salt of inositol phosphate examples include alkali metal salts and alkaline earth metal salts, and more specifically, sodium salts, potassium salts, magnesium salts, calcium salts, barium salts, and the like. These inositol phosphates or salts thereof may be used alone or in combination of two or more.
- the phytic acid sodium salt includes, for example, several kinds having different crystal water contents such as sodium phytate salt 38 hydrate, sodium phytate salt 47 hydrate, sodium phytate salt 12 hydrate, and the like. Although known, any of them can be preferably used.
- the concentration of the aqueous solution in which the inositol phosphate or salt thereof is dissolved is not particularly limited, but is preferably 1000 to 11000 ppm, more preferably 5000 to 11000 ppm, and still more preferably 7000 to 10000 ppm.
- an alkaline aqueous solution is added to the aqueous solution in advance, and it is preferably adjusted to pH 6 to 11, more preferably pH 6 to 8.
- the aqueous alkali solution used for adjusting the pH is not particularly limited, and examples thereof include an aqueous sodium hydroxide solution and an aqueous potassium hydroxide solution.
- the method for immersing and pulverizing the fine particles of the calcium salt in an aqueous solution in which the inositol phosphate or a salt thereof is dissolved is not particularly limited.
- the method is preferably 20 to 60 ° C., more preferably 20 to 40 ° C.
- Fine particles comprising the calcium salt are added to an aqueous solution in which the inositol phosphoric acid or a salt thereof has been kept warm, and the mixture is preferably stirred for 0.5 to 24 hours, more preferably 0.5 to 10 hours using a pulverizer.
- the method of shaking is mentioned.
- the molar ratio of the inositol phosphate or its salt to the calcium salt is preferably 0.001 to 0.1, and more preferably 0.01 to 0.08.
- the fine particles comprising the calcium salt are mixed with the aqueous solution in which the inositol phosphoric acid or a salt thereof is dissolved to adsorb the inositol phosphoric acid or the salt on the surface of the fine particles, and then the obtained fine particles are separated and dried. By doing so, the inositol phosphate-adsorbing calcium salt fine particles can be obtained.
- the preferable lower limit of the average particle diameter of the inositol phosphate-adsorbed calcium salt fine particles is 0.5 ⁇ m, and the preferable upper limit is 100 ⁇ m. If the inositol phosphate-adsorbed calcium salt fine particles have an average particle size of less than 0.5 ⁇ m, the viscosity may increase when the mixture is mixed with the aqueous medium to form a paste, making injection difficult. If the average particle diameter exceeds 100 ⁇ m, the strength of the cured product may be low and the mechanical strength of the bone may not be sufficiently compensated.
- a more preferable upper limit of the average particle size of the inositol phosphate-adsorbed calcium salt fine particles is 50 ⁇ m.
- the bone regeneration material kit of the present invention further includes fine particles made of a calcium phosphate compound (hereinafter also simply referred to as “fine particles made of a calcium phosphate compound”) in which inositol phosphate or a salt thereof is not adsorbed on the surface. preferable.
- the mechanical strength of the cured product can be further improved by using the inositol phosphate-adsorbing calcium salt fine particles together with fine particles comprising a calcium phosphate compound.
- cured material can also be changed by adjusting the time at the time of preparing the fine particle which consists of a calcium-phosphate type compound by grind
- the calcium phosphate compound is not particularly limited.
- These calcium phosphate compounds may be used alone or in combination of two or more. Of these, ⁇ -tricalcium phosphate or ⁇ -tricalcium phosphate is preferable, and ⁇ -tricalcium phosphate is more preferable.
- the preferable lower limit of the average particle diameter of the fine particles comprising the calcium phosphate compound is 0.5 ⁇ m, and the preferable upper limit is 100 ⁇ m.
- the average particle size of the fine particles comprising the calcium phosphate compound is less than 0.5 ⁇ m, the viscosity may increase when the mixture is mixed with the aqueous medium to form a paste, making injection difficult. If the average particle diameter exceeds 100 ⁇ m, the strength of the cured product may be low and the mechanical strength of the bone may not be sufficiently compensated.
- a more preferable upper limit of the average particle size of the fine particles comprising the calcium phosphate compound is 50 ⁇ m.
- the fine particles composed of the bioabsorbable polymer have a role of being gradually absorbed in the living body after the treatment and generating continuous pores into which osteoblasts can enter the filling portion.
- the bioabsorbable polymer include natural polymers such as proteins such as gelatin, collagen, hyaluronic acid, albumin and fibrin, and polysaccharides such as starch, alginic acid, chitin, pectic acid and derivatives thereof; Polyglycolic acid, lactic acid-glycolic acid copolymer, glycolic acid- ⁇ -caprolactone copolymer, lactic acid- ⁇ -caprolactone copolymer, polymalic acid, poly- ⁇ -cyanoacrylate, poly- ⁇ -hydroxy acid, polytri Methylene oxalate, polytetramethylene oxalate, polyorthoester, polyorthocarbonate, polyethylene carbonate, poly- ⁇ -benzyl-L-glutamate, poly-L-glutamic acid, poly- ⁇
- bioabsorbable polymers may be used alone or in combination of two or more.
- the fine particles made of the bioabsorbable polymer are made of gelatin, collagen or hyaluronic acid
- the gelatin, collagen or hyaluronic acid is preferably crosslinked.
- cross-linked gelatin is preferred.
- fine particles made of crosslinked gelatin are used as the fine particles made of the bioabsorbable polymer, a sufficient non-disintegrating property can be exhibited particularly by short-time curing.
- crosslinked gelatin is a highly hydrophilic polymer, it swells when it contains moisture.
- the crosslinked state of the fine particles comprising the crosslinked gelatin can be controlled by adjusting the conditions for crosslinking the gelatin using a conventionally known crosslinking method such as thermal dehydration crosslinking, ultraviolet crosslinking, chemical crosslinking, or ionic crosslinking. .
- a conventionally known crosslinking method such as thermal dehydration crosslinking, ultraviolet crosslinking, chemical crosslinking, or ionic crosslinking.
- heat treatment is performed under vacuum at 110 to 170 ° C. for about 5 minutes to 48 hours.
- the fine particles of crosslinked gelatin obtained by adjusting the crosslinking temperature and heat treatment time are used.
- the crosslinking state can be controlled.
- Fine particles made of the bioabsorbable polymer may be those that have been subjected to radiation treatment such as ⁇ rays and electron beams.
- radiation treatment such as ⁇ rays and electron beams.
- excellent performance as a bone regeneration material kit can be maintained, and the mechanical strength of the cured product can be further improved.
- the fine particles composed of the bioabsorbable polymer are sterilized by the radiation treatment, there is an advantage that it is not necessary to perform another sterilization treatment such as ethylene oxide gas sterilization.
- the preferable lower limit of the average particle size of the fine particles comprising the bioabsorbable polymer is 10 ⁇ m, and the preferable upper limit is 400 ⁇ m. If the average particle size of the fine particles comprising the bioabsorbable polymer is less than 10 ⁇ m, continuous pores into which osteoblasts can enter may not be formed. If the average particle size exceeds 400 ⁇ m, the strength of the cured product is low and sufficient bone The mechanical strength of may not be compensated. The more preferable lower limit of the average particle diameter of the fine particles comprising the bioabsorbable polymer is 20 ⁇ m, and the more preferable upper limit is 200 ⁇ m.
- the aqueous medium is a medium for paste-like bone regeneration material.
- the aqueous medium include water for injection.
- the aqueous medium may contain a buffer component for the purpose of adjusting pH.
- bone marrow fluid or cell suspension can also be used as the aqueous medium.
- the aqueous medium contains a small amount of a water-soluble polymer for the purpose of adjusting viscosity, contains an antibacterial agent for the purpose of preventing infection, and various growth factors for the purpose of promoting bone regeneration. You may contain.
- water-soluble polymer examples include polymers such as lactic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, and malic acid, chondroitin sulfate, hyaluronic acid, dextran sulfate, heparan sulfate, alginic acid, and chitosan.
- the bone regeneration material kit of the present invention may further have various cell growth factors, antibacterial agents, antibiotics and other drugs. If a bone regeneration material kit having these is used, the cured product is decomposed and the drug is gradually released after filling in a bone defect or damaged part, and the drug is gradually released. It can be demonstrated. For example, early bone regeneration is expected by sustained release of cell growth factors. Further, the sustained release of antibacterial agents, antibiotics and the like enables use in an environment (for example, a bone infection example or an oral cavity) where there are many bacteria in the vicinity of the bone defect.
- the drug is not limited to a drug related to bone regeneration.
- a paste-like bone regeneration material can be prepared using the bone regeneration material kit of the present invention.
- the paste-like bone regenerative material is a paste that is in use and can be easily filled into a bone defect or damaged part manually or by an injector and can be cured in the body after filling. Recycled material is meant.
- Paste prepared by mixing fine particles made of calcium salt adsorbed on the surface of inositol phosphate or its salt constituting the bone regeneration material kit of the present invention, fine particles made of a bioabsorbable polymer, and an aqueous medium.
- the osseous bone regeneration material is also one aspect of the present invention.
- the ratio of the inositol phosphate-adsorbed calcium salt fine particles, the fine particles composed of a bioabsorbable polymer, and the aqueous medium is not particularly limited, and the kneading operation is performed. It is determined in consideration of ease, ease of injection using an injector, time to cure, strength of the cured product, and the like.
- the porosity of the cured product can be adjusted, whereby the strength of the cured product and the bone regeneration rate can be adjusted. And can be controlled.
- the blending ratio of the inositol phosphate-adsorbed calcium salt fine particles (when the calcium phosphate compound is included, the total of the inositol phosphate-adsorbed calcium salt fine particles and the calcium phosphate compound) and the fine particles composed of the bioabsorbable polymer is as follows: The weight ratio is preferably in the range of 97: 3 to 76:24.
- the weight ratio is more preferably in the range of 95: 5 to 80:20, and still more preferably in the weight ratio of 90:10 to 85:15.
- the blending ratio may be determined in consideration of the application site within the preferable blending ratio range of the inositol phosphate-adsorbing calcium salt microparticles and the bioabsorbable polymer microparticles.
- the blending ratio of the fine particles composed of the bioabsorbable polymer is set to be low.
- the skull, humerus, forearm (ulna) bone, phalange, etc. are parts that do not receive a large load. Therefore, when applying to these parts, the bone regeneration speed should be given priority over strength. is there. That is, the blending ratio of the fine particles composed of the bioabsorbable polymer is set high.
- the blending ratio of the inositol phosphate-adsorbed calcium salt fine particles and the calcium phosphate compound in preparing the paste-like bone regeneration material is 90 by weight. : 10 to 10:90 is preferable. Within this range, the mechanical strength of the cured product can be improved. More preferably, it is 10:90 to 50:50.
- a preferable lower limit with respect to 100 parts by weight in total of the inositol phosphate-adsorbing calcium salt fine particles and fine particles made of a bioabsorbable polymer is 50 parts by weight, and a preferable upper limit is 150 parts by weight.
- the content of the aqueous medium is less than 50 parts by weight, the viscosity of the pasty bone regeneration material may be high and injection may be difficult.
- the content exceeds 150 parts by weight the paste shrinks when cured.
- the minimum with more preferable content of the said aqueous medium is 60 weight part, and a more preferable upper limit is 100 weight part.
- the method for mixing the inositol phosphate-adsorbing calcium salt fine particles, the fine particles comprising the bioabsorbable polymer and the aqueous medium is not particularly limited, but the inositol phosphate-adsorbing calcium salt fine particles, the fine particle comprising the bioabsorbable polymer and the aqueous system are not limited.
- a method of kneading and mixing in a medium and a syringe, or a method of kneading and mixing the above-described inositol phosphate-adsorbing calcium salt fine particles, fine particles comprising a bioabsorbable polymer and an aqueous medium are suitable.
- the procedure for blending the inositol phosphate-adsorbing calcium salt fine particles, the fine particles comprising a bioabsorbable polymer, and the aqueous medium is not particularly limited, and the inositol phosphorus
- the total amount of the acid-adsorbed calcium salt fine particles, the fine particles composed of the bioabsorbable polymer, and the aqueous medium may be mixed at the same time.
- the aqueous medium is added to the mixture, or the inositol phosphate adsorbing calcium salt fine particles are added to the aqueous medium.
- a method is preferred in which a part of the above is added and kneaded and mixed, and then the fine particles comprising the bioabsorbable polymer and the remaining part of the aqueous medium are added and mixed.
- the paste-like bone regeneration material of the present invention can be easily filled into a bone defect or damage using a manual or injector such as a syringe.
- the filled paste-like bone regeneration material hardens even at room temperature to become a bone regeneration material, and complements the mechanical strength of the bone.
- the paste-like bone regeneration material of the present invention uses fine particles made of a bioabsorbable polymer. By using the inositol phosphate-adsorbed calcium salt fine particles together, the paste-like bone regeneration material comes into contact with moisture such as blood and body fluid after filling. However, the non-disintegrating property which does not disintegrate can be exhibited.
- the bone regeneration material After the treatment, continuous pores are formed by absorbing fine particles made of the bioabsorbable polymer over time, and osteoblasts enter the continuous pores to regenerate the patient's own bone.
- the paste-like bone regeneration material of the present invention is once cured externally to form a bone regeneration material
- the bone regeneration material is filled into a bone defect or damaged portion or used as an osteosynthesis material. May be.
- the bone regeneration material and the bone cement obtained by curing the pasty bone regeneration material of the present invention are also one aspect of the present invention.
- the present invention contains fine particles composed of a bioabsorbable polymer, and in the short term, it can compensate for a bone defect or damaged portion to ensure the mechanical strength of the bone, and in the long term, the bone of the patient's own bone.
- Providing bone regeneration material kit, paste-like bone regeneration material, bone regeneration material, and bone jointing material that can promote regeneration and can exhibit non-disintegration that does not disintegrate even after contact with moisture such as blood or body fluid after filling can do.
- the slurry was collected by suction filtration and frozen overnight in a ⁇ 80 ° C. freezer.
- the frozen slurry was dried for 48 hours using a freeze dryer (manufactured by LABCONCO, Free Zone (trademark)) to obtain a wet synthetic hydroxyapatite powder.
- Inositol hexaphosphate was adsorbed on hydroxyapatite using a planetary ball mill (P-6 type, manufactured by FRITCH) under the following conditions.
- a planetary ball mill P-6 type, manufactured by FRITCH
- Into a pot made of zirconia 50 mL of the obtained inositol hexaphosphate aqueous solution, 10.0 g of wet synthetic hydroxyapatite powder (average particle size 10 ⁇ m) and 180 g of ⁇ 2 mm zirconia balls were added and stirred at a rotation speed of 300 rpm for 1 hour. Thereafter, the mixture was centrifuged at 9000 rpm for 30 minutes, the residue was filtered, and the resulting slurry was frozen at ⁇ 80 ° C. overnight.
- the frozen slurry was freeze-dried for 24 hours using a freeze dryer (manufactured by LABCONCO, Free Zone (trademark)) to obtain inositol hexaphosphate-adsorbed hydroxyapatite fine particles.
- ⁇ -tricalcium phosphate was pulverized under the following conditions using a planetary ball mill (manufactured by FRITCH, type P-6). In a zirconia pot, 40 mL of purified water, 10.0 g of ⁇ -tricalcium phosphate fine particles (average particle size 10 ⁇ m, manufactured by Taihei Chemical Industrial Co., Ltd.) and 180 g of ⁇ 2 mm zirconia balls were added and stirred for 1 hour at a rotation speed of 300 rpm. Thereafter, it was filtered and frozen at ⁇ 80 ° C. overnight. The frozen slurry was freeze-dried for 24 hours using a freeze dryer (manufactured by LABCONCO, Free Zone (trademark)) to obtain ⁇ -tricalcium phosphate fine particles.
- a freeze dryer manufactured by LABCONCO, Free Zone (trademark)
- Example 2 A bone regeneration material kit and a paste-like bone regeneration material were produced in the same manner as in Experimental Example 1 except that the blending amount of the heat-crosslinked gelatin fine particles was 5% by weight.
- Calcium phosphate fine particles with an average particle size of 10 ⁇ m that do not adsorb inositol hexaphosphate ( ⁇ -type tricalcium phosphate 75 wt%, tetracalcium phosphate 18 wt%, calcium hydrogen phosphate dihydrate 5 wt%, and hydroxyapatite 2 %)), Thermally crosslinked gelatin microparticles, and an aqueous medium (5.4% sodium chondroitin sulfate, 13% disodium succinate anhydrous, 0.3% sodium bisulfite aqueous solution) to constitute a bone regeneration material kit .
- heat-crosslinked gelatin fine particles are added to the calcium phosphate-based fine particles so that the blending amount is 10% by weight, 700 ⁇ L of an aqueous medium is added to 1.5 g of the fine particles, and mixed for 120 seconds to regenerate paste-like bone. Obtained material.
- paste-like bone regeneration material is filled into a split mold having a diameter of 6.0 mm and a height of 12 mm in a constant temperature and humidity chamber at 37 ° C. and a relative humidity of 100%. For each hour. According to JIS T 6602, the hardness of the cured product after each time curing was measured, and the time until reaching the Gilmore (light) was the initial curing time, and the time until reaching the Gilmore (heavy) was the final curing time.
- the present invention contains fine particles composed of a bioabsorbable polymer, and in the short term, it can compensate for a bone defect or damaged portion to ensure the mechanical strength of the bone, and in the long term, the bone of the patient's own bone.
- Providing bone regeneration material kit, paste-like bone regeneration material, bone regeneration material, and bone jointing material that can promote regeneration and can exhibit non-disintegration that does not disintegrate even after contact with moisture such as blood or body fluid after filling can do.
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Abstract
Description
従来の人工骨としては、リン酸カルシウムからなる緻密体と多孔体の人工骨が知られていた。このような人工骨は、治療の対象となる骨の状態に合わせて、形状等を整える必要がある。しかし、手術現場において人工骨を切断加工したり、切削加工したりすることは困難であり、使いにくいという問題があった。
以下に本発明を詳述する。
上記イノシトールリン酸又はその塩が表面に吸着したカルシウム塩からなる微粒子は、水系媒体と混合するとペースト状となり、体内で硬化して、骨の力学強度を補う役割を有するとともに、表面に吸着したイノシトールリン酸又はその塩が上記生体吸収性高分子からなる微粒子と相互作用することにより、得られるペースト状骨再生材料に比較的短時間の硬化で充分な非崩壊性を発揮することができる性能を付与することができる。
上記リン酸カルシウムとしては、例えば、ヒドロキシアパタイト、α-リン酸三カルシウム、β-リン酸三カルシウム、リン酸四カルシウム、リン酸八カルシウム、リン酸水素カルシウム、リン酸二水素カルシウム、非晶質リン酸カルシウム等が挙げられる。これらのリン酸カルシウムは単独で用いてもよく、2種以上を併用してもよい。なかでも、ヒドロキシアパタイト、α-リン酸三カルシウム又はβ-リン酸三カルシウムが好ましく、ヒドロキシアパタイトがより好ましい。
なお、上記カルシウム塩からなる微粒子の比表面積は、例えば、マイクロメリティックス自動比表面積測定装置フローソーブIII2305(島津製作所社製)を用いてBET法により測定することができる。
また、イノシトールリン酸の塩としては、アルカリ金属塩又はアルカリ土類金属塩が挙げられ、より具体的には、ナトリウム塩、カリウム塩、マグネシウム塩、カルシウム塩、バリウム塩等が挙げられる。これらのイノシトールリン酸又はその塩は単独で用いてもよく、2種以上を併用してもよい。なかでも、フィチン酸、フィチン酸ナトリウム塩又はフィチン酸カリウム塩が好ましい。
なお、フィチン酸ナトリウム塩には、例えば、フィチン酸ナトリウム塩38水和物、フィチン酸ナトリウム塩47水和物、フィチン酸ナトリウム塩12水和物等のように、結晶水含量の異なる数種が知られているが、いずれも好ましく用いることができる。
なお、上記イノシトールリン酸又はその塩を溶解した水溶液を調製する際には、水溶液に予めアルカリ水溶液を添加し、好ましくはpH6~11、より好ましくはpH6~8に調整しておくことが好ましい。pHの調整に用いるアルカリ水溶液は、特に限定されず、水酸化ナトリウム水溶液、水酸化カリウム水溶液等が挙げられる。
また、この際の上記イノシトールリン酸又はその塩とカルシウム塩とのモル比としては、0.001~0.1が好ましく、0.01~0.08がより好ましい。
なお、リン酸カルシウム系化合物からなる微粒子は、粉砕して調製する際の時間を調整することによって、硬化物の力学的強度を変化させることもできる。
上記生体吸収性高分子としては、例えば、ゼラチン、コラーゲン、ヒアルロン酸、アルブミン、フィブリン等のタンパク質や、デンプン、アルギン酸、キチン、ペクチン酸及びその誘導体等の多糖類等の天然高分子;ポリ乳酸、ポリグリコール酸、乳酸-グリコール酸共重合体、グリコール酸-ε-カプロラクトン共重合体、乳酸-ε-カプロラクトン共重合体、ポリリンゴ酸、ポリ-α-シアノアクリレート、ポリ-β-ヒドロキシ酸、ポリトリメチレンオキサレート、ポリテトラメチレンオキサレート、ポリオルソエステル、ポリオルソカーボネート、ポリエチレンカーボネート、ポリ-γ-ベンジル-L-グルタメート、ポリ-L-グルタミン酸、ポリ-γ-メチル-L-グルタメート、ポリ-L-リジン、ポリ-L-アラニン等の合成高分子等が挙げられる。これらの生体吸収性高分子は単独で用いてもよく、2種以上を併用してもよい。
上記生体吸収性高分子からなる微粒子が、ゼラチン、コラーゲン又はヒアルロン酸からなる場合、ゼラチン、コラーゲン又はヒアルロン酸は架橋されていることが好ましい。
なかでも架橋ゼラチンが好適である。上記生体吸収性高分子からなる微粒子として架橋ゼラチンからなる微粒子を用いた場合には、特に短時間の硬化で充分な非崩壊性を発揮できる。また、架橋ゼラチンは親水性の高い高分子であることから、水分を含むことで膨潤する。このため、骨孔内に移植した後、周囲の水分を吸い、体積を増し、充填部分への密着性が向上するという効果も得られる。また、従来の無機材料のみを含むペースト状骨補填材料の場合、適用部に体液や血液が多く存在したときに、硬化が遅延したり、硬化せずに流出してしまったりすることがあった。更に、硬化した場合にでも強度が低下したり、崩壊して流出してしまったりするという問題があった。親水性の高い架橋ゼラチンからなる微粒子を用いた場合には、止血効果が発揮されることから、多少の出血のある部位にも用いることができる。
上記水系媒体は、注射用水等が挙げられる。上記水系媒体は、pHを調整する目的で、バッファー成分を含有してもよい。また、上記水系媒体として、骨髄液や細胞懸濁液も使用することができる。
更に、上記水系媒体は、粘度を調整する目的で少量の水溶性高分子を含有したり、感染を予防する目的で抗菌剤を含有したり、骨再生を促進する目的で各種の成長因子等を含有してもよい。
上記水溶性高分子は、例えば、乳酸、グリコール酸、コハク酸、マレイン酸、フマル酸、リンゴ酸等の重合体、コンドロイチン硫酸、ヒアルロン酸、デキストラン硫酸、ヘパラン硫酸、アルギン酸、キトサン等が挙げられる。
ここでペースト状骨再生材料とは、使用時にはペースト状であって、用手的又はインジェクターにより骨の欠損部又は損傷部に容易に充填することができ、充填後に体内で硬化させることができる骨再生材料を意味する。
本発明の骨再生材料キットを構成するイノシトールリン酸又はその塩が表面に吸着したカルシウム塩からなる微粒子と、生体吸収性高分子からなる微粒子と、水系媒体とを混合してペースト状としたペースト状骨再生材料もまた、本発明の1つである。
上記イノシトールリン酸吸着カルシウム塩微粒子(上記リン酸カルシウム系化合物を含む場合には、上記イノシトールリン酸吸着カルシウム塩微粒子とリン酸カルシウム系化合物との合計)と生体吸収性高分子からなる微粒子との配合比率は、重量比で97:3~76:24の範囲であることが好ましい。この範囲内であると、短期的な骨の力学的強度の確保と、長期的な骨の再生とを両立することができる。この範囲よりも上記生体吸収性高分子からなる微粒子が少ない場合には、充分な連続孔が形成されずに骨の再生が進まないことがあり、この範囲よりも上記生体吸収性高分子からなる微粒子が多い場合には、硬化物の強度が低いことがある。より好ましくは重量比で95:5~80:20の範囲であり、更に好ましくは重量比で90:10~85:15の範囲である。
例えば、踵骨、大腿骨、脛骨、椎体等は、大きな荷重がかかる部位であることから、これらの部位に適用する場合には、骨の再生速度よりも強度を優先させるべきである。即ち、生体吸収性高分子からなる微粒子の配合比率を低めに設定する。
例えば、頭蓋骨、上腕骨、前腕(橈尺)骨、指骨等は、大きな荷重はかからない部位であることから、これらの部位に適用する場合には、強度よりも骨の再生速度を優先させるべきである。即ち、生体吸収性高分子からなる微粒子の配合比率を高めに設定する。
しかしながら、上記イノシトールリン酸吸着カルシウム塩微粒子と生体吸収性高分子からなる微粒子とを混合した後、この混合物に上記水系媒体を加えていく方法や、上記イノシトールリン酸吸着カルシウム塩微粒子に上記水系媒体の一部量を加え練和混合した後、上記生体吸収性高分子からなる微粒子、上記水系媒体の残部量を加えて混合する方法が好ましい。このような方法でペースト状骨再生材料を調製することにより、強度の高い骨再生材料が得られる。
なお、本発明のペースト状骨再生材料をいったん外部で硬化させて骨再生材料を形成した後、該骨再生材料を骨の欠損部又は損傷部に充填したり、骨接合材として使用したりしてもよい。本発明のペースト状骨再生材料を硬化してなる骨再生材料、骨接合材もまた、本発明の1つである。
(1)湿式合成ハイドロキシアパタイト粉体の調製
0.5M水酸化カルシウム懸濁液1000mLを調製し、それに0.3Mリン酸水溶液1000mLを滴下した。水酸化カルシウムとリン酸の濃度はCa/P=1.67(モル比)となるように調整した。また、反応槽中のpHが10<pH<11となるようにpH調整剤(25%アンモニア水)で調整した。リン酸水溶液滴下が終了した後、更に1時間撹拌してから、37℃に設定したインキュベータ内に24時間静置し、熟成させた。熟成後、吸引濾過にてスラリーを回収し、-80℃のフリーザーで一晩凍結させた。凍結させたスラリーは凍結乾燥機(LABCONCO社製、Free Zone(商標))を用いて48時間乾燥し、湿式合成ハイドロキシアパタイト粉体とした。
イノシトール六リン酸の50重量%水溶液(和光純薬工業社製)を8.00g精秤し、精製水で300mL程度に希釈した後、水酸化ナトリウム水溶液と塩酸を用いてpHを7.3に調整し、メスフラスコを用いて500mLにメスアップすることで濃度8000ppmのイノシトール六リン酸水溶液を調製した。
遊星式ボールミル(FRITCH社製、P-6型)を用いて下記の条件でα-リン酸三カルシウムを粉砕した。ジルコニア製ポットに、精製水40mL、α-リン酸三カルシウム微粒子(平均粒子径10μm、太平化学産業社製)10.0g、φ2mmジルコニアボール180gを入れ、回転数300rpmで1時間撹拌した。その後、ろ過し、-80℃で一晩凍結させた。凍結させたスラリーを凍結乾燥機(LABCONCO社製、Free Zone(商標))を用いて24時間凍結乾燥して、α-リン酸三カルシウム微粒子粉砕体を得た。
V型混合機(筒井理化学器械社製)に、イノシトール六リン酸吸着ハイドロキシアパタイト微粒子とα-リン酸三カルシウム微粒子粉砕体を重量比で0:100、10:90、20:80、50:50、80:20、100:0となるように入れ、5分間攪拌して混合粉体を得た。
平均粒子径が200μmの未架橋ゼラチン微粒子を、真空下で140℃で14時間熱処理し、熱架橋ゼラチン微粒子を得た。
得られたイノシトール六リン酸吸着ハイドロキシアパタイト微粒子とα-リン酸三カルシウム微粒子粉砕体の混合粉体、得られた熱架橋ゼラチン微粒子、水系媒体(10%キトサン、2.5%リン酸二水素ナトリウム)で骨再生材料キットを構成した。即ち、上記混合粉体に対して配合量が10重量%となるように熱架橋ゼラチン微粒子を加え、その1.0gに対して700~800μLの水系媒体を加えて120秒間混合して、ペースト状骨再生材料を得た。
熱架橋ゼラチン微粒子の配合量が5重量%となるようにした以外は実験例1と同様にして骨再生材料キット及びペースト状骨再生材料を製造した。
イノシトール六リン酸吸着ハイドロキシアパタイト微粒子に代えて、イノシトール六リン酸を吸着させないハイドロキシアパタイト微粒子を用いた以外は実験例1、2と同様にして骨再生材料キット及びペースト状骨再生材料を製造した。
なお、イノシトール六リン酸を吸着させないハイドロキシアパタイト微粒子は、遊星式ボールミルを用いて、精製水と湿式合成ハイドロキシアパタイト粉体を攪拌することにより得たものを用いた。
イノシトール六リン酸を吸着させない平均粒子径が10μmのリン酸カルシウム系微粒子(α型リン酸三カルシウム75重量%、リン酸四カルシウム18重量%、リン酸水素カルシウム二水和物5重量%及びハイドロキシアパタイト2重量%)と、熱架橋ゼラチン微粒子と、水系媒体(5.4%コンドロイチン硫酸ナトリウム、13%コハク酸二ナトリウム無水物、0.3%亜硫酸水素ナトリウム含有水溶液)とで骨再生材料キットを構成した。即ち、上記リン酸カルシウム系微粒子に対して配合量が10重量%となるように熱架橋ゼラチン微粒子を加え、その1.5gに対して700μLの水系媒体を加えて120秒間混合して、ペースト状骨再生材料を得た。
実験例、比較例及び参考例で得られたペースト状骨再生材料について、以下の方法で評価を行った。結果を表1に示した。
製造直後のペースト状骨再生材料を直径6.0mm、高さ12mmの割型に充填し、37℃、相対湿度100%の恒温恒湿器中で各時間硬化させた。
JIS T 6602に従い、各時間硬化後の硬化物の硬度を測定し、ギルモア(軽)に達するまでの時間を初期硬化時間、ギルモア(重)に達するまでの時間を最終硬化時間とした。
製造直後のペースト状骨再生材料を直径6.0mm、高さ12mmの割型に充填し、室温下で5分間硬化させた。得られた硬化物を直ちに蒸留水中に投下し、室温下で24時間静置した。その後、目視にて蒸留水中の硬化物の状態を観察して、以下の基準により非崩壊性を評価した。
○:崩壊はほとんど確認されなかった
△:端部に僅かながら崩壊が認められた
×:完全に崩壊した
製造直後のペースト状骨再生材料を直径6mm、高さ12mmの割型に充填し、37℃、相対湿度100%の恒温恒湿器の中で24時間養生した。その後、割型からサンプルを取り出し硬化物を得た。
万能試験機(EZ-Graph、島津製作所社製)を用いて、試験速度0.5mm/minの条件で、得られた硬化物の圧縮強度を測定した。
また、各硬化物の直径、高さ及び重さを測定して、かさ密度(g/cm3)を算出した。
Claims (8)
- イノシトールリン酸又はその塩が表面に吸着したカルシウム塩からなる微粒子と、生体吸収性高分子からなる微粒子と、水系媒体とを含むことを特徴とする骨再生材料キット。
- イノシトールリン酸又はその塩は、イノシトール六リン酸であることを特徴とする請求項1記載の骨再生材料キット。
- 生体吸収性高分子からなる微粒子は、架橋ゼラチンからなる微粒子であることを特徴とする請求項1又は2記載の骨再生材料キット。
- 更に、イノシトールリン酸又はその塩が表面に吸着していないリン酸カルシウム系化合物からなる微粒子を含むことを特徴とする請求項1、2又は3記載の骨再生材料キット。
- イノシトールリン酸又はその塩が表面に吸着したカルシウム塩からなる微粒子と、イノシトールリン酸又はその塩が表面に吸着していないリン酸カルシウム系化合物からなる微粒子との配合比が、重量比で10:90~50:50であることを特徴とする請求項4記載の骨再生材料キット。
- 請求項1、2、3、4又は5記載の骨再生材料キットを用いてなるペースト状骨再生材料であって、イノシトールリン酸又はその塩が表面に吸着したカルシウム塩からなる微粒子と、生体吸収性高分子からなる微粒子と、水系媒体とを混合してペースト状としたことを特徴とするペースト状骨再生材料。
- 請求項6記載のペースト状骨再生材料を硬化してなることを特徴とする骨再生材料。
- 請求項6記載のペースト状骨再生材料を硬化してなることを特徴とする骨接合材。
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EP14834226.4A EP3031478B1 (en) | 2013-08-09 | 2014-08-08 | Bone regeneration material kit, paste-like bone regeneration material, bone regeneration material, and bone bonding material |
US14/910,183 US9642934B2 (en) | 2013-08-09 | 2014-08-08 | Bone regeneration material kit, paste-like bone regeneration material, bone regeneration material, and bone bonding material |
CN201480044178.4A CN105451785B (zh) | 2013-08-09 | 2014-08-08 | 骨再生材料试剂盒、糊状骨再生材料、骨再生材料和骨接合材料 |
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US (1) | US9642934B2 (ja) |
EP (1) | EP3031478B1 (ja) |
JP (1) | JP6288723B2 (ja) |
KR (1) | KR20160042064A (ja) |
CN (1) | CN105451785B (ja) |
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Cited By (4)
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JP2016150205A (ja) * | 2015-02-19 | 2016-08-22 | グンゼ株式会社 | アプリケータ |
JP6006847B1 (ja) * | 2015-08-07 | 2016-10-12 | ゼライス株式会社 | 骨再生材調製用組成物および骨再生材調製用キット |
JP2020069216A (ja) * | 2018-11-01 | 2020-05-07 | 学校法人明治大学 | 骨再生材料キット、ペースト状骨再生材料、骨再生材料及び骨接合材 |
JP2021019933A (ja) * | 2019-07-29 | 2021-02-18 | グンゼ株式会社 | 椎間スペーサーキット |
Families Citing this family (3)
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CN110354305B (zh) * | 2019-07-23 | 2020-06-26 | 山东大学 | 植酸钠制备骨水泥固化液的应用及基于植酸钠的骨水泥 |
CN111012952B (zh) * | 2019-12-20 | 2023-05-12 | 广州润虹医药科技股份有限公司 | 一种椎体强化磷酸钙骨水泥及其制备方法 |
CN115770320A (zh) * | 2022-12-12 | 2023-03-10 | 浙江工业大学 | 一种磷酸镁/植酸/明胶/煅烧白云石骨粘合剂的制备方法 |
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JP2016150205A (ja) * | 2015-02-19 | 2016-08-22 | グンゼ株式会社 | アプリケータ |
JP6006847B1 (ja) * | 2015-08-07 | 2016-10-12 | ゼライス株式会社 | 骨再生材調製用組成物および骨再生材調製用キット |
JP2020069216A (ja) * | 2018-11-01 | 2020-05-07 | 学校法人明治大学 | 骨再生材料キット、ペースト状骨再生材料、骨再生材料及び骨接合材 |
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Also Published As
Publication number | Publication date |
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US9642934B2 (en) | 2017-05-09 |
KR20160042064A (ko) | 2016-04-18 |
US20160175481A1 (en) | 2016-06-23 |
EP3031478A4 (en) | 2017-04-05 |
JP6288723B2 (ja) | 2018-03-07 |
JPWO2015020192A1 (ja) | 2017-03-02 |
CN105451785A (zh) | 2016-03-30 |
EP3031478B1 (en) | 2018-09-19 |
EP3031478A1 (en) | 2016-06-15 |
CN105451785B (zh) | 2018-07-17 |
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