Porous wet calcium phosphate, curable wet calcium phosphate composition, and related materials

Abstract

The objective is to provide wet-process apatite porous materials and wet-process apatite curable compositions exhibiting excellent osteoconductivity and bone replacement properties, as well as wet-process apatite and related materials for cartilage regeneration. Furthermore, another objective is to provide the necessary apatite-based curable compositions, calcium phosphate compositions, calcium carbonate compositions, supports, and related manufacturing methods. [Solution] The problem was solved by discovering wet apatite porous materials, wet apatite curable compositions, wet apatite compositions and related materials for regenerating cartilage, and methods for manufacturing these materials.

Description

[Technical Field]

[0001] The present invention relates to a wet-process porous calcium phosphate, a wet-process curable calcium phosphate composition, and related materials. More specifically, it relates to a wet-process porous apatite, a wet-process curable apatite composition, and related materials. These materials are useful as medical materials used in tissue reconstruction surgery for hard and soft tissues. Hollow structures are also useful for agricultural, forestry, and fisheries applications. [Background technology]

[0002] In medicine, artificial materials are sometimes used in tissue reconstruction procedures for hard and soft tissues. For example, artificial bone may be used in bone defect reconstruction. Recently, wet apatite has been manufactured by a dissolution extraction method (Patent Document 1) rather than dry apatite produced by sintering. Wet carbonate apatite, in particular, exhibits excellent osteoconductivity because it is composed of wet carbonate apatite, which is the inorganic component of bone, and is replaced by new bone through bone remodeling. Wet carbonate apatite artificial bone is being used clinically in Japan and the United States. To accelerate bone remodeling by cells, it is useful to make wet apatite a porous structure so that cells can penetrate the artificial bone. Bone conduction depends on the surface composition of the artificial bone. On the other hand, bone replacement, the next process after bone conduction, also depends on the absorption of the artificial bone. Therefore, wet carbonate apatite-coated calcium carbonate, for example, has excellent bone conduction properties and can lead to rapid bone replacement. Wet apatite is a brittle material and has issues with mechanical strength, but these issues can sometimes be resolved by compounding it with a support. Furthermore, curable compositions that form and harden wet apatite have excellent operability (Patent Document 2). In addition, bone is bound to soft tissues such as cartilage, so materials that regenerate cartilage and materials that bond with soft tissues are also useful. Therefore, there is a need for medical materials and related materials that satisfy these properties. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Patent No. 4854300 [Patent Document 2] Japanese Patent Publication No. 2021-037281 [Overview of the project] [Problems that the invention aims to solve]

[0004] The problem that this invention aims to solve is to provide a wet apatite porous material or a wet apatite curable composition that has excellent osteoconductivity and bone replacement properties, as well as wet apatite and related materials that regenerate cartilage. [Means for solving the problem]

[0005] As a result of diligent research, the inventors have discovered wet-process apatite porous material, a wet-process apatite curable composition, a wet-process apatite composition and related materials for regenerating cartilage, and methods for producing these materials, thus completing the present invention.

[0006] <Definitions of Terms, etc.> In this invention, terms are defined as follows. Furthermore, for simplicity, unless otherwise specified, the values ​​stated herein shall apply to the following matters. <Apatite composition> Apatite composition is a type of calcium phosphate composition that exhibits an apatite structure. One classification of apatite composition is dry apatite composition and wet apatite composition. Dry apatite composition is manufactured by sintering, while wet apatite composition is manufactured under wet conditions, such as in an aqueous solution. Dry apatite does not contain crystal water and has limited adhering water. It also has characteristics such as high crystallinity. Wet apatite contains crystal water and adhering water and has low crystallinity. In this invention, dry apatite composition and wet apatite composition are classified based on the content of crystal water and adhering water from the viewpoint of simplicity. First, the apatite composition is dried at 80°C for 2 hours. After that, the moisture content is evaluated. While dry apatite compositions generally show no weight loss, wet apatite compositions experience a weight loss of 0.2% by mass or more. Therefore, in this invention, a wet apatite composition is defined as an apatite composition in which the weight loss after drying at 50°C for 2 hours followed by heat treatment at 300°C for 2 hours is 0.2% by mass or more. Apatite compositions are further classified into hydroxyapatite compositions that do not contain carbonate groups and carbonateapatite compositions that do contain carbonate groups. The chemical formula ignoring the water of crystallization is: Stoichiometric hydroxyapatite is [Ca 10 [(PO4)6(OH)2], calcium-deficient hydroxyapatite is [Ca9(HPO4)(PO4)5(OH)], and carbonate apatite is [Ca 10-a (PO4) 6-b (CO3) c ](a, b, and c are invariant). Apatite is used clinically as an artificial bone because it is a bone component or similar to a bone component. Carbonate apatite is preferred because it undergoes bone remodeling and is replaced by new bone. In this invention, apatite containing carbonate groups is defined as carbonate apatite. The carbonate group content is preferably 3% by mass or more, more preferably 5% by mass or more, and even more preferably 7% by mass or more.

[0007] In this invention, a wet apatite composition is defined as a composition in which at least a portion of the surface is wet apatite. Compositions whose surface is wet apatite but whose interior is not, as exemplified by wet apatite-coated calcium carbonate, and composite materials with a support are also defined as wet apatite compositions if at least a portion of the surface of the support is coated with wet apatite. Compositions that harden by forming wet apatite are also wet apatite compositions because their surface is wet apatite.

[0008] <Dissolution reaction> In the present invention, a wet carbonated apatite composition may be produced using a dissolution-precipitation reaction. A method for producing wet carbonated apatite by a dissolution-precipitation reaction from calcium carbonate will be outlined. When CaCO3, which is a precursor of wet carbonated apatite, is immersed in an aqueous solution of Na2HPO4 or the like, a small amount of CaCO3 dissolves and Ca 2+ and CO3 2- are separated. Since PO4 3- exists in the aqueous solution, the solution becomes supersaturated with respect to carbonated apatite, and carbonated apatite crystals precipitate on the surface of CaCO3. Since carbonated apatite is formed in water, the precipitated carbonated apatite is wet carbonated apatite. Due to the precipitation of carbonated apatite, the solution becomes unsaturated with respect to CaCO3, so a small amount of CaCO3 dissolves and Ca 2+ and CO3 2- are separated, the solution becomes supersaturated with respect to carbonated apatite, and wet carbonated apatite precipitates. This dissolution reaction and precipitation reaction continuously occur, and the precursor CaCO3 is converted into wet carbonated apatite while maintaining its macro form. In the dissolution-precipitation method, wet carbonated apatite is formed on the surface of the precursor. Therefore, if the dissolution-precipitation method is interrupted before the precursor is completely compositionally converted into wet carbonated apatite, wet carbonated apatite-coated calcium carbonate is produced. Perhaps because the wet carbonated apatite produced by the dissolution-precipitation reaction has a form in which crystals are intertwined, the volume of wet carbonated apatite is larger than the volume of CaCO3, which is the precursor. That is, the composition exhibits the property of expanding during the dissolution-precipitation reaction. Also, in the dissolution-precipitation reaction, wet carbonated apatite crystals are formed on the surface of the precursor. Therefore, if the dissolution-precipitation reaction is caused by bringing the precursor powder, granules, etc. into close contact, the wet carbonated apatite crystals formed on the surfaces of the powder, granules, etc. bind to each other and harden, and wet carbonated apatite blocks, etc. are produced.

[0009] <Aspect ratio> The aspect ratio is the value obtained by dividing the length of a crystal or fibrous composition by its maximum thickness. When crystals or other materials with an aspect ratio greater than 1 are aggregated, the porosity may increase. In principle, an aspect ratio greater than 1 is useful for improving porosity, but from a practical standpoint, this invention targets materials with an aspect ratio of 1.5 or higher. An aspect ratio of 3 or higher is preferable, and 10 or higher is more preferable. An aspect ratio of 51 or higher may be even preferable in some cases. Agglomerates of crystals and other materials with a large aspect ratio have high porosity but low mechanical strength. Therefore, when prioritizing mechanical strength, crystals and other materials with an aspect ratio of 1.5 to less than 3, or 50 or less, may be selected. When prioritizing porosity over mechanical strength, a larger aspect ratio is preferable. There is no upper limit to the aspect ratio, but from the standpoint of ease of handling, an aspect ratio of 200 or less is preferable, 100 or less is more preferable, and 50 or less is even more preferable. There are no particular restrictions on the thickness of crystals or other materials with an aspect ratio of 1.5 or greater. In the case of vaterite crystals, the thickness is generally between 0.3 μm and 3 μm, but in the case of fibrous compositions, any thickness is possible through extrusion molding, etc. On the other hand, from a practical standpoint, for crystals or fibrous compositions having an aspect ratio of 1.5 or greater, the thickness is preferably between 0.3 μm and 1 mm.

[0010] <Sphericity> In this invention, "sphericity" refers to Wadel's practical sphericity, which is obtained by dividing the diameter of a circle equal to the projected area of ​​the material by the diameter of the smallest circle that circumscribes the projected image of the material. <Integrated Structure> In this invention, an aggregated structure is a structure in which crystals or the like are accumulated, and is a structure that exhibits an aggregated structure. It should be noted that an aggregated structure is a structure that remains as a single mass even when immersed in water, and is different from an aggregate that breaks apart when immersed in water. <Surface roughness> In this invention, the surface roughness (Ra) is the arithmetic mean surface roughness (Ra) as defined in ISO 25178. <Bioabsorbable polymers> In the present invention, a bioabsorbable polymer is a polymer that is absorbed in the body. Examples include polymers or copolymers of compounds selected from the group consisting of lactic acid, glycolic acid, caprolactone, lactide, dioxanone, dioxane, glycerol sebaciate, malic acid, and hydroxycarboxylic acid, as well as collagen, gelatin, chitin, chitosan, hyaluronic acid, chondroitin sulfate, fibronectin, vitronectin, and laminin.

[0011] <Curable composition> Curable compositions are sometimes classified into those in which a paste formed by mixing a powder portion and a liquid portion hardens, and those in which a paste formed by mixing a powder portion with water hardens. The former is sometimes called a curable kit. However, if the liquid portion is composed of a water-soluble salt and the powder portion also contains a water-soluble salt, then mixing the solid portion with water will result in the exact same reaction and thus they are essentially identical. Since the liquid component of the curable composition of the present invention is entirely an aqueous solution of a water-soluble salt, if the powder component contains the water-soluble salt that makes up the liquid component and is mixed with water, it hardens through the exact same reaction. Therefore, in this invention, the two are not distinguished and are defined as a curable composition. Note that a curable composition and cement are the same thing. In addition, the powder component may contain granules, and in that case as well, it is defined as a curable composition.

[0012] <Water-soluble phosphate> In this invention, a water-soluble phosphate is defined as a phosphate with a solubility in water of 0.1 or higher at 20°C. Examples include disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate. The pH of the phosphate aqueous solution is not limited, but unless otherwise specified, it is generally preferred to have a pH of 3 to 10, more preferably 4 to 9, and even more preferably 5 to 8.

[0013] <Porosity and pore volume of particles smaller than 10 μm> In this invention, the porosity and pore formation may be increased to promote bone conduction and bone replacement. Unless otherwise specified, the porosity is preferably 30% or higher, more preferably 40% or higher, and even more preferably 50% or higher. 60% or higher is ideal. For promoting osteoconduction and bone replacement, a larger pore volume of 10 μm or less is preferable. Unless otherwise specified, a pore volume of 10 μm or less is 0.2 cm³. 3 Preferably 0.4 cm or more per gram. 3 More preferably 0.6cm or more per gram. 3 A value of 0.8cm or more is even more preferable. 3 A value of 1 / g or higher is ideal. In this invention, pore volume is measured by the mercury intrusion method. The mercury intrusion method is a type of pore distribution measurement method that utilizes the high surface tension of mercury to apply pressure to infiltrate mercury into the pores of a powder, and determines the pore distribution from the pressure and the amount of mercury injected. In this invention, the pore volume is calculated assuming that the advancing and receding contact angles between mercury and the material are 130°, and the surface tension of mercury is 485 mN / m. Pore ​​diameter is a value calculated based on mercury intrusion analysis results, assuming that mercury is injected into cylindrical pores, regardless of the pore shape.

[0014] <Average volume diameter> The volume-average diameter is the value specified in JIS-Z8819-2:2019. If there are discrepancies in measurement, the value measured using the ELSZ-2000ZS zeta potential, particle size, and molecular weight measurement system manufactured by Otsuka Electronics Co., Ltd. shall be used. <Mixture ratio> The liquid-to-solid ratio is the mass ratio of the liquid to the solid when mixing a medical-grade curable composition. For example, when mixing 1 g of powder with 0.8 g of liquid, the liquid-to-solid ratio is 0.8. <Surface morphology exhibiting scale-like, spherical, or needle-like structures> A key feature of this invention is the surface morphology of the wet-process apatite, which may exhibit scaly, spherical, or needle-like forms. Furthermore, a greater height from the base to the highest point of the surface morphology may be preferable. For simplicity, in this invention, the height from the base to the highest point of the surface morphology, selected from the group of scaly, spherical, and needle-like forms, may be referred to as the surface morphology height.

[0015] The present invention is as follows. (Hereinafter, the inventions described in [1] to

[14] below may be referred to as the present invention [1] to

[14] .) [1] A wet apatite composition characterized by satisfying at least one of the following conditions (A1) to (A5). (A1) A form selected from the group consisting of an aspect ratio of 1.5 or more and less than 3, an aspect ratio of 3 or more, and a spiky form in which needle-like crystals extend in multiple directions, and the surface exhibits a form selected from the group consisting of scaly, spherical, and needle-like. Alternatively, having an aspect ratio of 1.5 or greater and a hollow structure, Alternatively, the sphericity is 0.9 or higher, the surface exhibits one morphology selected from the group consisting of scaly, spherical, and needle-like shapes, and the height from the base to the highest point of the surface morphology is 0.2 μm or higher. A wet carbonate apatite powder that satisfies any of the following conditions, or a wet carbonate apatite block exhibiting an aggregated structure in which the wet carbonate apatite powder is bonded. (A2) A wet apatite-coated support that satisfies at least one of the following conditions (A21) to (A24), wherein wet apatite covers at least a portion of the support, or a wet apatite-embedded support in which wet apatite exists inside the support. (A21) At least a portion of the support surface having an arithmetic mean surface roughness (Ra) of 1.0 μm or more is covered with a wet carbonate apatite layer. The wet apatite layer has an arithmetic surface roughness (Ra) of 4 μm or more, the wet apatite layer has a recess with a depth of 10 μm or more, or the wet apatite layer has a hollow structure. Alternatively, the structure may include a wet apatite layer in which any of the following types of wet apatite, selected from the group having an aspect ratio of 3 or more, a spiky shape with needle-like crystals extending in multiple directions, and a sphericity of 0.9 or more, penetrates the wet apatite layer. Alternatively, the wet apatite layer has a porosity of 5% or more and a specific surface area of ​​3 m² as determined by mercury intrusion analysis. 3 The amount is 1 / g or more, or the pore volume is 0.03 cm³ with a pore diameter product of 0.01 μm or more and 1 μm or less. 3 It is 1 / g or more. It satisfies one of the following conditions. (A22) At least a portion of the support, which is a bioabsorbable polymer, is covered with a wet apatite layer. Support structure is a three-dimensional interconnected structure, porous membrane, membrane with holes, membrane containing wet apatite, It is one of the following: (A23) The support has a screw structure, Wet apatite covers more than 5% of the thread height of the screw thread. And / or, at least one selected from the group consisting of a portion of the screw thread having an arithmetic mean surface roughness (Ra) of 1.0 μm or more, a recess or protrusion on the surface of the screw thread, a groove formed on the crest side of the screw thread, or a portion of the crest of the screw thread being removed, is coated with wet apatite. (A24) Inside a support without an undercut, or inside a support with an undercut, Porosity of 30% or more, and / or pores with a pore diameter of 10 μm or less and a pore volume of 0.2 cm³ 3 Wet apatite is fixed to the surface, having a density of 1 / g or more and exhibiting a structure selected from the group consisting of a honeycomb structure with multiple through-holes extending in one direction, a structure with frost-pillar-like pores, a three-dimensional interconnected structure with multiple through-holes extending in multiple directions, a sponge structure, a gyro structure, a porous structure, and an aggregated structure. (A3) A curable composition that satisfies any of the following conditions (A31) to (A33). (A31) The powder part is At least one selected from the group (A311) below, or a mixture of at least one selected from the group (A311) and a water-soluble phosphate, Alternatively, a mixture of calcium carbonate and tricalcium phosphate with an average particle size less than 2 μm as described in (A312) below, a mixture of calcium carbonate and tricalcium phosphate with an average particle size less than 2 μm as described in (A312) below, and a water-soluble phosphate, a mixture of calcium carbonate and calcium hydrogen phosphate as described in (A312) below, a mixture of calcium carbonate, calcium hydrogen phosphate and a water-soluble phosphate as described in (A312) below, Or, at least one selected from group (A313), A mixture of one selected from the group consisting of tricalcium phosphate, a mixture of tricalcium phosphate and a water-soluble phosphate, calcium hydrogen phosphate, and a mixture of calcium hydrogen phosphate and a water-soluble phosphate. This is a curable composition in which the powder portion hardens by forming wet apatite when exposed to a water-soluble phosphate aqueous solution or water. (A311) Calcium carbonate, calcite, aragonite, vaterite, amorphous calcium carbonate, calcium carbonate with an aspect ratio of 3 or more, spiky calcium carbonate with needle-like crystals extending in multiple directions, hollow calcium carbonate, calcium carbonate with a sphericity of 0.9 or more, calcium sulfate (A312) Calcium carbonate with an aspect ratio of 3 to 51 (A313) Calcium carbonate with needle-shaped crystals extending in multiple directions to form a chestnut-like structure, hollow calcium carbonate, hollow calcium carbonate with an aspect ratio of 3 or more, amorphous calcium carbonate, volume of 5 × 10 -13 m 3 The above is 2 x 10 -8 m 3 The following calcium carbonate aggregates, calcium carbonate with an aspect ratio greater than 51 (A32) Volume is 5 × 10 -13 m 3 The above is 2 x 10 -8 m 3 The following comprises wet carbonate apatite granules and a powder portion that hardens to form wet apatite: A paste that hardens to form wet carbonate apatite when mixed with an aqueous phosphate solution or water is a curable composition in which at least a portion of the wet carbonate apatite granules are bridged by the wet carbonate apatite to form a interconnected porous body, and / or the hardened body of the paste is absorbed more quickly in the body than the wet carbonate apatite granules. Alternatively, the volume of tricalcium phosphate powder, or a mixed powder of tricalcium phosphate and calcium carbonate, bonded by calcium phosphate bridging is 5 × 10 -13 m 3 The above is 2 x 10 -8 m 3 This is a curable composition comprising a granular portion, which consists of the following granules, and a liquid portion, which consists of at least one selected from the group consisting of water, a phosphate aqueous solution, and a polyvalent carboxylate aqueous solution. When the granular portion and the liquid portion are mixed, the granular portion becomes wet apatite granules, and the granules are bonded together. (A33) Volume is 5 × 10 -13 m 3 The above is 2 x 10 -8 m 3 The following curable composition comprises tricalcium phosphate granules and a liquid portion which is a phosphate aqueous solution with a pH of 3.0 or higher and less than 8.0, and when the granules are exposed to the liquid portion, they bond together to form wet apatite. (A4) This is a chemically synthesized wet apatite that, when implanted in a bone defect in the trochlear groove of a rabbit femur so as to form a recess of 2.0 mm to 3.0 mm from the cartilage surface of the trochlear groove, binds to the host bone and forms cartilage on the trochlear groove side surface that binds to the cartilage covering the trochlear portion. (A5) One surface selected from the group consisting of calcium carbonate, dry hydroxyapatite, and dry tricalcium phosphate is coated with wet apatite. [2] The wet apatite composition according to [1], characterized by comprising 3% by mass or more, 5% by mass or more, or 7% by mass or more of carbonate groups. [3] The wet apatite composition according to [1], characterized in that it contains at least one selected from the group consisting of a metal salt, a metal with a diameter of 1 μm or less, a growth factor, a drug, and a bioabsorbable polymer within the wet carbonate apatite composition. [4] At least one selected from the group consisting of metal salts, metals with a diameter of 1 μm or less, growth factors, drugs, and bioabsorbable polymers, which has a solubility in water of 1 or less, is coated with wet carbonate apatite having a carbonate group content of 3% by mass or more, 5% by mass or more, or 7% by mass or more. The wet carbonate apatite composition according to [2], characterized in that the wet carbonate apatite is a powder having a hollow structure and / or an aspect ratio of 3 or more and / or a surface having one form selected from the group consisting of flaky, spherical, and needle-shaped, or an aggregate structure formed by the bonding of the powder. [5](A1) The aggregated structures formed by bonding the wet carbonate apatite powder described above include honeycomb structures having multiple through-holes extending in one direction, three-dimensional porous bodies having multiple through-holes extending in multiple directions, gyroid structures, sponge-like structures, structures having frost-column-like pores, tetrahedrons, hexahedrons, cylinders, and structures with a volume of 5 × 10 -7 m 3 It exhibits at least one structure selected from the group of granules and structures having multiple legs, and / or the porosity of the aggregated structure is 30% or more, and / or the pore diameter of the aggregated structure is 0.10 μm or more and 10 μm or less and the pore volume is 0.2 cm³ 3 / g or more, and / or, the height from the base to the highest part of one form selected from the group of scaly, spherical, and needle-like shapes covering the aggregate structure is 0.2 μm or more. A wet apatite composition according to [1] characterized by satisfying any of the following conditions. [6] Calcium carbonate powder that satisfies one of the following conditions: aspect ratio of 1.5 or more and less than 3, aspect ratio of 3 or more, burr-like structure with needle-shaped crystals extending in multiple directions, or hollow structure. Alternatively, an aggregated structure in which these powders combine to form an aggregated structure, Alternatively, a calcium carbonate structure having frost-like pores is produced by performing, in this order, a step of lowering the temperature of a slurry consisting of calcium carbonate and an aqueous solution of a water-soluble polymer from one or all directions to cause ice to grow in a frost-like shape, and a step of removing the water-soluble polymer by heat treatment. The method involves exposing the substance to an aqueous phosphate solution. A wet carbonate apatite powder satisfying one of the following conditions selected from the group: an aspect ratio of 1.5 or more and less than 3, an aspect ratio of 3 or more, a burr-like structure in which needle-like crystals extend in multiple directions, or a hollow structure; a wet carbonate apatite aggregate structure exhibiting a structure formed by the accumulation of such wet carbonate apatite powders; or a method for producing a wet carbonate apatite structure having frost-pillar-like pores. [7] A method for manufacturing a wet apatite-coated support, wherein at least a portion of the surface of the support having an arithmetic mean surface roughness (Ra) of 1.0 μm or more is coated with a wet apatite layer, characterized in that it satisfies either (B1) or (B2) below. (B1) Calcium carbonate exhibiting one form selected from the group of having an aspect ratio of 3 or more, a spiky shape with needle-like crystals extending in multiple directions, or a sphericity of 0.9 or more on the support surface, Alternatively, a step of applying a mixture of a pore-forming material and a calcium nitrate solution or a calcium carboxylate solution, Subsequently, by thermally decomposing calcium nitrate in the presence of carbon dioxide, or by thermally decomposing calcium carboxylate, A step of fixing calcium carbonate exhibiting at least one form selected from the group consisting of an aspect ratio of 3 or more, a spiky shape with needle-like crystals extending in multiple directions, and a sphericity of 0.9 or more, to the surface of a support via a calcium carbonate layer, or a step of coating a support with calcium carbonate that includes a pore-forming material, or from which the pore-forming material has been removed. The process then includes a phosphorylation step in which the product of the first step is exposed to an aqueous phosphate solution to convert the calcium carbonate portion of the product into wet carbonate apatite. (B2) A step of applying at least one selected from the group consisting of calcium oxide, calcium hydroxide, calcium carbonate, and a curable composition that hardens to form wet apatite, to a recess on the surface of a support modified with a polycarboxylic acid salt or a support that is not modified with a polycarboxylic acid. Subsequently, in the case of calcium oxide, (B21), (B23), and (B25) are performed in this order, or (B22) and (B25) in this order; in the case of calcium hydroxide, (B23) and (B25) are performed in this order; in the case of calcium carbonate, (B24) and (B25) are performed in this order; and in the case of a curable composition that hardens to form wet apatite, (B26) is performed. (B21) Exposure to moisture and the addition of moisture (B22) A process of simultaneously exposing to moisture and carbon dioxide, and adding moisture and carbon dioxide. (B23) Exposure to carbon dioxide and carbon dioxide addition process (B24) A step of applying calcium carbonate to the recesses of the support by either method (B241) or (B242). (B241) Step of applying calcium carbonate powder to the recesses of the support. (B242) Step of applying a calcium carbonate solution or a calcium bicarbonate solution to the recesses of the support. (B25) A step of exposing the calcium carbonate to an aqueous phosphate solution to convert at least a portion of the calcium carbonate into wet carbonate apatite. (B26) A process for curing a curable composition that hardens to form wet apatite. [8] A step of exposing one selected from the group consisting of a composition satisfying either (C1) or (C2) below, a mixture of a composition satisfying either (C1) or (C2) and a water-soluble pore-forming material, a mixture of a composition satisfying either (C1) or (C2) and a water-soluble phosphate, or a mixture of a composition satisfying either (C1) or (C2), a water-soluble pore-forming material, and a water-soluble phosphate, to an aqueous phosphate solution or water inside a support. A method for manufacturing a wet carbonate apatite-embedded support, characterized by containing a wet carbonate apatite composition fixed inside the support. (C1) Calcium carbonate powder exhibiting one form selected from the group consisting of an aspect ratio of 1.5 or more and less than 3, an aspect ratio of 3 or more, a sphericity of 0.5 or more and less than 0.9, a sphericity of 0.9 or more, or a burr-like form with needle-like crystals extending in multiple directions, or one selected from the group consisting of aragonite, vaterite, calcite, or amorphous calcium carbonate. (C2) A calcium carbonate block exhibiting one structure selected from the group consisting of a honeycomb structure with multiple through-holes extending in one direction, a structure with frost-pillar-like pores, a three-dimensional interconnected structure with multiple through-holes extending in multiple directions, a sponge structure, a gyro structure, and an aggregated structure. [9] One selected from the group of calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, apatite, and octacalcium phosphate, having an aspect ratio of 3 or more and exhibiting a hollow structure. Alternatively, the composition is calcium carbonate, it exhibits a hollow structure, and satisfies at least one of the following: aspect ratio of 10 or more, length of the major axis of 60 μm or more, maximum length of the minor axis of 5 μm or more, and shell thickness of 1 μm or more. A hollow-structured wet calcium powder characterized by the above, or a hollow-structured wet calcium aggregate exhibiting a structure in which the hollow-structured wet calcium powder is aggregated.

[10] A method for producing calcium carbonate powder, calcium phosphate powder, calcium hydrogen phosphate powder, tricalcium phosphate powder, apatite powder, octacalcium phosphate powder, and aggregates exhibiting a hollow structure, characterized by comprising the step of exposing calcium sulfate having an aspect ratio of 3 or more to an aqueous carbonate solution or an aqueous phosphate solution.

[11] A medical dispensing device that dispenses a paste that hardens to form apatite in a strip shape, characterized in that it satisfies any of the following conditions (D1) to (D6). (D1) The value obtained by dividing the width of the discharge port by the thickness is 2 or more. (D2) The maximum area of ​​the space through which the paste passes in the dispenser, the plane perpendicular to the line passing through the center of the dispenser port and the center of the inlet port overlap, divided by the area of ​​the dispenser port, is greater than 1. (D3) The thickness of the space through which the paste passes from the center of the discharge port toward the injection port is the same as the thickness of the discharge port for a length of 0.3 mm or more from the discharge port. (D4) The thickness of the discharge surface of the discharger is less than or equal to the thickness of the discharge port plus 3 mm, and / or the width of the discharge surface of the discharger is less than or equal to the width of the discharge port plus 3 mm. (D5) The maximum thickness of the outer surface of the discharger where a plane perpendicular to the straight line passing through the center of the discharge port and the center of the inlet port overlaps is less than or equal to the thickness of the discharge port plus 3 mm, and / or the maximum width is less than or equal to the thickness of the discharge port plus 6 mm. (D6) The portion extending 1 mm or more from the discharge port towards the inlet port is transparent or semi-transparent.

[12] At least a portion of the support surface is coated with a wet apatite composition, and the wet apatite coating is 1 cm 2 A wet apatite-coated support characterized in that when its surface is pressed against 1 cm thick rabbit femoral muscle tissue at 30 kPa for 10 seconds and then peeled off from the muscle tissue, the muscle surface is raised by 0.5 mm or more.

[13] A medical composite characterized in that at least a portion of the surface of the support has at least one selected from the group consisting of a sponge-like structure, a connected porous structure, and an uneven structure, and the interior of the sponge-like structure, the interior of the connected porous structure, and / or the recesses contain at least one selected from the group consisting of metallic silver, metallic silver and wet apatite, silver compounds, silver compounds and wet apatite, metallic copper, metallic copper and wet apatite, copper compounds, copper compounds and wet apatite.

[14] Composition is wet carbonate apatite and / or calcium carbonate, and has a sphericity of 0.9 or more and / or exhibits a hollow structure, and has a volume of 5 × 10 -15 m 3 The above 5 x 10 -13 m 3 A medical calcium composition characterized by the following: [Effects of the Invention]

[0016] This invention provides a wet apatite porous material and a wet apatite curable composition that are excellent in osteoconductivity and bone replacement properties useful in medical applications, a wet apatite composition equipped with a support, a wet apatite composition and related materials for regenerating cartilage, and methods for manufacturing these materials. [Brief explanation of the drawing]

[0017] [Figure 1] This is an explanatory diagram of the names of the screw parts used in the present invention. [Figure 2] These are conceptual diagrams relating to a method of forming interconnected pores from the outset by compounding a hardening composition that hardens to form wet carbonate apatite with wet carbonate apatite granules, and a method of forming bone up to the central part by allowing the hardened paste of the hardening composition to be absorbed in the body. (A) is a conceptual diagram relating to a method in which the paste bridges the wet carbonate apatite granules in general to form interconnected porous bodies. (B) is a conceptual diagram relating to a surgical procedure in the case of medial cavities, etc., in which only the wet carbonate apatite granules on the cavity surface are bridged. (C) is a conceptual diagram relating to a method in which bone is formed up to the central part by allowing the hardened paste to be absorbed in the body. [Figure 3] This is a conceptual diagram of an evaluation method for wet-process apatite compositions useful for cartilage regeneration. [Figure 4] These are schematic diagrams of the dispenser. (A) A perspective view showing the discharge port surface of the dispenser. (B) A perspective view showing the inlet surface of the dispenser. (C) A cross-sectional view perpendicular to the width direction of the discharge port, showing the space through which the paste passes from the center of the discharge port towards the inlet. (D) The dispenser as seen from the discharge surface. [Figure 5] These are SEM images of the wet apatite blocks produced in Experimental Examples 2 and 3. (A) SEM image of the wet apatite block of Example 2 produced at 40°C. (B) SEM image of the wet apatite block of Example 2 produced at 80°C. (C) SEM image of the wet apatite block of Example 3 produced at 40°C. (D) SEM image of the wet apatite block of Example 3 produced at 80°C. [Figure 6] These are SEM images of the product manufactured in Experimental Example 4. (A) SEM image of burr-like aragonite with needle-shaped crystals extending in multiple directions. (B) SEM image of a wet carbonate apatite block with a structure in which burr-like wet carbonate apatite with needle-shaped crystals extending in multiple directions is accumulated. (C) High-magnification SEM image of Figure 6(B). [Figure 7]These are SEM images of the product manufactured in Experimental Example 5. (A) SEM image of wet apatite-coated titanium in which wet apatite with an aspect ratio of 3 or more penetrates the wet apatite layer. (B) SEM image of wet apatite-coated titanium in which wet carbonate apatite with a sphericity of 1 penetrates the wet apatite layer. [Figure 8] These are μ-CT and SEM images of the product manufactured in Experimental Example 11. (A) μ-CT image when wet carbonate apatite honeycomb is used as a support and sponge-structured wet carbonate apatite is fixed inside it. (B) SEM image of sponge-structured wet carbonate apatite formed inside the wet carbonate apatite honeycomb. [Figure 9] These are SEM images of the products manufactured in Experimental Example 20. (A) and (B) are wet carbonate apatite compositions manufactured using aragonite as a raw material. (C) and (D) are wet carbonate apatite compositions manufactured using vaterite as a raw material. (E) and (F) are wet carbonate apatite compositions manufactured using calcite as a raw material. [Figure 10] These are SEM images, mercury intrusion test results, and μCT images related to Experimental Example 23. (A), (B) SEM images of the hardened body manufactured in Experimental Example 23. (C) Results of pore distribution analysis by mercury intrusion method, a graph of cumulative pore volume for pores with a diameter of 10 μm or less relative to the pore diameter. The results for Cytotrans granules are also shown with a dashed line. (D) μCT image at 4 weeks post-surgery when a rabbit femoral defect was reconstructed with Cytotrans granules. (E) μCT image at 4 weeks post-surgery when a rabbit femoral defect was reconstructed with wet carbonate apatite granules manufactured in Experimental Example 23. [Figure 11]These are intraoperative photographs and HE staining images related to Reference Example 3 and Experimental Examples 26-28. (A) Intraoperative photograph when the bone defect was reconstructed using only a hardening composition paste. (B) HE staining image at 12 weeks when the bone defect was reconstructed using a paste formed with Biopex. (C) HE staining image at 12 weeks postoperatively when the bone defect was reconstructed using only a hardening composition paste, which is an equimolar mixture of α-type tricalcium phosphate powder and vatelite powder manufactured in Reference Example 3. (D) Intraoperative photograph when granules are bridged as shown in Figure 1(A). (E) Histopathological image at 4 weeks after reconstruction using the surgical procedure shown in Figure 11(D). (F) Intraoperative photograph when surface granules are bridged as shown in Figure 1(B). (G) Histopathological image at 4 weeks after reconstruction using the surgical procedure shown in Figure 11(F). (H) Histopathological image at 12 weeks related to Experimental Example 28. [Figure 12] These are the macroscopic findings, μCT images, and safranin O staining images at 4 weeks post-surgery for experimental case 30. (A) Macroscopic findings at 4 weeks post-surgery for reconstruction with a wet carbonate apatite honeycomb structure. (B) Macroscopic findings at 4 weeks post-surgery for reconstruction with a wet carbonate apatite gyro structure. (C) Macroscopic findings at 4 weeks post-surgery for reconstruction with a wet carbonate block. (D) Macroscopic findings at 4 weeks post-surgery for the control. (E) μCT image at 4 weeks post-surgery for reconstruction with a wet carbonate apatite honeycomb structure. (F) μCT image at 4 weeks post-surgery for reconstruction with a wet carbonate apatite gyro structure. (G) μCT image at 4 weeks post-surgery for reconstruction with a wet carbonate block. (H) μCT image at 4 weeks post-surgery for the control. (I) Safranin O staining image at 4 weeks post-surgery for reconstruction with a wet carbonate apatite honeycomb structure. (J) This is a safranin O stained image 4 weeks post-surgery after reconstruction with a wet carbon dioxide block. [Figure 13] This is an SEM image of the calcium carbonate aggregate produced in Example 33. [Figure 14] This is a μCT image of a wet carbonate apatite composition with frost crystal pores, relating to Experimental Example 35. [Figure 15] This is a SEM image of a sponge-like, interconnected porous material formed on the surface of a titanium alloy in Experimental Example 45. [Modes for carrying out the invention]

[0018] Hereinafter, the present invention will be described. <1. Wet apatite composition> The present invention relates to a wet apatite composition, and a composition such as a dry apatite like an apatite sintered body is a composition outside the scope of the present invention. Since the usefulness of the wet apatite composition is also affected by the structure and the like, in the present invention [1], it is necessary to be a wet apatite composition and satisfy at least one of the following conditions (A1) to (A5). In some cases, it is more preferable to satisfy a plurality of conditions. <H <A1. Structure of wet apatite composition> The structure of A1 is a wet calcium carbonate apatite powder that satisfies any one of the conditions selected from three groups, or a wet calcium carbonate apatite block having an aggregated structure in which this wet calcium carbonate apatite powder is bonded. The first group is one form selected from the group of a herringbone shape with an aspect ratio of 1.5 or more and less than 3, an aspect ratio of 3 or more, and acicular crystals extending in a plurality of directions, and the surface is wet apatite presenting one form selected from the group of scaly, spherical, and acicular. Wet calcium carbonate apatite with an aspect ratio of 1.5 or more and less than 3, an aspect ratio of 3 or more, and a herringbone shape in which acicular crystals extend in a plurality of directions has a large specific surface area, and thus shows advantages from the viewpoints of osteoconduction and bone substitution. Furthermore, if the surface of these wet calcium carbonate apatites presents any of scaly, spherical, or acicular shapes, osteoclasts and osteoblasts can easily adhere, and it is useful because it increases the adsorption amount of M-CSF and RANKL that promote cell growth and differentiation. The second group is wet apatite having an aspect ratio of 1.5 or more and having a hollow structure. Wet apatite having a hollow structure has a large specific surface area, so the adsorption amount of factors that promote cell growth and differentiation is large, and it is also useful in DDS and the like. Furthermore, if the aspect ratio is 1.5 or more, the DDS effect is large. The third group is wet apatite with a sphericity of 0.9 or more, having a surface in one form selected from the group of scaly, spherical, and needle-like shapes, and a height of 0.2 μm or more. The wet apatite with a sphericity of 0.9 or more has a smaller specific surface area compared to the carbonated apatite in the first group, but the specific surface area increases as the surface morphology height increases. The surface morphology height needs to be 0.2 μm or more, preferably 0.4 μm or more, and more preferably 0.6 μm or more. In the first and third groups, the wet carbonated apatite with an aspect ratio of 3 or more has a particularly large specific surface area, and its aggregate forms a porous body. On the other hand, as the aspect ratio increases, the porosity increases and the mechanical strength decreases. Therefore, when prioritizing mechanical strength, the aspect ratio is preferably 1.5 or more and less than 3.

[0019] <Wet apatite equipped with an <A2 support>> Although wet apatite exhibits excellent tissue affinity and the like, it is a brittle material, so there are still problems with mechanical strength. The composite material (wet apatite-coated support, wet apatite-incorporated support) of wet apatite and a support that satisfies at least one of the conditions (A21) to (A24) is a wet apatite composition having tissue affinity and excellent mechanical strength.

[0020] (A21)'s common essential condition is that at least a part of the support surface with an arithmetic mean surface roughness (Ra) of 1.0 μm or more is coated with a wet carbonated apatite layer. The wet carbonated apatite layer refers to the layer that coats the support surface. Although the mechanism by which the wet apatite layer bonds to the support is not fully understood, it is believed that the wet apatite is bonded to the support by interlocking force, as the wet apatite layer peels off from the support when the support is smooth and free of irregularities, and conversely, the wet apatite layer is strongly bonded to the support when the arithmetic mean surface roughness (Ra) of the support is 1.0 μm or more. If the arithmetic mean surface roughness (Ra) of the support is 1.0 μm or greater, the wet apatite layer can be firmly bonded to the support surface. However, it is the wet apatite layer and / or the wet apatite bonded to the wet apatite layer that come into contact with biological tissue. Therefore, the surface structure and internal structure of the wet apatite layer are important, and the wet carbonate apatite layer of (A21) must satisfy one of the following three conditions. The first group of conditions relates to the surface shape of the wet apatite layer. In order for the wet apatite layer to exhibit excellent bone conduction properties, it must satisfy one of the following conditions: the arithmetic surface roughness (Ra) is 4 μm or more, the wet apatite layer has depressions with a depth of 10 μm or more, or the wet apatite layer contains wet apatite with a hollow structure. The arithmetic mean surface roughness (Ra) of the wet apatite layer is preferably 4 μm or more, more preferably 6 μm or more, and even more preferably 10 μm or more. The depth of the recesses on the surface of the wet apatite layer is preferably 10 μm or more, more preferably 15 μm or more, and even more preferably 20 μm or more. If the wet apatite layer comprises wet apatite having a hollow structure, it is particularly preferable from the viewpoint of accelerating bone replacement. The second group relates to wet apatite penetrating a wet carbonate apatite layer. When any wet apatite selected from the group consisting of an aspect ratio of 3 or more, a spiky shape with needle-like crystals extending in multiple directions, and a sphericity of 0.9 or more penetrates the wet apatite layer, this form of wet carbonate apatite integrates with the wet apatite layer, which is preferable because it induces effects such as increasing the specific surface area. Furthermore, since any wet apatite selected from the group consisting of an aspect ratio of 3 or more, a spiky shape with needle-like crystals extending in multiple directions, and a sphericity of 0.9 or more is integrated with the wet apatite layer, it can also be considered that the structure has a portion of wet carbonate apatite with an aspect ratio of 3 or more, a spiky shape with needle-like crystals extending in multiple directions, and a sphericity of 0.9 or more on the surface of the wet apatite layer. The third group concerns the conditions of the wet apatite layer itself. The wet apatite layer has a porosity of 5% or more and a specific surface area of ​​1 m² as determined by mercury intrusion analysis. 3 The pore volume is 0.1 cm³ or more, with a pore diameter product of 1 μm to 10 μm and a pore volume of 0.1 cm³ or more. 3 If any of the following conditions are met, such as being 1 / g or more, it is preferable because not only will an uneven structure be formed on the surface, but the interior will also become porous, thereby accelerating the bone conduction and bone replacement of the wet apatite layer. A porosity of 10% or more is more preferable, and 15% or more is even more preferable. The specific surface area is 2m². 3 More preferably 3m 3 A concentration of 1 μm or more per g is even more preferable. The pore volume for a pore diameter area of ​​1 μm to 10 μm is 0.2 cm³. 3 More preferably 0.3cm or more per gram. 3 A value of 1 / g or more is even more preferable. The bonding strength between the support and the wet apatite layer is not limited, but a bonding strength of 10 MPa or more is preferred, 15 MPa or more is more preferred, and 20 MPa or more is even more preferred.

[0021] (A22) is the case where a bioabsorbable polymer is used as the support. Because bioabsorbable polymers exhibit flexibility, the wet apatite-coated bioabsorbable polymer becomes flexible when the wet carbonate apatite on the support surface ruptures. Three-dimensional interconnected structures, exemplified by sponges and three-dimensional woven fabrics, are useful for reconstructing damaged areas because they are easy to shape. Porous membranes, such as meshes and nonwoven fabrics, are resistant to delamination because wet apatite is introduced into the interior of the support and composited with it. Membranes with holes are also resistant to delamination because wet apatite is bonded at the holes. Membranes containing wet apatite are resistant to delamination because the wet apatite inside the support and the wet apatite covering the support are bonded together. In the case of a film, if the wet apatite on the support surface has notches, it will break at the notches when bending stress or other forces are applied, reducing the force that would cause the wet apatite to peel off the support. Therefore, it can be useful if the wet apatite on the support surface has notches that divide it vertically and horizontally like a grid. Furthermore, since wet apatite is replaced by bone and other materials, if the support is a bioabsorbable polymer, the entire composition will be replaced by bone and other materials. Since it is the wet apatite that exhibits osteoconductivity, it is essential that the wet apatite coats at least a portion of the bioabsorbable polymer. The coating rate of the support with wet apatite is preferably 40% or more, more preferably 70% or more, and even more preferably 90% or more.

[0022] (A23) is the case of a support exhibiting a screw structure. Screws are sometimes called threaded screws, but the two are the same. The names of the threaded parts used in this invention are as shown in Figure 1. One condition is that the wet apatite covers at least 5% of the thread height from the valley to the peak. The peak height is half the difference between the outer and inner diameters of the thread. The covering height is preferably 10% or more of the peak height, more preferably 20% or more, and even more preferably 30% or more. Even less than 5% is effective in improving bone conduction, but the effect may be limited. This height is the height to cover the thread, not the height to completely block the thread. For the wet apatite layer to bond with the screw, it is preferable that the wet apatite covers at least one of the following areas: areas where the arithmetic mean surface roughness (Ra) of the screw is 1.0 μm or more, recesses or protrusions on the surface of the screw, grooves formed on the crest side of the screw, or areas where part of the crest of the screw has been removed. Except for the condition where part of the crest of the screw is removed, the bonding strength is thought to be increased by the mechanism described in explanation (A21). On the other hand, when wet apatite covers a portion of the threads of a screw that has been partially removed, it is thought that the wet carbonate apatite present in the removed threads is bonded to the wet apatite in the valleys, etc., which reduces the shear stress on the wet apatite in the valleys, etc., that occurs when the screw is embedded. Furthermore, it is thought that the force that causes the wet apatite to peel off due to the surrounding threads when the screw is embedded is not applied to the wet carbonate apatite present in the removed threads.

[0023] (A24) relates to a wet apatite-embedded support in which wet apatite of a specific structure is fixed inside the support. The support may or may not have undercuts. An undercut is a recess that is larger than the opening when the support is viewed from the central axis direction of the pores inside the support. If a material with the same structure as the pores is placed in the pore portion of a support with undercuts, the material cannot be removed from the support. During the process of forming wet apatite inside the support, precursors such as calcium carbonate honeycomb expand, or wet carbonate apatite with a specific structure is manufactured inside the support, allowing wet apatite to be installed even in supports with undercuts. In the case of supports without undercuts, it can be installed tightly. The support structure ensures mechanical strength, while the wet-process apatite performs functions such as bone conduction and bone replacement. Porosity of 30% or more, and / or pores with a pore diameter of 10 μm or less and a pore volume of 0.2 cm³ 3 One condition is that wet apatite with a concentration of 1 / g or more is fixed. A porosity of 40% or more is more preferable, and 50% or more is even more preferable. In addition, the pore volume of pores with a pore diameter of 10 μm or less is 0.2 cm³. 3 / g or more, but 0.3cm3 Preferably 0.4 cm or more per gram. 3 More preferably 0.5 cm or more, 3 A value of 1 / g or more is even more preferable. Furthermore, the wet apatite must exhibit a structure selected from the group consisting of a honeycomb structure with multiple through-holes extending in one direction, a structure with frost-pillar-like pores, a three-dimensional interconnected structure with multiple through-holes extending in multiple directions, a sponge structure, a gyro structure, a porous structure, and an aggregated structure.

[0024] (A3) is a condition relating to a specific curable composition that comprises a water-soluble phosphate in a solid or liquid portion and hardens by forming wet apatite. Basically, solids other than the water-soluble phosphate contained in the solid part react with the phosphate aqueous solution to form wet apatite, which then hardens. If the solid part contains water-soluble phosphate, when the solid part is exposed to water, the water-soluble phosphate becomes a phosphate aqueous solution. As a result, it reacts with solids other than the water-soluble phosphate contained in the solid part to form wet apatite, which then hardens. Therefore, both harden by substantially the same hardening mechanism. The formation of wet carbonate apatite is an essential condition, but it is not necessary for the entire hardened body to become wet carbonate apatite. Basically, it is a curable composition consisting of a solid part and a liquid part, but (A32) is a curable composition consisting of granules, a powder part, a liquid part, or granules only, or granules and a liquid part.

[0025] To date, curable compositions that form and harden wet apatite have required calcium phosphate as an essential component. Furthermore, curable compositions containing multiple calcium phosphates required control of the particle size of the calcium phosphate. Among (A31), the effective composition related to (A311) is essentially different from the curable compositions invented to date, in which the calcium component necessary for wet apatite formation is supplied from calcium carbonate or calcium sulfate, and the phosphate component is supplied from a water-soluble phosphate. This makes it easier to control the microstructure of the hardened material, eliminates the need to control the particle size of powders of different compositions, and reduces manufacturing costs. There are no restrictions on the polymorphism of calcium carbonate; calcite, vaterite, aragonite, and amorphous calcium carbonate can be used. From the viewpoint of reactivity, vaterite, aragonite, and amorphous calcium carbonate, which are metastable phases, are preferred. Furthermore, from the viewpoint of microstructure control, when forming a porous body, calcium carbonate with an aspect ratio of 3 or more, a spiky structure with needle-like crystals extending in multiple directions, a hollow structure, or a sphericity of 0.9 or more is preferred. In the case of a curable composition that hardens by forming a wet hydroxyapatite composition, calcium sulfate that does not contain carbonate groups is preferred.

[0026] The curable composition (A312) is a curable composition that requires rapid curing and a balance between mechanical strength and porosity. The powder portion is a mixture of calcium carbonate with an aspect ratio of 3 to 51 and tricalcium phosphate or calcium hydrogen phosphate with a particle size smaller than 2 μm. The powder portion may also contain a water-soluble phosphate. Calcium phosphate with a smaller average particle size dissolves faster. Therefore, using tricalcium phosphate with a particle size smaller than 2 μm, or calcium hydrogen phosphate with high solubility, will shorten the curing time. Tricalcium phosphate with an average particle size smaller than 2 μm dissolves faster and has a shorter curing time. The average particle size needs to be smaller than 2 μm, but 1.8 μm or less is more preferable, and 1.4 μm or less is even more preferable. The curable composition according to (A313) is a curable composition with a high porosity of the cured body. The powder portion is a mixture of the specific calcium carbonate described in (A312) and tricalcium phosphate or calcium hydrogen phosphate. The powder portion may also contain a water-soluble phosphate.

[0027] (A32) is a hardening composition intended to harden or fix granules within the bone defect, as shown in Figure 2, thereby enabling rapid bone formation up to the center of the bone defect. The paste formed by mixing the powder and liquid portions has a volume of 5 × 10⁻¹⁴, as shown in Figure 2(A) or Figure 2(B). -13 m 3 The above is 2 x 10 -8 m 3At least a portion of the following wet-processed carbonate apatite granules can be bridged to form a interconnected porous body. This allows for rapid bone formation up to the center of the bone defect. Furthermore, even when granules and paste are mixed as shown in Figure 2(C), if the wet carbonate apatite formed when the paste hardens is absorbed faster in the body than the wet carbonate apatite granules, bone will be rapidly formed up to the center of the bone defect. To accelerate the absorption rate of the wet carbonate apatite formed when the paste hardens, the porosity can be increased.

[0028] When using wet-process carbonate apatite granules, direct bonding between granules cannot be expected, but the volume of tricalcium phosphate powder, or a mixed powder of tricalcium phosphate and calcium carbonate, bonded by calcium phosphate bridging is 5 × 10 -13 m 3 The above is 2 x 10 -8 m 3 By using the following granules, wet apatite crystals are formed on the granule surface through a dissolution reaction, and the granules are directly bonded to each other by the entanglement of the formed wet apatite crystals. This granular curable composition can be cured with water, but the curing time is long. Therefore, an aqueous solution of phosphate or an aqueous solution of polycarboxylic acid salt is preferred from the viewpoint of shortening the curing time. An aqueous solution of polycarboxylic acid salt is effective for initial curing, and even when an aqueous solution of polycarboxylic acid is used, the granular curable composition hardens due to the entanglement of wet apatite crystals formed on the surface.

[0029] (A33) is a curable composition consisting of tricalcium phosphate granules and an aqueous phosphate solution at a specific pH. When tricalcium phosphate granules are exposed to an aqueous phosphate solution at a specific pH (pH 3 or higher and less than 8), wet apatite crystals precipitate on the surface of the granules, and the granules harden due to the entanglement of the wet apatite crystals. The pH of the aqueous phosphate solution is more preferably 3.3 or higher and 6 or lower, and even more preferably 3.6 or higher and 5 or lower. α-type tricalcium phosphate is preferred as the tricalcium phosphate. Although tricalcium phosphate hardens even at a pH lower than 3, hemolysis is induced, so the pH must be 3 or higher. It is essential that the hardened product ultimately forms wet apatite, but octacalcium phosphate or the like may be formed immediately after the reaction. The tricalcium phosphate granules may be made by grinding a sintered body to a specific size, or by bonding tricalcium phosphate powder with wet apatite.

[0030] (A4) is a chemically synthesized wet apatite composition related to cartilage formation. The ability to regenerate cartilage is evaluated by the presence or absence of cartilage regeneration in bone defects in the trochlea of ​​the femur of rabbits. If there is doubt about the evaluation, a tissue defect of φ3.5 mm is created in the trochlea of ​​the femur of rabbits as shown in Figure 3, and the defect is reconstructed with wet apatite so as to be 2.0 mm to 3.0 mm below the surrounding hyaline cartilage. Four weeks postoperatively, the tissue including the tissue defect is excised, and the evaluation is made by checking whether the wet apatite has bonded with the surrounding bone and whether cartilage bonded with the surrounding cartilage has formed on the surface of the wet apatite. Since this is an evaluation using experimental animals, the study is performed on both sides of four individual animals, and if bonding with the surrounding bone and cartilage formation are observed in 50% or more, it is judged to have the ability. Although the mechanism by which wet apatite promotes cartilage regeneration is not yet understood, it is hypothesized that wet apatite allows bone marrow-derived mesenchymal stem cells supplied from the bone marrow to engraft and differentiate into cartilage in areas in contact with the cartilage.

[0031] (A5) relates to a specific wet apatite-coated support composition. Wet apatite has excellent osteoconductivity, but calcium carbonate, which dissolves easily, may have superior bioabsorption. Therefore, wet apatite-coated calcium carbonate may exhibit the same osteoconductivity as a composition consisting only of wet apatite, and may also have superior bioabsorption. Furthermore, sintered dry hydroxyapatite and dry tricalcium phosphate exhibit excellent mechanical strength. Therefore, dry apatite coated with wet apatite may exhibit the same osteoconductivity as a composition consisting solely of wet apatite, while also possessing superior mechanical strength. Wet apatite-coated calcium carbonate can be produced by exposing calcium carbonate to a phosphate aqueous solution and stopping the exposure before all of the calcium carbonate is converted to wet apatite. Dry apatite-coated wet apatite can be produced by immersing dry apatite in a phosphoric acid aqueous solution, converting the surface to calcium hydrogen phosphate, and then immersing it in a phosphate aqueous solution or carbonate aqueous solution.

[0032] <2. Wet-process carbonate apatite composition> The present invention [2] is a wet carbonate apatite composition comprising 3% or more by mass, 5% or more by mass, or 7% or more by mass of carbonate groups. The amount of carbonate groups is the content in the total apatite composition. The composition may also comprise a composition other than wet carbonate apatite. Perhaps because the inorganic composition of bone is carbonate apatite, wet carbonate apatite has superior bone replacement properties compared to wet hydroxyapatite. In the present invention [2], the amount of carbonate groups is 3% or more by mass, 5% or more by mass, or 7% or more by mass, but generally, the more carbonate groups there are, the better the bone replacement properties, so carbonate apatite comprising 7% or more by mass of carbonate groups is most preferred.

[0033] <3. Wet-processed apatite containing metal salts, etc.> The present invention [3] is a wet apatite composition according to the present invention [1], characterized by comprising at least one selected from the group consisting of a metal salt, a metal with a diameter of 1 μm or less, a growth factor, a drug, and a bioabsorbable polymer. Unlike dry apatite produced by sintering, wet apatite can be made to contain metal salts, growth factors, drugs, and bioabsorbable polymers that are thermally decomposed at high temperatures. The wet apatite composition creates a weakly acidic environment within the fossa formed by osteoclasts, dissolving the bone and thus harmonizing with bone remodeling, resulting in replacement with new bone. Meanwhile, the infection site also becomes a weakly acidic environment. Therefore, by incorporating antimicrobial drugs, antimicrobial metals such as silver or copper with a diameter of 1 μm or less, or antimicrobial metal salts such as silver compounds or copper compounds into the wet apatite composition of the present invention [1], an infection-sensitive wet apatite composition is obtained. Furthermore, by incorporating growth factors, strontium with a diameter of 1 μm or less, or strontium compounds, it becomes possible to promote bone remodeling and wound healing. The wet apatite composition of the present invention [1] not only replaces the bone with new bone, but also regenerates cartilage when implanted in cartilage defects. To improve this function, it is extremely useful to impart copper, copper compounds, or bioabsorbable polymers such as collagen, gelatin, and chondroitin sulfate. Furthermore, wet carbonate apatite has greater solubility in the weakly acidic range compared to wet hydroxyapatite. For this reason, a wet carbonate apatite composition is preferred over a wet hydroxyapatite composition in the present invention [3]. It is also preferable that the entire composition be wet carbonate apatite.

[0034] <4. Wet-process carbonate apatite with a specific structure coated with metal salts, etc.> The present invention [4] relates to a wet carbonate apatite composition in which a specific material such as a metal salt is coated with wet carbonate apatite, and exhibits a specific structure such as a hollow structure. The specified material is at least one selected from the group consisting of metal salts, metals with a diameter of 1 μm or less, growth factors, drugs, and bioabsorbable polymers, and the specified material must be coated with wet carbonate apatite having a carbonate group content of 3% by mass or more, 5% by mass or more, or 7% by mass or more. The specific structure may satisfy any of the following conditions: having a hollow structure and / or an aspect ratio of 3 or more, and / or having a surface that exhibits one form selected from the group consisting of flaky, spherical, or needle-shaped, or exhibiting an aggregate structure formed by the bonding of such powders. It is not limited to other structures exemplified by powders, powder aggregates, film-like structures, etc. The wet apatite composition of the present invention [4] is not limited to a manufacturing method, but for the purpose of understanding the wet apatite composition of the present invention [4], an example of a manufacturing method of the present invention [4] using aragonite powder as a raw material will be described. When aragonite powder is immersed in an aqueous silver nitrate solution, silver carbonate, which has a solubility of 0.0032 in water, precipitates on the surface of the aragonite powder through a dissolution and extraction reaction. Next, when the silver carbonate-supported aragonite powder is immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C, the aragonite powder is transformed into wet carbonate apatite powder through a dissolution and extraction reaction. In this dissolution and extraction reaction, Ca 2+ and CO3 2- It is separated. PO4 is present in the aqueous solution. 3- Because of the presence of these substances, the solution becomes supersaturated with respect to the carbonate apatite, and the wet carbonate apatite precipitates on the silver carbonate-supported aragonite surface. Therefore, the wet carbonate apatite, having a carbonate group content of 3% or more by mass, 5% or more by mass, or 7% or more by mass, coats with at least one selected from the group consisting of metal salts, metals with a diameter of 1 μm or less, growth factors, drugs, and bioabsorbable polymers, which have a solubility in water of 1 or less. Because metal salts and the like are coated with wet carbonate apatite, they possess functionalities different from simple mixtures. For example, antibacterial metals such as silver, silver compounds, copper, and copper compounds change pH upon infection. The material is not exposed to biological tissue until the wet carbonate apatite dissolves. In other words, it becomes an infection-sensitive composition.

[0035] In the present invention [4], from the viewpoint of the manufacturing method, the solubility of metal salts, etc., in water must be 1 or less. In principle, it is possible for wet carbonate apatite to coat metal salts, etc., even if the solubility in water is greater than 1, but from the viewpoint of manufacturing efficiency, the solubility in water is limited to 1 or less. Solubility varies with temperature, but it is sufficient if the solubility in water is 1 or less at any temperature. Wet-processed carbonate apatite has metal salts or the like coated on the centrifugal side from the central axis of its hollow structure, or from the center to the centrifugal side. When the wet-processed carbonate apatite coating the metal salts is absorbed by osteoclasts, the metal salts are exposed to body fluids. Therefore, it is extremely useful from the viewpoint of controlling the concentration of metal salts.

[0036] <5. A specific structure of aggregated material formed by the bonding of wet-process carbonate apatite powder> The present invention [5] is a wet apatite composition in which the aggregated structure formed by the wet carbonate apatite powder described in (A1) exhibits a specific structure. The aggregated structure formed by the wet carbonate apatite powder described in (A1) exhibits a specific microstructure, and further exhibiting a specific structure may improve biological functions. Honeycomb structures with multiple through-holes extending in one direction, three-dimensional porous bodies with multiple through-holes extending in multiple directions, gyroid structures, sponge-like structures, and structures with frost-pillar-like pores are useful for forming bone and other tissues within the structure because they have through-holes. On the other hand, the gaps between granules are useful for forming bone and other tissues in the central part of bone defects, etc. Tetrahedrons, hexahedrons, cylinders, with a volume of 5 × 10 -7 m 3The granules described below have excellent ability to form tissue such as bone between particles by allowing the structures to adhere closely to each other. Structures with multiple legs, such as tetrapods and hexapods, not only allow tissue to form between granules but also fix the granules together, making them useful for reconstructing lateral defects. Cylinders are also useful when fitting standardized tissue defects using drills, etc. Note that the compositions of the present invention are medical materials, and since structures useful for tissue formation are desired, the structure of the composition is defined as a general shape. For example, the vertices of a tetrahedron structure do not need to be acute angles. Compositions with rounded vertices or edges of a tetrahedron structure are also defined as tetrahedron structures. Furthermore, the porosity is 30% or more, and / or the pore diameter is 0.10 μm or more and 10 μm or less, and the pore volume is 0.2 cm³. 3 Accumulated structures with a concentration of 1 / g or higher are useful for bone replacement and bone conduction. Furthermore, it is a requirement of the present invention [1](A1) that the aggregated structure be coated with wet carbonate apatite in one form selected from the group of flaky, spherical, and needle-shaped, but a larger surface morphology height is preferable. The surface morphology height is preferably 0.2 μm or more, more preferably 0.4 μm or more, and even more preferably 0.6 μm or more. The height is measured by scanning electron microscopy or the like.

[0037] <6. Specific method for producing wet carbonate apatite with a specific structure> The present invention [6] is a method for producing calcium carbonate of a specific structure by exposing it to an aqueous phosphate solution to convert the composition from calcium carbonate to wet carbonate apatite while maintaining the macrostructure. The method for manufacturing an aggregate structure formed by bonding calcium carbonate powder that satisfies any of the following conditions: an aspect ratio of 1.5 or more and less than 3, an aspect ratio of 3 or more, a burr-like structure in which needle-shaped crystals are extended in multiple directions, or a hollow structure. For example, the powder may be sintered by heat treatment under a carbon dioxide gas stream. Calcium carbonate structures with frost-like pores are produced by forming frost-like ice in a slurry consisting of calcium carbonate and an aqueous solution of a water-soluble polymer such as gelatin. The slurry temperature is lowered in one or all directions to allow the ice to grow into frost-like structures, and then the water-soluble polymer is removed by heat treatment. When these specific structures of calcium carbonate are exposed to an aqueous phosphate solution, they maintain their macrostructure while their composition is converted from calcium carbonate to wet carbonate apatite from the surface. To produce wet carbonate apatite-coated calcium carbonate, exposure to the aqueous phosphate solution should be terminated before the calcium carbonate is completely converted to wet carbonate apatite. On the other hand, to produce a composition that is entirely wet carbonate apatite, exposure to the aqueous phosphate solution should be continued until the calcium carbonate is completely converted to wet carbonate apatite. Furthermore, when calcium carbonate of a specific structure is exposed to a phosphate aqueous solution to convert its composition from calcium carbonate to wet carbonate apatite, the surface of the wet carbonate apatite is covered with either flaky, spherical, or needle-shaped wet carbonate apatite crystals. The factors that determine the microstructure of the wet apatite crystals formed on the surface are not yet fully understood, but it is thought that the microstructure is basically determined by crystal nucleation and crystal growth. For example, wet carbonate apatite with a low degree of crystallinity close to amorphous has limited crystal growth, making it difficult to form flaky, spherical, or needle-shaped crystal forms, and even if they do form, the height of the surface morphology is small. Crystal growth is extremely complex and cannot be controlled by a single factor, but temperature and concentration are important factors. Generally, crystals grow larger at higher temperatures, but in the case of carbonate apatite production by dissolution extraction, crystal growth is limited at higher temperatures, possibly because many crystal nuclei grow. Therefore, the temperature of the phosphate aqueous solution is preferably between 0°C and 50°C, more preferably between 5°C and 40°C, and even more preferably between 10°C and 30°C.

[0038] The concentration of the phosphate aqueous solution also controls crystal growth. If the concentration of the phosphate aqueous solution is high, the degree of supersaturation with respect to carbonate apatite increases, making it difficult to form crystalline forms such as flaky, spherical, and needle-like structures, and even if they do form, the surface height of the crystalline structure will be small. The concentration of the phosphate solution is preferably 0.5 mol / L or less, more preferably 0.4 mol / L or less, and even more preferably 0.3 mol / L or less. However, if the phosphate concentration is low, the time required for compositional conversion increases, and it becomes necessary to expose the material to a large amount of phosphate solution. Therefore, in manufacturing, it is necessary to consider the balance between crystal growth and manufacturing time.

[0039] <7. Method for manufacturing a specific wet carbonate apatite coated support> The manufacturing method of the present invention [7] is useful as a method for manufacturing a wet apatite coated support that satisfies the conditions of the present invention [1](A2). (B1) is a manufacturing method for producing a specific wet carbonate apatite coated support by coating the surface of the support with a specific calcium carbonate layer, and then exposing the specific calcium carbonate coated support to a water-soluble phosphate. To form a calcium carbonate layer on the surface of a support, calcium carboxylates such as calcium nitrate solution or calcium acetate solution are used. Calcium nitrate decomposes into calcium carbonate when heated in the presence of carbon dioxide, and calcium carboxylate also decomposes into calcium carbonate when heated. Since both are solutions, they are useful for forming calcium carbonate in depressions on the surface of the support. On the other hand, to form a specific structure such as irregularities on the surface of a wet calcium carbonate layer covering a support, it is useful to either impart calcium carbonate with a specific structure to a calcium carbonate layer formed from a calcium nitrate solution or a calcium acetate solution, or to impart a pore-forming material to the calcium carbonate layer. In the former case, calcium carbonate exhibiting one form selected from the group consisting of an aspect ratio of 3 or more, a spiky shape with needle-like crystals extending in multiple directions, or a sphericity of 0.9 or more is mixed into the solution. In the latter case, a pore-forming material is mixed into the solution. The solvent for the calcium nitrate solution or calcium acetate solution is not particularly limited, but ethanol, isopropanol, water, etc. are useful from the viewpoint of drying, etc.

[0040] These mixtures are applied to a support having an arithmetic mean surface roughness (Ra) of 1.0 μm or more by methods such as coating or dipping, and after drying as necessary, the calcium nitrate or calcium carboxylate on the support surface is thermally decomposed to convert it to calcium carbonate. In the case of calcium carboxylate, it is converted to calcium carbonate simply by thermal decomposition, but to convert calcium nitrate to calcium carbonate, thermal decomposition in the presence of carbon dioxide is necessary. Calcium carbonate exhibiting one form selected from the group consisting of an aspect ratio of 3 or more, a spiky shape with needle-like crystals extending in multiple directions, or a sphericity of 0.9 or more, is fixed to the support by the calcium carbonate layer formed by thermal decomposition. In addition, if the porosity-forming material is a polymer, the porosity-forming material is incinerated during the heat treatment stage. After the calcium carbonate coating step, the product of this step is exposed to an aqueous phosphate solution to convert the calcium carbonate portion of the product into wet carbonate apatite. If the porosity-forming agent is a water-soluble inorganic porosity-forming agent such as sodium chloride, the porosity-forming agent dissolves at this stage. As described in (A21), wet apatite is thought to be bonded to the support by interlocking forces. The manufacturing method of producing wet carbonate apatite by exposing calcium carbonate to an aqueous phosphate solution is a dissolution-precipitation reaction, and generally the precursor is detached from the support at the dissolution stage of the precursor. However, in the case of calcium carbonate, the dissolution reaction and the precipitation reaction occur almost simultaneously, and the precipitated wet apatite expands, so it is thought to be firmly bonded to a support with an arithmetic mean surface roughness (Ra) of 1.0 μm or more.

[0041] In (B1), the expansion reaction in the depressions on the support surface during the formation of wet carbonate apatite from calcium carbonate is the mechanism for the strong bonding between the support and the wet carbonate apatite layer. Therefore, by applying a precursor of wet apatite to the depressions on the support surface, a wet apatite-coated support can be manufactured in which the wet apatite and the support are strongly bonded. In (B2), a precursor of solid wet apatite is applied to the recesses on the surface of the support. Useful precursors for wet carbonate apatite include calcium oxide, calcium hydroxide, calcium carbonate, and curable compositions that harden to form wet carbonate apatite. Similarly, useful precursors for wet hydroxyapatite include curable compositions that harden to form wet hydroxyapatite. Except for (B242), these are solids and therefore more difficult to apply to recesses compared to liquids. For this reason, methods such as application as a suspension or pressure welding are effective. Furthermore, modifying the support with a polyvalent carboxylate can increase the bonding strength because the polyvalent carboxylate binds to hydroxyl groups on the support and precursor surfaces. In the case of calcium oxide, adding water converts it to calcium hydroxide, which then expands. Adding carbon dioxide to calcium hydroxide converts it to calcium carbonate, which also expands. When calcium carbonate is treated with phosphate, it becomes wet carbonate apatite and expands. In the case of calcium carbonate, it is possible to impart calcium carbonate to the recesses of the support not only using the powder (B241) but also using a solution. As described in (B242), calcium carbonate solution and calcium bicarbonate solution are preferred. Since the calcium carbonate concentration of the calcium carbonate solution is limited, a calcium bicarbonate solution is more preferred. Calcium carbonate can be imparted to the recesses of the support by drying or heating these solutions. Curable compositions that harden to form apatite expand during the curing reaction.

[0042] <8. Method for manufacturing a wet carbonate apatite-containing support> The manufacturing method of the present invention [8] is useful as a method for manufacturing a support containing a wet apatite composition. Basically, calcium carbonate is exposed to an aqueous phosphate solution inside the support to form wet carbonate apatite by a dissolution and extraction reaction. As described in the explanation of the term dissolution and extraction reaction, expansion and hardening reactions occur in the dissolution and extraction reaction. Furthermore, even in composite materials that contain a wet carbonate apatite-coated calcium carbonate composition inside the support, as described above, if the exposure to the aqueous phosphate solution is interrupted before the calcium carbonate powder or calcium carbonate block is completely converted to wet carbonate apatite, a composite material containing a wet carbonate apatite-coated calcium carbonate inside the support can be manufactured. The manufacturing method for (C1) is a method that utilizes the hardening reaction accompanying the dissolution and extraction reaction to convert one of the calcium carbonate powders of (C1) into a wet carbonate apatite composition inside the support and fix it to the support. When one of (C1) is mixed with a water-soluble pore-forming agent or a water-soluble phosphate and the dissolution and extraction method is performed, the water-soluble pore-forming agent or water-soluble phosphate is dissolved, so that pores can be further imparted to the wet carbonate apatite composition. The manufacturing method for (C2) is useful when the external shape of any of the (C2) calcium carbonate blocks is approximately the same as and slightly smaller than the internal shape of the support. By utilizing the expansion reaction associated with the dissolution and extraction reaction, any of the (C2) calcium carbonate blocks are converted to wet carbonate apatite inside the support, and the wet carbonate apatite is fixed to the support by the expansion associated with the dissolution and extraction reaction.

[0043] <9. Hollow structures with specific compositions> The present invention [9] relates to a hollow structure wet calcium powder, or a hollow structure wet calcium aggregate having a structure in which hollow structure wet calcium powder is accumulated. The requirements for hollow structures vary depending on their composition. If the composition is one of the following: calcium phosphate powder, calcium hydrogen phosphate powder, tricalcium phosphate powder, apatite powder, or octacalcium phosphate powder, then the aspect ratio must be 3 or greater. On the other hand, when the composition is calcium carbonate, it is necessary to satisfy one of the following conditions: an aspect ratio of 10 or more, a major axis length of 60 μm or more, a major axis maximum length of 5 μm or more, or a shell thickness of 1 μm or more. These conditions are due to the characteristics of calcium carbonate, such as its high solubility compared to hollow structures of other compositions. The shell thickness that forms the hollow structure is half the value obtained by subtracting the inner diameter from the outer diameter of the hollow structure, and is preferably 1 μm or more, more preferably 1.5 μm or more, and even more preferably 2 μm or more.

[0044] <10. Manufacturing method for hollow structures of specific composition> The present invention

[10] relates to a method for producing hollow-structured wet calcium. When calcium sulfate under specific conditions, which is a precursor, is immersed in an aqueous carbonate solution, the calcium sulfate is converted to calcium carbonate while maintaining its macrostructure by dissolution extraction. In this process, the calcium sulfate of the specific structure becomes calcium carbonate exhibiting a hollow structure. The production method is not limited as long as the calcium sulfate has the specific structure. It may be produced by suspending calcium sulfate hemihydrate in water or by extrusion molding. Immersing hollow-structured wet calcium carbonate in a weakly acidic phosphate solution produces hollow-structured calcium hydrogen phosphate or hollow-structured calcium-deficient hydroxyapatite. Heat treatment of hollow-structured calcium-deficient hydroxyapatite produces hollow-structured tricalcium phosphate, and immersing hollow-structured calcium hydrogen phosphate in a disodium hydrogen phosphate aqueous solution produces hollow-structured octacalcium phosphate. Immersing hollow-structured wet calcium carbonate in a sodium dihydrogen phosphate aqueous solution or the like produces hollow-structured wet octacalcium phosphate.

[0045] <11.Dispenser> The present invention

[11] is useful when forming a connected hardened body as shown in Figure 2(B) in a bone defect or the like using a hardened composition such as the present invention [1](A3). When reconstructing a medial cavity, granules are filled into the cavity, and then a hardened composition paste that forms wet apatite and hardens is applied to the surface of the granules using a cement spatula or the like. The hardening of the paste forms highly interconnected pores. However, when attempting to seal the surface of the granules with the paste using a cement spatula or the like, the granules move, making the operation complicated, and the thickness of the paste becomes thick. On the other hand, by using the dispenser shown in Figure 4 to dispense the strip-shaped paste onto the granule surface, and then shaping it with a cement spatula or the like, the granule surface can be sealed with a hardened body of the hardenable composition that is thin in thickness.

[0046] (D1) is a necessary condition for dispensing a strip-shaped cement paste. Theoretically, a strip-shaped paste will be dispensed if the value obtained by dividing the width of the discharge port by the thickness is greater than 1, but the effect is limited. Therefore, the value obtained by dividing the width (l1) of the discharge port by the thickness (t1) must be 2 or more. This value is preferably 3 or more, more preferably 5 or more, and even more preferably 10 or more. The thickness of the discharge port is not limited, but is preferably 2 mm or less, more preferably 1.5 mm or less, and even more preferably 1 mm or less. 0.5 mm or less is ideal.

[0047] (D2) is a condition for the space through which the paste passes in the dispenser. If the value obtained by dividing the maximum area of ​​the space through which the paste passes in the dispenser and the plane perpendicular to the straight line passing through the center of the dispenser opening and the center of the inlet opening overlap by the area of ​​the dispenser opening is greater than 1, the paste discharged from the dispenser opening is constricted, so that a band-shaped cement paste is stably discharged from the entire surface of the dispenser opening. This value is preferably 1.5 or more, more preferably 2 or more, and even more preferably 2.5 or more. (D3) is a condition relating to the thickness of the inner surface of the discharger near the discharge port, which is the surface of the space through which the discharger paste passes. When the thickness (t1) of the space through which the discharger paste passes from the center of the discharge port toward the injection port is the same as the thickness (T1) of the discharge port, and the length (f) from the discharge port is 0.3 mm or more, a stable strip-shaped cement paste is discharged. The length (f) is preferably 0.5 mm or more, more preferably 0.7 mm or more, and even more preferably 1.0 mm or more. 1.5 mm or more is ideal.

[0048] (D4) is a condition relating to the thickness of the discharge surface and the discharge port of the dispenser, or the width of the discharge surface and the discharge port of the dispenser. When dispensing the paste formed by the medical curable composition in a strip shape, it is necessary to dispensing uniformly under direct visualization of the bone defect, etc., and to move the dispenser at a constant speed. In addition, it is necessary to bring the discharge port close to the granules so that the angle between the surface of the granule aggregate and the paste is small. For this reason, the thickness of the discharge surface (T1) of the dispenser must be less than or equal to the thickness of the discharge port (t1) plus 2 mm. This value is preferably 0.6 mm or less, more preferably 0.4 mm or less, and even more preferably 0.2 mm or less. The thickness of the discharge surface and the discharge port of the dispenser may be the same. Similarly, the width of the discharge surface (L1) of the discharger must be less than or equal to the width of the outlet (l1) plus 2 mm. This value is preferably 0.6 mm or less, more preferably 0.4 mm or less, and even more preferably 0.2 mm or less. The width of the discharge surface and the width of the outlet of the discharger may be the same. While any one of the conditions regarding the thickness of the discharge surface and outlet of the discharger, or the width of the discharge surface and outlet of the discharger, may be useful, it is preferable to satisfy both.

[0049] (D5) is a condition relating to the overall external shape of the dispenser. As described above, when dispensing the paste formed by the medical curable composition onto the surface of granules in a strip, it is necessary to dispensing uniformly under direct visualization of bone defects, etc., and to move the dispenser at a constant speed. In addition, it is necessary to bring the dispensing port close to the granules so that the angle between the surface of the granule aggregate and the paste is small. For this reason, the dispenser must also satisfy the conditions regarding its external shape. Specifically, it is preferable that the maximum thickness of the outer surface of the dispenser where a plane perpendicular to the straight line passing through the center of the dispensing port and the center of the injection port overlaps is no more than the thickness of the dispensing port plus 3 mm, and / or the maximum width is no more than the thickness of the dispensing port plus 6 mm.

[0050] (D6) is a condition relating to the transparency of the dispenser. In order to dispense the paste in a strip onto the granules, it is preferable that the paste inside the dispenser be visible. Therefore, the dispenser must be transparent or semi-transparent for a length of 1 mm or more from the discharge port towards the injection port. This length is preferably 1.5 mm or more, more preferably 2 mm or more, and even more preferably 3 mm or more. Ideally, the entire dispenser should be transparent or semi-transparent. In the present invention

[11] , a dispenser is defined as transparent or translucent if the paste inside the dispenser can be visually inspected, but if there is any doubt, measurement shall be performed using a spectrophotometer. A dispenser is defined as translucent if the absorbance at any wavelength between 360 nm and 830 nm, which are visible light wavelengths, is 2 or less.

[0051] <12. Wet apatite-coated support that adheres to soft tissue> The present invention

[12] relates to a wet apatite-coated support that adheres to soft tissues such as muscle tissue. A wet apatite-coated support comprising a specific wet apatite adheres to soft tissues such as muscle tissue. The effectiveness is verified using muscle tissue, which is representative of soft tissues. For example, in measurements using the mercury intrusion method, if the pore volume is 0.03 cm³ with a pore diameter product of 0.01 μm or more and 1 μm or less, 3 If the amount is 1 cm or more, the wet apatite coating is 2When the surface is pressed against 1 cm thick rabbit femoral muscle tissue at 30 kPa for 10 seconds, and then peeled away from the muscle tissue, the muscle surface is elevated by 0.5 mm or more. The longer the elevation length from the muscle surface, the higher the adhesive strength between the wet apatite and the muscle tissue; therefore, an elevation length of 0.8 mm or more is more preferable, and 1 mm or more is even more preferable. Although the mechanism by which wet apatite bonded to the support material binds to soft tissues such as muscle tissue is not yet understood, titanium plates with arithmetic mean surface roughness of 1 μm and 5 μm do not elevate muscle tissue, suggesting that this may be a property unique to wet carbonate apatite-coated supports exhibiting a specific interconnected pore structure.

[0052] <13. Medical metal materials having a specific antimicrobial composition on their surface> The present invention

[13] is a medical metal material having a specific antimicrobial composition within a specific surface structure, which is useful for plates and screws for artificial hip joints, artificial knee joints, fracture fixation, etc. In this medical metal material, the surface of the metal material is provided with at least one selected from the group consisting of a sponge-like structure, a interconnected porous structure, and an uneven surface. This specific structure allows a specific antimicrobial composition to be fixed to the surface of the medical metal material, thereby exhibiting a sustained antimicrobial effect. The interior of the specific structure and / or the recesses of the uneven structure are provided with at least one selected from the group consisting of metallic silver, metallic silver and wet apatite, silver compounds, silver compounds and wet apatite, metallic copper, metallic copper and wet apatite, copper compounds, and copper compounds and wet apatite. The wet apatite controls the separation of the antibacterial composition and increases its bonding to bone.

[0053] In the medical metal material, metallic silver, silver compounds, metallic copper, and copper compounds are not limited, but from the viewpoint of sustained antibacterial function, silver phosphate, silver carbonate, silver nanoparticles, copper phosphate, and copper carbonate, which have low solubility, are preferred. To prevent infections that occur at different times, such as postoperative infections and opportunistic infections, it is preferable to support multiple metals, silver compounds, copper compounds, etc. From the viewpoint of antibacterial properties, silver is preferred over copper. The amount of silver supported is not specified, but from the viewpoint of antibacterial properties and tissue affinity, it is preferable that the silver equivalent mass is 0.01% to 10% and more preferably 0.05% to 5%.

[0054] <14. Specific medical-grade spherical calcium compositions> The present invention

[14] is useful as a medical artificial bone or as a cell carrier in the treatment of lower limb ischemia. The composition is wet carbonate apatite and / or calcium carbonate. While there are no restrictions on the carbonate group content of any wet carbonate apatite containing carbonate groups, from the viewpoint of usefulness, wet carbonate apatite with a carbonate group content of 2% by mass or more is preferred. Since calcium carbonate has high solubility, a mixture of wet carbonate apatite and calcium carbonate is also acceptable. For example, a core-shell structure with wet carbonate apatite as the shell and calcium carbonate as the core is also acceptable.

[0055] The sphericity is 0.9 or higher, preferably 0.92 or higher, and more preferably 0.94 or higher. Furthermore, to increase porosity, it is preferable to exhibit a hollow structure. It is sufficient to satisfy either the condition of having a sphericity of 0.9 or higher or exhibiting a hollow structure, but it is more preferable for the sphericity to be 0.9 or higher and for the material to exhibit a hollow structure. The volume is 5 × 10 -15 m 3 The above is 2 x 10 -8 m 3 The following applies: Furthermore, since it is dispensed from a syringe, the volume is 5 × 10 -15 m 3 The above 5 x 10 -13 m 3 The following is required:

[0056] <Examples of experiments, examples for reference> The present invention will be described in more detail below based on experimental and reference examples, but the scope of the present invention is not limited to the experimental examples. Unless otherwise specified in the experimental and reference examples, the raw materials, analysis, etc. were carried out under the following conditions. For example, in the examples and reference examples that mention vaterite powder, vaterite powder (manufactured by Sakai Chemical Industry Co., Ltd., Karumaru, average volume diameter approximately 5 μm) was used as the raw material. <Calcium carbonate> As calcium carbonate, we used aragonite powder, calcite powder (manufactured by Ube Materials Co., Ltd., average volume diameter approximately 1 μm), vaterite powder (manufactured by Sakai Chemical Industry Co., Ltd., Karumaru, average volume diameter approximately 5 μm), spiky vaterite powder with needle-like crystals extending in multiple directions (manufactured by Shiraishi Industries Co., Ltd., Callite-SA, aggregated particle size approximately 1 μm), and amorphous calcium carbonate. Aragonite powder was prepared according to the Journal of the Ceramic Society of Japan 104 [3] 196-200 (1996) by suspending 0.5 mol of Ca(OH)2 in 2 L of 0.4 mol / L magnesium chloride aqueous solution and introducing 0.1 L of carbon dioxide per minute at 80°C. The aspect ratio of the produced aragonite powder was 20-40 and the diameter was 0.5-2 μm. Aragonite with different aspect ratios was also produced by grinding. For example, aragonite powder with an aspect ratio of approximately 2 is aragonite obtained by grinding aragonite powder with an aspect ratio of 20-40 to an aspect ratio of approximately 2. Amorphous calcium carbonate was prepared by suspending 10 g of calcium hydroxide in 100 mL of 95% methanol, introducing 200 mL of carbon dioxide per minute at 0°C, stirring for 2 hours, freezing with liquid nitrogen, and then freeze-drying. Calcite powder is cubic, while vaterite powder is spherical. The Wadel sphericity of the vaterite powder is 0.98 to 1.00, and since it was substantially 1, it is denoted as having a sphericity of 1. In other words, vaterite with a sphericity of 1 is Karumaru manufactured by Sakai Chemical Industry Co., Ltd.

[0057] <Tricalcium phosphate> As the tricalcium phosphate powder, we used αTCP-B manufactured by Taiheiyo Chemical Industries, with an average volume diameter of approximately 5 μm, and its pulverized form. <Support> As the metal support, a sheet of medical-grade titanium type 2 (manufactured by T&I Corporation) was used. The arithmetic surface roughness (Ra) was 0.7 ± 0.1 μm. For the roughened metal support, a sheet of medical-grade titanium type 2 was immersed in a mixed acid aqueous solution containing 50 vol% sulfuric acid and 7 vol% hydrochloric acid at 70°C for 30 minutes to perform acid etching, and then washed with distilled water. The arithmetic surface roughness (Ra) of the manufactured roughened titanium sheet was 2.2 ± 0.7 μm. <Analysis method> The composition was analyzed using a BRUKER D8 ADVANCE powder X-ray diffractometer under the following conditions: output power of 40kV, 40mA, and an X-ray source of CuKα (λ=0.15418nm). Furthermore, for samples in which carbonate apatite was suspected to have formed, its identity as carbonate apatite was confirmed using a JASCO 6200-type Fourier transform infrared spectrophotometer, and the carbonate group content in the carbonate apatite was calculated as needed. In some cases, the carbonate group content in the carbonate apatite was also analyzed by elemental analysis. The structure was analyzed using a Hitachi High-Tech S3400N scanning electron microscope, an Olympus MVX10 stereomicroscope, or a Bruker μ-CT (SkyScan). Surface elements were analyzed using an energy-dispersive X-ray analyzer (EDAX) attached to the scanning electron microscope.

[0058] <Tissue reaction> Tissue response was evaluated by reconstructive surgery of bone defects created in rabbit tibia or beagle jawbone. After a certain period following the reconstruction surgery, the sample was excised en bloc with the surrounding tissue, decalcified tissue sections were prepared according to standard procedures, and histopathological analysis was performed after hematoxy eosin staining (HE staining). <Common matters> The composition produced in the experimental example and labeled as wet apatite showed a weight loss of approximately 0.5 to 0.8% by mass after drying at 50°C for 2 hours followed by heat treatment at 300°C for 2 hours. Furthermore, the carbonate group content was 9-12% by mass. On the other hand, dry carbonate apatite was produced using the method described in Cells and Materials 7(2), 111-122, 1997. No weight loss was observed when it was dried at 50°C for 2 hours and then heat-treated at 300°C for 2 hours.

[0059] [Experimental Example 1] When aragonite powder with an aspect ratio of approximately 2, vaterite powder with a sphericity of 1, aragonite powder with an aspect ratio of 20 to 40, and vaterite powder with needle-like crystals extending in multiple directions in a chestnut-shaped form were suspended in a 0.1 mol / LNa2HPO4 aqueous solution at 40°C and stirred for 24 hours, wet carbonate apatite powder with an aspect ratio of approximately 2, wet carbonate apatite powder with a sphericity of 1, wet carbonate apatite powder with an aspect ratio of 20 to 40, and powdered wet carbonate apatite with needle-like crystals extending in multiple directions in a chestnut-shaped form were produced. These surfaces exhibited a scaly morphology. Some surfaces exhibited a spherical morphology. The spherical morphology consisted of needle-shaped crystals arranged radially. Powdered wet carbonate apatite compositions with an aspect ratio of approximately 2 and 20-40, each possessing a hollow structure, were also produced from aragonite powder with an aspect ratio of approximately 2 and 20-40, respectively. The wet carbonate apatite produced from aragonite powder with an aspect ratio of 20-40 had a higher proportion of carbonate apatite compositions with a hollow structure compared to the wet carbonate apatite produced from aragonite powder with an aspect ratio of approximately 2. In all cases, the surface morphology height was 0.2 μm to 0.4 μm.

[0060] [Experimental Example 2] The calcium carbonate powder used in Experimental Example 1 was mixed with a 1 mol / L Na2HPO4 aqueous solution at a mixing ratio (L / P) of 1.6. The mixture was placed in a mold with a diameter of 6 mm and a thickness of 3 mm, and initial curing was performed at 40°C and 100% relative humidity for 24 hours. A cylindrical wet-processed calcium carbonate block coated with carbonate apatite was produced, possessing a hollow structure and exhibiting a flaky, spherical, or needle-like surface. The surface morphological height of these blocks was 0.25 μm. When this wet-process apatite-coated calcium carbonate block was immersed in a 1 mol / L Na2HPO4 aqueous solution and held at 40°C or 80°C for 4 days, cylindrical wet-process apatite blocks exhibiting an aggregated structure in which wet-process apatite powder with a hollow structure was bonded were produced. The surfaces of these blocks all exhibited a flaky, spherical, or needle-like morphology. Figures 5(A) and (B) show SEM images of wet apatite blocks prepared at 40°C or 80°C using aragonite powder with an aspect ratio of 20 to 40. As shown in Figure 5(A), the surface of the wet carbonate apatite coating the surface of the product manufactured at 40°C exhibited a flaky appearance, with a surface morphological height of 0.25 μm. On the other hand, the wet carbonate apatite composition coating the surface of the product manufactured at 80°C had a spherical appearance with needle-like crystals radially arranged, and a surface morphological height of 0.2 μm. In other words, it was found that the surface morphological height of the wet carbonate apatite hollow structure block manufactured at 40°C was higher than that of the product manufactured at 80°C. Furthermore, when vaterite powder was used as the raw material, the surface morphology height of the wet carbonate apatite coating the product at 40°C was 0.2 μm. On the other hand, when the product was manufactured at 80°C, the surface morphology height of the wet carbonate apatite composition coating the surface was 0.17 μm, which was a composition outside the scope of the present invention. Although the mechanism is unclear, the fact that aragonite has a greater surface morphological height compared to vaterite, which has the highest solubility, suggests that calcium carbonate, which has a slower dissolution rate, may also have a greater surface morphological height.

[0061] [Experimental Example 3] Aragonite powder, vaterite powder, and a 30% gelatin aqueous solution were mixed in a 1.0 ratio and placed in a mold measuring φ5 mm and 10 mm in height. After drying, the mixture was removed from the mold and degreased at 650°C under an equivolute oxygen-carbon dioxide flow. The mixture was then immersed in a 0.2 mol / L Ca(NO3)2 ethanol solution, excess solution was removed, and then degreased again at 550°C under an equivolute oxygen-carbon dioxide flow, while simultaneously forming calcium carbonate between the powder particles. When immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C or 80°C for 7 days, the composition was converted to wet carbonate apatite under all conditions. Furthermore, the macrostructure of the precursor was maintained. Figures 5(C) and (D) show SEM images of cylindrical wet apatite blocks exhibiting an aggregated structure formed by the bonding of wet carbonate apatite powder from vaterite powder at 40°C and 80°C. In both cases, the surface of the manufactured product exhibited a needle-like structure, and the surface morphology heights of the products manufactured at 40°C and 80°C were 0.7 μm and 0.35 μm, respectively. The compressive strengths of the cylindrical wet apatite blocks manufactured at 40°C and 80°C were approximately 7 MPa and approximately 4 MPa, respectively.

[0062] [Experimental Example 4] Carbon dioxide was introduced into a mixed solution of 500 mL of 0.25 mol / L calcium chloride at 80°C and 500 mL of 0.325 mol / L magnesium chloride at 80°C. The pH was adjusted to 7 with a 1 mol / L sodium hydroxide aqueous solution, and the mixture was reacted for 2 hours to produce burr-shaped aragonite with needle-like crystals extending in multiple directions, larger than the burr-shaped aragonite with needle-like crystals extending in multiple directions manufactured by Shiraishi Kogyo (Figure 6(A)). After drying, the material was immersed in 0.3 mol / L calcium nitrate, then removed, excess calcium nitrate aqueous solution was removed with filter paper, heat-treated at 700°C for 3 hours under a carbon dioxide stream, and immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 6 days. As shown in Figures 6(B) and (C), a wet carbonate apatite block with a structure in which burr-shaped wet carbonate apatite with needle-like crystals extending in multiple directions was produced. The surface of the wet carbonate apatite block exhibited a needle-like morphology.

[0063] [Experimental Example 5] Honeycomb structures and gyroid structures were fabricated from a suspension of aragonite powder and photocurable resin using a stereolithography 3D printer (ANYCUBIC, Photon Mono 4K). The calcium carbonate honeycomb structures and calcium carbonate gyroid structures, prepared by degreasing at 800°C under an isocclusive carbon dioxide-oxygen flow, were immersed in a 0.2 mol / L Ca(NO3)2 ethanol solution. After removing excess solution with filter paper, the structures were heat-treated at 550°C under an isocclusive carbon dioxide-oxygen flow to convert calcium nitrate to calcium carbonate. The calcium carbonate honeycomb structures and calcium carbonate gyroid structures, prepared after calcium nitrate immersion and heat treatment, were then immersed in a 0.1 mol / L Na2HPO4 aqueous solution at 80°C for 7 days to produce wet carbonate apatite honeycomb structures and wet carbonate apatite gyroid structures. The surfaces of the wet carbonate apatite honeycomb structures and wet carbonate apatite gyroid structures exhibited a needle-like structure. Furthermore, a gyroid structure is a type of three-dimensional porous body that has multiple through-holes extending in multiple directions.

[0064] [Reference example 1] Apply 8 μL / cm² of 0.5 mol / L Ca(NO3)2 ethanol solution to the rough titanium surface. 2 The surface was coated in this manner, and then heat-treated at 550°C for 5 hours under a carbon dioxide stream to produce calcium carbonate-coated titanium. Next, the calcium carbonate-coated titanium was immersed in a 0.2 mol / L Na2HPO4 aqueous solution at 80°C for 7 days to produce wet carbonate apatite-coated titanium with a carbonate group content of 9.6 mass% and an arithmetic surface roughness (Ra) of 2.8 μm. The bond strength between the rough titanium and the wet carbonate apatite layer was approximately 77 MPa. This product has an arithmetic surface roughness (Ra) of less than 4 μm in the wet apatite layer, does not have depressions with a depth of 10 μm or more, does not have a hollow structure in the wet apatite layer, does not have a structure in which any wet apatite selected from the group of those with an aspect ratio of 3 or more, a spiky shape with needle-like crystals extending in multiple directions, or a sphericity of 0.9 or more penetrates the wet apatite layer, and the wet apatite layer has a porosity of 3.5% and a specific surface area of ​​2.5 m² in mercury intrusion analysis. 3If the pore diameter area is 0.01 μm or more and the pore volume is 0.2 cm³ or less, and the pore diameter area is 0.01 μm or more and 1 μm or less. 3 Because it is / g, this composition falls outside the scope of the present invention.

[0065] [Experimental Example 6] The rough titanium surface was dip-coated with a suspension prepared from a 2 mol / L Ca(NO3)2 ethanol solution and aragonite powder in a 4.0 ratio, a suspension prepared from a 2 mol / L Ca(NO3)2 ethanol solution and vaterite powder in a 0.5 ratio, a suspension prepared from a 2 mol / L Ca(NO3)2 ethanol solution and NaCl powder with an average particle size of 18 μm in a 4.0 ratio, and a suspension prepared from a 2 mol / L Ca(NO3)2 ethanol solution and burr-shaped aragonite powder with needle-like crystals extending in multiple directions in a 0.5 ratio. Next, after drying at 40°C for 24 hours, the surface was heat-treated at 550°C for 5 hours under a carbon dioxide stream to produce calcium carbonate-coated titanium. Next, the calcium carbonate-coated titanium was immersed in a 0.2 mol / L Na2HPO4 aqueous solution at 80°C for 7 days to produce wet carbonate apatite-coated titanium. Figure 7(A) shows an SEM image of wet carbonate apatite-coated titanium produced using aragonite powder, and Figure 7(B) shows an SEM image of wet carbonate apatite-coated titanium produced using vaterite powder. It was found that when aragonite powder was used, the structure was such that wet apatite with an aspect ratio of 3 or more penetrated the wet apatite layer, and when vaterite was used, the structure was such that wet apatite with a sphericity of 1 penetrated the wet apatite layer. Furthermore, it was found that when burr-shaped vaterite powder with needle-like crystals extended in multiple directions, or NaCl powder with an average particle size of 18 μm, the structure was such that burr-shaped wet apatite with needle-like crystals extended in multiple directions penetrated the wet carbonate apatite layer, and the wet apatite layer had a recess approximately 12 μm deep. The arithmetic surface roughness (Ra) of wet-process carbonate apatite-coated titanium produced using aragonite powder, NaCl powder, and burr-like powder in which needle-like crystals are extended in multiple directions, and the bond strength between the rough titanium surface and the wet-process carbonate apatite layer, were 20 μm, 12 μm, 4.2 μm, and 40 MPa, 52 MPa, and 35 MPa, respectively. In a mercury intrusion analysis of wet-process apatite-coated titanium prepared using vaterite powder, the porosity was 7% and the specific surface area was 5 m². 3 / g, pore diameter product of 0.01 μm or more and 1 μm or less, pore volume of 0.1 cm³ 3 It was / g. From a comparison of this experimental example with Reference Example 1, it was found that the wet-processed apatite-coated titanium produced by manufacturing calcium carbonate-coated titanium from a suspension of aragonite powder and a 2 mol / L Ca(NO3)2 ethanol solution, and then immersing it in a Na2HPO4 aqueous solution, exhibited improved bone conductivity due to its high arithmetic surface roughness (Ra), making it a superior wet-processed apatite-coated titanium.

[0066] [Experimental Example 7] CaO, which was heat-treated with CaCO3 at 1000°C, was pressed onto a rough titanium surface, and water was added. Alternatively, a slurry prepared from Ca(OH)2 and water was applied to the rough titanium surface. In both cases, the materials were pressed at approximately 50 MPa with filter paper in between to remove excess water, and then carbonized for 3 days under a carbon dioxide stream at 100% relative humidity to produce CaCO3-coated titanium. Furthermore, a slurry prepared from CaCO3 and a 1 mol / L Na2HPO4 aqueous solution was applied, pressed at approximately 50 MPa with filter paper in between to remove excess water, and then cured for 2 days at 37°C and 100% relative humidity to produce partially phosphorylated CaCO3-coated titanium. Next, CaCO3-coated titanium and partially phosphorylated CaCO3-coated titanium were immersed in a 0.2 mol / L Na2HPO4 aqueous solution at 80°C for 7 days. In all cases, wet-process carbonate apatite-coated titanium with a carbonate group content of 9-11 mass% was produced. The bond strength between the rough titanium surface and the wet carbonate apatite layer was 30-35 MPa in all cases. The specific surface area was 8-12 m². 3 The specific surface area of ​​wet carbonate apatite is 5-8 m² / g. 3 The pore volume for pores with a diameter product of 0.01 μm to 1 μm is 0.05 to 1.0 cm³ / g. 3 It was / g.

[0067] [Experimental Example 8] A paste made from α-type tricalcium phosphate with a particle size of approximately 1-2 μm and water, in a mixture ratio of 2, was applied to a rough titanium surface. Excess water was removed by pressing the mixture with filter paper in between at approximately 50 MPa. Next, the mixture was cured at 37°C and 100% relative humidity for 48 hours to produce wet-process Ca-deficient hydroxyapatite. The bond strength between the rough titanium surface and the wet-process carbonate apatite layer was approximately 35 MPa in both cases. The specific surface area was 9 m². 3 The specific surface area of ​​wet apatite is 6 m² / g. 3 The pore volume for pores with a diameter product of 0.01 μm or more and 1 μm or less is 0.07 cm³ / g. 3 It was / g. [Experimental Example 9] CaCO3-coated titanium was produced by dropwise adding an aqueous solution of carbon dioxide bubbling into a CaCO3 suspension for 3 hours, while maintaining the surface temperature of rough titanium at 60°C to 80°C. Next, the CaCO3-coated titanium was immersed in a 0.2 mol / L Na2HPO4 aqueous solution at 80°C for 7 days to produce wet carbonate apatite-coated titanium. A hollow structure was observed in a portion of the wet carbonate apatite layer. The bond strength between the rough titanium and the wet carbonate apatite layer was approximately 30 MPa.

[0068] [Experimental Example 10] A jungle gym-like calcium carbonate structure with an arithmetic mean surface roughness (Ra) of approximately 8 μm was used as the support. A jungle gym-like structure is one in which pores separated by a grid are connected in three or more directions, and is a structure in which trabeculae are assembled three-dimensionally in a grid pattern. Aragonite powder was suspended in a 1 mol / L Ca(NO3)2 aqueous solution, and a jungle gym-shaped calcium carbonate structure was immersed in the suspension, thereby coating the trabecular surface of the jungle gym-shaped calcium carbonate structure with aragonite powder. When heat treatment was performed in an electric furnace at 550°C for 24 hours under a carbon dioxide gas flow of 100 mL per minute, a calcite aggregate structure with an aspect ratio of 20-40 was formed on the trabecular surface of the jungle gym-like calcium carbonate structure. Next, when immersed in a 1 mol / L Na2HPO4 aqueous solution at 80°C for 7 days, the entire structure was recomposed of wet carbonate apatite containing approximately 11% carbonate groups. The porosity of the wet carbonate apatite aggregate formed inside the trabecular structure was approximately 70%, and the pore volume of pores with a diameter of 10 μm or less was 1 cm³. 3 The concentration was above / g. Furthermore, the surface of the wet-process carbonate apatite exhibited a spherical morphology with an accumulation of needle-like crystals. Additionally, wet-process carbonate apatite exhibiting a hollow structure with an aspect ratio of at least 20 was also observed.

[0069] [Experimental Example 11] A suspension was prepared by dissolving 6% by mass of polycaprolactone (manufactured by Taki Chemical Co., Ltd.) in 1,4-dioxane and adding vaterite so that the polycaprolactone:vaterite ratio was 30:160. This suspension was introduced into the pores of a honeycomb structure composed of calcium carbonate and an organic binder, with a septum thickness of 0.8 mm and a pore short diameter of 0.8 mm. The structure was held at -20°C for 5 hours, then at -80°C for 12 hours, and subsequently freeze-dried. The honeycomb structure composed of calcium carbonate and an organic binder becomes a calcium carbonate honeycomb structure with an arithmetic mean surface roughness (Ra) of approximately 8 μm after degreasing. After freeze-drying, it was heated at 650 °C for 24 hours under an equi-volume gas flow of carbon dioxide-oxygen. By the heat treatment, the organic components were degreased, and a sponge-structured calcium carbonate structure was formed within the calcium carbonate honeycomb. When immersed in a 1 mol / L aqueous solution of Na2HPO4 and subjected to hydrothermal treatment at 120 °C for 7 days, both the honeycomb structure and the sponge structure inside the honeycomb structure were compositionally converted into wet calcium apatite containing approximately 6% by mass of carbonate groups. Figures 8(A) and Figures 8(B) show μCT of the carbonate apatite honeycomb and the sponge-like structure inside the honeycomb pores, and SEM images of the sponge-like structure. The porosity of the sponge-like structure inside the honeycomb was approximately 80%. Although the mechanical strength of the sponge-like structure inside the honeycomb was small, it was found that by installing it inside the honeycomb structure as a support, the problem of mechanical strength was eliminated and it could be used as an artificial bone or the like.

[0070] [Experimental Example 12] 0.5% by mass of polyvinyl alcohol (Kuraray Poval PVA-205C) was added to calcium hydroxide, and the suspension was spray-dried to produce calcium hydroxide spheres. The calcium hydroxide spheres that passed through a 200 μm sieve and did not pass through a 100 μm sieve were heated at 5 °C per minute up to 1000 °C and fired at 1000 °C for 6 hours to produce CaO spheres. The sphericity was 0.99, the average diameter was 1.6×10 -4 m, and the average volume was 1.6×10 -12 m 3 and it was. The produced CaO spheres were placed in a calcium carbonate honeycomb (with square pores, one side of the pore being 5 mm and the trabecular width being 5 mm) whose arithmetic mean surface roughness (Ra) of the surface as a support was approximately 8 μm. When moisture was imparted, the CaO spheres expanded and were fixed in the support to become calcium hydroxide. Next, when the calcium hydroxide was exposed to carbon dioxide saturated with 90% isopropanol and 10% water, the calcium hydroxide was carbonated to become wadalite. The porosity of the wadalite in the calcium carbonate honeycomb was approximately 80%. Next, the calcium carbonate honeycomb was immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 24 hours. The vaterite composition was transformed into wet carbonate apatite containing approximately 11% carbonate groups. The porosity of the wet carbonate apatite formed within the wet carbonate apatite honeycomb was approximately 80%.

[0071] [Experimental Example 13] A calcium carbonate honeycomb with an arithmetic mean surface roughness (Ra) of approximately 8 μm was used as the support. A paste prepared by mixing aragonite powder and a 1 mol / L Na2HPO4 aqueous solution in a mixing ratio of 1.75 was introduced into the pores of the support, stored at 0°C for 24 hours, and then reacted in a constant temperature bath at 40°C with 100% relative humidity for 24 hours, followed by washing with water and drying. The composition formed inside the honeycomb structure was a wet carbonate apatite aggregate structure exhibiting a hollow structure with an aspect ratio of 20 to 40, with a carbonate group content of approximately 11% and a porosity of approximately 80%. In addition, flaky wet carbonate apatite was formed on the surface of the wet carbonate apatite aggregate structure. Furthermore, possibly due to the temperature distribution during manufacturing, the honeycomb structure had frost-pillar-like pores near the pore openings, while the central part had a sponge-like structure.

[0072] [Experimental Example 14] A porous two-dimensional membrane was fabricated by dispensing a 30 mass% gelatin aqueous solution at 70°C from a syringe and drying it. Additionally, a two-dimensional membrane with holes spaced 2 mm apart was fabricated by filling a mold with the gelatin aqueous solution and drying it. The gelatin was thermally crosslinked by heating under reduced pressure at 130°C for 24 hours. Vatelite powder and a 1 mol / L Na2HPO4 aqueous solution were mixed in a 0.5 ratio. A porous two-dimensional membrane was immersed in the paste and subjected to vibrator treatment to allow the paste to penetrate into the membrane. In addition, for two-dimensional membranes with holes, the paste was applied to the inside and around the holes. Next, a paste with a thickness of approximately 0.5 mm was applied to both sides using a mold, and notches were formed at 2 mm intervals. In the case of a two-dimensional film with holes, the notches were formed so that they overlapped with the holes. After initial curing at 100% relative humidity and 40°C for 3 hours, the film was immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 3 days to produce a wet carbonate apatite gelatin film that completely covered the gelatin support. When the wet-process carbonate apatite-coated gelatin film was bent, the wet-process carbonate apatite cracked at the notches in all cases, but the wet-process carbonate apatite remained largely fixed to the gelatin film.

[0073] [Experimental Example 15] A plate-shaped wet carbonate apatite block, approximately 1 mm thick and manufactured from aragonite, was immersed in a 30 mass% gelatin aqueous solution at 80°C, and excess gelatin solution was removed using filter paper. After drying, the block was heated under reduced pressure at 130°C for 24 hours to thermally crosslink the gelatin, thereby producing an aragonite-gelatin composite film. Next, a paste prepared by mixing vaterite and a 1 mol / L Na2HPO4 aqueous solution in a 0.5 ratio was applied to both sides of the aragonite-gelatin composite film. Using a mold, the paste was made to a thickness of approximately 0.5 mm and notches were formed at 2 mm intervals. After initial curing at 100% relative humidity and 40°C for 3 hours, the film was immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 3 days to produce a wet carbonate apatite gelatin film that completely covered the gelatin support. When the wet carbonate apatite-coated gelatin film was bent, the wet carbonate apatite cracked at the notches, but the wet carbonate apatite remained largely fixed to the gelatin film.

[0074] [Experimental Example 16] The wet carbonate apatite gyroid structure prepared in Experimental Example 5 was immersed under reduced pressure in a 30 mass% gelatin aqueous solution at 80°C to introduce gelatin into the trabecular structure of the gyroid structure, after which the excess gelatin aqueous solution was removed with filter paper. After immersion in water to remove the gelatin from the surface of the wet carbonate apatite, it was dried and then heated under reduced pressure at 130°C for 24 hours to thermally crosslink the gelatin, thereby producing a wet carbonate apatite gyroid structure with a three-dimensional interconnected structure using gelatin as a support.

[0075] [Experimental Example 17] A titanium tapping screw with the shape shown in Figure 1 was subjected to the same surface roughening treatment as medical-grade titanium plates, resulting in a roughened screw with an arithmetic surface roughness (Ra) of approximately 2 μm. Screws with recesses were also manufactured by cutting holes with a diameter of 0.5 mm and a depth of 0.5 mm at 1 mm intervals in the thread root. Screws with grooves 0.4 mm wide and 0.4 mm deep on the side of the thread were also manufactured. Furthermore, screws with a V-shape cut from the thread to a portion of the thread root in the direction of the central axis were manufactured. A control was provided for screws without these added irregularities. The calcium carbonate application process to the screw threads was carried out using two methods: coating with a 2 mol / L Ca(NO3)2 ethanol solution and applying calcium hydroxide paste. In the former method, the screw threads were immersed in a 2 mol / L Ca(NO3)2 ethanol solution and heat-treated at 550°C for 5 hours under a carbon dioxide stream to produce calcium carbonate coated titanium screws. For some screws, Ca(NO3)2 was removed from the crest portion to a extent equivalent to 5% of the length between the crest and root before the calcium carbonate application process was performed. In the calcium hydroxide paste application method, calcium hydroxide paste was applied to the threads, and excess water was removed by pressing. Then, the threads were exposed to carbon dioxide at 100% relative humidity to produce calcium carbonate coated titanium screws. For some screws, Ca(OH)2 was removed from 5% of the length between the crest and root before exposure to carbon dioxide. Finally, when the calcium carbonate-coated screws were immersed in a 0.2 mol / L Na2HPO4 aqueous solution at 80°C for 7 days, wet-process carbonate apatite-coated screws were produced.

[0076] Compared to control screws without any added texture, all screws with added texture showed increased bonding strength between the carbonate apatite and the screw. Screws with roughened surfaces had the highest bonding strength, followed by those with grooves and then those with recesses created by cutting. In the case of screws with a portion of the screw root cut off, the bonding strength in the direction perpendicular to the central axis was unaffected, but the ability to hold the wet carbonate apatite was enhanced when a load was applied in the direction of rotation of the screw. In a comparison between applying Ca(NO3)2 ethanol solution and calcium hydroxide paste, the calcium hydroxide paste method produced thicker, wet-processed apatite-coated screws. However, the bond strength was higher with the Ca(NO3)2 ethanol solution method. When screws were implanted into simulated bone, the wet carbonate apatite on the crest tended to peel off, while the wet carbonate apatite on the valley remained intact. This suggests that in some cases, it may be preferable not to cover a portion of the crest with the wet carbonate apatite layer.

[0077] [Experimental Example 18] A stainless steel pipe with a diameter of 10 mm and a thickness of 1 mm was used as a support without an undercut. Alternatively, a support with an undercut was manufactured by cutting approximately 0.3 mm off the inner surface of the pipe that was not in contact with the opening. When a φ9.9mm wet carbonate apatite honeycomb structure was placed in both pipes, it could not be fixed, and when a pressure of 20kPa was applied, the wet carbonate apatite honeycomb structure was expelled from the pipes. On the other hand, when a φ9.9mm wet calcium carbonate honeycomb structure was placed in pipes without undercuts and pipes with undercuts, and immersed in a 0.2mol / L Na2HPO4 aqueous solution at 80°C for 7 days, in both cases the wet carbonate apatite honeycomb structure was fixed inside the pipes, and even when a pressure of 20kPa was applied, the wet carbonate apatite honeycomb structure was not expelled from the pipes. The manufactured wet carbonate apatite honeycomb has a porosity of 65% and a pore volume of 0.2 cm³ for pores with a diameter of 10 μm or less. 3The result was / g. When calcium carbonate honeycomb is exposed to a phosphate aqueous solution inside a support, the calcium carbonate honeycomb becomes a wet carbonate apatite honeycomb structure. It was found that, perhaps due to expansion during this process, it comes into close contact with the support, allowing the wet carbonate apatite composition to be fixed inside the support regardless of the presence or absence of undercuts. From a principle standpoint, it was inferred that structures not limited to wet carbonate apatite honeycomb structures, such as structures with frost-pillar-like pores, three-dimensional interconnected structures with multiple through-holes extending in multiple directions, sponge structures, gyro structures, porous structures, and aggregated structures, can also be fixed inside a support.

[0078] [Experimental Example 19] A paste prepared by mixing aragonite powder and a 1.0 mol / L Na2HPO4 aqueous solution in a 1.6 ratio was filled into the undercut support prepared in Experimental Example 18. After curing at 40°C and 100% relative humidity for 3 hours, the pipe was immersed in a 1.0 mol / L Na2HPO4 aqueous solution at 40°C for 7 days. The wet carbonate apatite composition hardened and fixed inside the pipe, and did not discharge from the pipe even when a pressure of 20 kPa was applied. The porosity of the prepared wet carbonate apatite composition was 73%.

[0079] [Experimental Example 20] Calcite powder, aragonite powder, vaterite powder, amorphous calcium carbonate powder, calcium carbonate powder with an aspect ratio of 3 or higher, burr-shaped calcium carbonate powder with needle-like crystals extending in multiple directions, hollow calcium carbonate powder, and calcium sulfate dihydrate powder were mixed with a 1 mol / L aqueous solution of Na2HPO4, a water-soluble phosphate. The mixture was placed in a mold with a hole 6 mm in diameter and 3 mm in height, and stored at a relative humidity of 37°C for 4 hours, after which all hardened. FT-IR analysis of the hardened bodies confirmed the formation of wet hydroxyapatite in the case of calcium sulfate dihydrate powder, and carbonate apatite in the cases of the other materials. Since unreacted substances remained in the hardened body, the hardened body was taken out of the mold and immersed in 100 mL of 0.5 mol / L Na2HPO4 aqueous solution at 80 °C for 3 days. From powder XRD analysis and elemental analysis, it was found that in the case of calcium sulfate dihydrate powder, the hardened body was wet hydroxyapatite, and in other cases, it was wet carbonated apatite with a carbonate group content of about 12 mass% or more. SEM images of the hardened bodies when using aragonite, vaterite, and calcite are shown in Fig. 9. They are SEM images of carbonated apatite (Fig. 9(A), (B)) produced from a medical curable composition containing aragonite, carbonated apatite (Fig. 9(C), (D)) produced from a medical curable composition containing vaterite, and carbonated apatite (Fig. 9(E), (F)) produced from a medical curable composition containing calcite, respectively. It was found that all of them were hardened while maintaining almost the fine morphology of calcium carbonate. In addition, it was confirmed that wet carbonated apatite crystals were formed on the surface.

[0080] [Experimental Example 21] A powder part obtained by mixing calcite powder, aragonite powder, vaterite powder and Na2HPO4 which is a water-soluble phosphate at a mass ratio of 4:3 was kneaded with water, put into a mold having a hole with a diameter of 6 mm and a height of 3 mm, and stored at 37 °C and a relative humidity of 100% for 48 hours, and all of them were hardened. After washing with water and drying, composition analysis showed that all of them were wet carbonated apatite with a carbonate group content of about 12 mass%.

[0081] [Experimental Example 22] Calcium hydroxide was suspended in a mixed solvent of 90% methanol and 10% water, and carbon dioxide was introduced to produce vaterite powder with a diameter of about 1 μm. When the vaterite powder was kneaded with a 2.5 mol / L Na 1.2 H 1.8 PO4 aqueous solution with a mixing ratio of 0.7, bubbles were generated. It expanded to form a porous body, and the curing time when stored at 37 °C and a relative humidity of 100% was 35 minutes. Na 1.3 H 1.7 PO4 aqueous solution, Na 1.4 H 1.6 PO4 aqueous solution, Na 1.5 H1.5 The pH of the PO4 aqueous solution was approximately 5.7, 6.1, and 6.6, and slight bubble formation was observed when mixed with vaterite powder at a water-to-liquid ratio of 0.7. The curing times when stored at 37°C and 100% relative humidity were 15 minutes, 10 minutes, and 10 minutes, respectively. Analysis after 24 hours of storage at 37°C and 100% relative humidity revealed that the vaterite powder and phosphate aqueous solution are curable compositions that harden by forming wet carbonate apatite-coated calcium carbonate.

[0082] [Experimental Example 23] A curable composition consisting of aragonite powder as the solid part and a 1 mol / L Na2HPO4 aqueous solution as the liquid part was mixed at a mixing ratio of 1.75. The paste was placed in a mold and held at 100% relative humidity and 40°C for 24 hours, at which point wet carbonate apatite was formed and hardened. The hardened body was removed from the mold and immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 7 days, producing a hardened block exhibiting an aggregate structure in which powders with an aspect ratio of 20 to 40 were bonded together. The resulting product was a wet carbonate apatite composition with a porosity of approximately 80% and a carbonate group content of approximately 12% by mass. SEM images of the wet carbonate apatite composition produced in this experiment are shown in Figures 10(A) and (B). It was found that the surface of the wet carbonate apatite composition with an aspect ratio of 10 to 40 was coated with spherical wet carbonate apatite. Furthermore, the hardened body was a structure composed of accumulated wet carbonate apatite with an aspect ratio of 10 to 40. Figure 10(C) shows the cumulative pore volume of wet-processed apatite carbonate hardened material produced in this experiment, and of commercially available granular wet-processed apatite carbonate artificial bone (GC Corporation, Cytotrans Granule M), measured by mercury intrusion, for pore diameters of 10 μm or less. The cumulative pore volume of 10 μm or less for the wet-processed apatite porous material in this experiment was 1.2 cm³. 3 / g, 0.1cm in Cytotrans granules 3 It was / g.

[0083] The wet-processed apatite carbonate hardened material produced in this experiment was crushed and sieved to the size of Cytotrans granules M, which is 0.6 mm to 1.0 mm, and used to fill a bone defect in a rabbit femur with a diameter of 6 mm and a depth of 5 mm. Figure 10(D) shows Cytotrans granules, which are outside the scope of the present invention, and Figure 10(E) shows a μCT image of the granular wet-processed apatite carbonate composition produced in this experiment four weeks after implantation. Compared with the results for Cytotrans granules, it was found that the granular wet-processed apatite carbonate composition produced in this experiment had vigorous bone formation around it, and while Cytotrans granules had a large portion that was not absorbed, much of the granular wet-processed apatite carbonate composition produced in this experiment was replaced by new bone.

[0084] [Experimental Example 24] A solid was prepared by mixing aragonite powder with an aspect ratio of 20-40 and α-type tricalcium phosphate powder with average volume diameters of approximately 5 μm, 2 μm, and 1.3 μm in equimolar amounts. In addition, a 1 mol / L NaH2PO4 aqueous solution and a 1 mol / L Na2HPO4 aqueous solution were mixed to obtain a pH of 7.0, resulting in a Na phosphate concentration of 1 mol / L. 2-x H x An aqueous solution of PO4 (x approximately 0.1) was prepared and used as the liquid portion. Another liquid portion was prepared by adding disodium citrate to this phosphate aqueous solution to a concentration of 0.5 mol / L. The two substances were mixed to a ratio of 0.60, placed in a mold with a hole 6 mm in diameter and 3 mm deep, and stored under conditions of 100% relative humidity and 37°C. The presence or absence of hardening was checked after 3 hours. When an aqueous phosphate solution was used, the medical-grade hardening composition containing tricalcium phosphate with a volume-average particle size of approximately 1.3 μm had hardened. The hardened material was carbonate apatite containing approximately 11% by mass of carbonate groups. The medical-grade hardening composition containing tricalcium phosphate with a volume-average particle size of approximately 2 μm showed slight hardening defects, and the medical-grade hardening composition containing tricalcium phosphate with a volume-average particle size of approximately 5 μm showed even more severe hardening defects. On the other hand, when a phosphate aqueous solution containing disodium citrate was used, all of the α-type tricalcium phosphate powder hardened regardless of its volume-average diameter. From this experiment, it was found that when the solid portion contains calcium carbonate with an aspect ratio of 2 to 50 and is mixed with a phosphate aqueous solution, it is preferable to mix it with tricalcium phosphate with a volume-average diameter smaller than 2 μm. Furthermore, it was found that when the solid portion contains calcium carbonate with an aspect ratio of 2 to 50, curing defects can be prevented by using a phosphate aqueous solution containing disodium citrate. Although the mechanism is not fully understood, it is presumed that this is because a water-soluble polycarboxylic acid chelates with calcium carbonate.

[0085] [Experimental Example 25] Calcium sulfate crystals with an aspect ratio of approximately 100 were immersed in an aqueous sodium carbonate solution to produce calcium carbonate with an aspect ratio of approximately 100. The same experiment as in Experimental Example 23 was performed, except that calcium carbonate with different aspect ratios was used. All medical-grade curable compositions containing tricalcium phosphate with volume-average particle sizes of approximately 5 μm, 2 μm, and 1.3 μm cured in 3 hours. The cured bodies were carbonate apatite containing approximately 11% by mass of carbonate groups.

[0086] [Reference example 2] Aragonite powder with an aspect ratio of 20-40 was ground in an alumina mortar and sieved to produce aragonite powder with aspect ratios of approximately 5 and 10. This calcium carbonate was mixed with tricalcium phosphate with a volume-average particle size of approximately 2 μm in equimolar amounts to produce the solid portion. The liquid portion was prepared using Na with a phosphoric acid concentration of 1 mol / L, as used in Experimental Example 23. 2-x H x The solutions used were an aqueous solution of PO4 (x approximately 0.1) and a 1.2 mol / L aqueous solution of NaH2PO4. Therefore, this curable composition is a medical curable composition that falls outside the scope of the present invention. When the solid portion was mixed with the liquid portion at a liquid-to-solid ratio of 0.8, and the mixture was placed in a mold with a 6mm diameter and 3mm high hole, and stored for 3 hours at a relative humidity of 37°C, curing failure occurred in all cases. Furthermore, the curable composition containing aragonite with an aspect ratio of approximately 5 cured worse than the curable composition containing aragonite with an aspect ratio of approximately 10. On the other hand, curing occurred after 24 hours. From a comparison of this reference example with experimental examples 24 and 25, it was found that when using calcium carbonate with an aspect ratio between 2 and 50, it is necessary to use tricalcium phosphate with a volume-average diameter smaller than 2 μm, or to use a polyvalent carboxylate.

[0087] [Reference example 3] Biopex Excellent (manufactured by HOYA Technosurgical Corporation), which forms hydroxyapatite upon hardening, was mixed at a standard mixing ratio of 0.53. Under conditions of 100% relative humidity and 37°C, the hardening time was approximately 10 minutes, and the main component of the hardened material after 24 hours was hydroxyapatite. Biopex Excellent is mainly composed of tricalcium phosphate and does not contain calcium carbonate. Therefore, this hardening composition is a cement that falls outside the scope of the present invention. Furthermore, a curable composition was prepared in which the solid portion was an equimolar mixture of α-type tricalcium phosphate powder with an average volume diameter of approximately 1.5 μm and vatelite powder (Karumaru, manufactured by Sakai Chemical Industry Co., Ltd.; average volume diameter of approximately 5 μm), and the liquid portion was an aqueous solution of hydroxypropyl cellulose dissolved in a 1 mol / L sodium phosphate aqueous solution at pH 7.0. The paste formed by mixing the solid portion with the liquid portion in a specific ratio took approximately 5 minutes to cure under conditions of 100% relative humidity and 37°C, and the main component of the cured body after 24 hours was wet carbonate apatite with a carbonate group content of 12% by mass. The porosity was 75%. It should be noted that this curable composition is also a curable composition that falls outside the scope of the present invention. A 6mm diameter defect in the rabbit tibia was reconstructed using a hardening composition paste, as shown in Figure 11(A). Figure 11(B) shows the HE stained image of Biopex Excellent 12 weeks postoperatively. It was found that the sclerotic body had been completely replaced by bone. Figure 11(C) shows the HE stained image of a hardening composition, which is an equimolar mixture of α-type tricalcium phosphate powder and vatelite powder with an average volume diameter of approximately 1.5 μm, at 12 weeks post-surgery. It was found that the hardened body was replaced by bone from the surrounding area. From a comparison of the two, it was found that when it is expected that the hardened body of the hardened composition will replace the new bone, a hardened composition that forms hydroxyapatite is unsuitable, and a hardened composition that hardens to form wet carbonate apatite is preferred.

[0088] [Experimental Example 26] Cytotrans Granule M (manufactured by GC Corporation, porosity 34%) with a carbonate group content of 12% by mass was used as the wet-process carbonate apatite granules. The volume of the granules was approximately 2 × 10⁻⁶. -10 m 3 The wet-process carbonate apatite granules were used to form a connecting structure by bridging some of the granules using a paste prepared from a curable composition which is a mixture of α-type tricalcium phosphate powder and vaterite powder with an average volume diameter of approximately 1.5 μm, as produced in Reference Example 3. This structure was then used to reconstruct a 6 mm diameter defect in the rabbit tibia as shown in Figure 11(D). Figure 11(E) shows the HE stained image at 4 weeks post-surgery. It was found that even at 4 weeks post-surgery, the bone had formed up to the central part of the interconnected porous body. From a comparison of this experimental example with Reference Example 2, it was found that a curable composition in which the paste formed when the powder and liquid parts are mixed hardens into wet carbonate apatite, and which bridges at least a portion of the wet carbonate apatite granules to form a wet carbonate apatite interconnected porous body, is extremely useful.

[0089] [Experimental Example 27] After implanting the wet carbonate apatite granules used in Experimental Example 26 into a 6 mm diameter defect in the rabbit tibia, the dispenser shown in Figure 4 was attached to a syringe, and the paste used in Experimental Example 26 was dispensed in a strip. This bridged the wet carbonate apatite granules on the surface of the bone defect, forming a connecting structure as shown in Figure 2(C) (Figure 11(F)). Figure 11(G) shows the HE stained image at 4 weeks post-surgery. It was found that even at 4 weeks post-surgery, bone had formed up to the central part of the interconnected porous body. From a comparison of this experimental case with Reference Example 2, it was found that a curable composition that forms a wet carbonate apatite interconnected porous body by bridging at least a portion of the wet carbonate apatite granules is extremely useful.

[0090] [Experimental Example 28] The wet-process apatite granules and paste used in Experimental Example 26 were mixed and implanted into the extraction socket of a beagle dog's mandible. Therefore, no interconnected porous bodies were formed in the hardened tissue. Figure 11(H) shows the HE stained image 6 months postoperatively. It can be seen that the hardened paste has been absorbed and new bone has formed around the bioabsorbable granules in the center of the bone defect. Since the porosity of the hardened paste is 75% and the porosity of the bioabsorbable granules is 34%, it was found that if the porosity of the hardened paste produced by mixing at the standard liquid-liquid ratio is 30% or higher, and the porosity of the hardened paste is greater than that of the bioabsorbable granules, then the hardened paste of the hardened composition is absorbed over time after surgery, and bone formation occurs up to the central part.

[0091] [Experimental Example 29] Tricalcium phosphate powder (αTCP-B, manufactured by Taihei Chemical Industry Co., Ltd.) was uniaxially pressurized at 100 MPa and heated in an electric furnace at 10°C per minute up to 1200°C, heat-treated at 1200°C for 12 hours, and then furnace-cooled to produce α-type tricalcium phosphate blocks. The blocks were crushed and sieved, resulting in a volume of approximately 7 × 10⁶. -11 m 3 We prepared α-type tricalcium phosphate granules. We also mixed the same tricalcium phosphate powder with a sodium phosphate aqueous solution with a phosphoric acid concentration of 1.7 mol / L and pH 7.0 in a mixing ratio of 0.6, allowed it to harden for 5 minutes, and then freeze-dried it. The freeze-dried product was then crushed and sieved to obtain a volume of approximately 7 × 10⁻⁶. -11 m 3 We produced α-type tricalcium phosphate aggregates. Sodium hydrogen phosphate aqueous solutions with pH values ​​of 1, 3, 5, 6, 7, and 8 were prepared by mixing 1 mol / L disodium hydrogen phosphate with 1 mol / L phosphoric acid. When tricalcium phosphate and water containing the water-soluble phosphate were mixed at a mixing ratio of 1.5, the pH of the mixtures was 1, 3, 5, 6, 7, and 8, respectively. When α-type tricalcium phosphate granules or aggregates were mixed with sodium hydrogen phosphate aqueous solution at a mixing ratio of 0.4, and placed in a mold with a hole of 6 mm in diameter and 3 mm in height, the curing time was measured at a relative humidity of 37°C. The curing times for α-type tricalcium phosphate granules were less than 20 minutes, 1-2 hours, 6-24 hours, 6-24 hours, 24-48 hours, and 48-72 hours, respectively. The curing times for α-type tricalcium phosphate aggregates were less than 2 minutes, 30 minutes, 50 minutes, 60 minutes, 90 minutes, and 6-24 hours, respectively. The sodium hydrogen phosphate aqueous solution with pH 1 showed hemolytic properties. In all cases, it was confirmed that a portion of the hardened material composition was wet apatite. Since medical curable compositions are required to not exhibit hemolysis and to have an appropriate curing time, it was considered that the pH of the sodium hydrogen phosphate aqueous solution should be between 3 and 8. Although the mechanism by which the pH of sodium hydrogen phosphate aqueous solution affects the hardening of α-tricalcium phosphate granules has not been elucidated, it is thought that one of the causes is that the α-tricalcium phosphate dissolves when mixed with a phosphate aqueous solution with a low pH, increasing the calcium ion concentration and phosphate ion concentration.

[0092] [Experimental Example 30] The wet carbonate apatite honeycomb structure and wet carbonate apatite gyro structure produced in Experimental Example 5, and the wet carbonate apatite block produced at 40°C in Experimental Example 2, were implanted in the bone defect of the trochlear groove of a rabbit femur, as shown in Figure 3, so as to create a space thickness of 2 mm from the cartilage on the surface of the trochlear groove. The control group was the group that did not have a block implanted. Figure 12 shows (A), (E), and (I) as the wet carbonate apatite honeycomb composition, (B) and (F) as the wet carbonate apatite gyroid composition, (C), (G), and (J) as the wet carbonate apatite block, and (D) and (H) as the control. (A) to (D) are macroscopic findings, (E) to (H) are μCT images, and (D) and (H) are safranin O stained images. Macroscopic findings at 4 weeks post-surgery, excluding the control group, showed that cartilage had formed in all cases. Furthermore, μCT and safranin O staining images at 4 weeks post-surgery also showed that, excluding the control group, the cartilage had bonded to the graft bone, and that cartilage connecting to the cartilage covering the trochlear region had formed on the trochlear groove side surface.

[0093] [Experimental Example 31] Silver phosphate, silver carbonate, copper phosphate, and copper carbonate were used as metal salts; silver nanoparticles were used as metals with a diameter of 1 μm or less; Alizarin Red was used as a simulated composition of growth factors and drugs; and glycolic acid lactate copolymer was used as a bioabsorbable polymer. At 750°C, the production condition for dry carbonate apatite, all metal salts decomposed. In addition, Alizarin Red and glycolic acid lactate copolymer were incinerated. Therefore, it was found that it is practically impossible to incorporate these into the dry apatite composition. Except for mixing 1% by mass of silver phosphate, silver carbonate, copper phosphate, copper carbonate, silver nanoparticles, alizarin red, and glycolic acid lactate copolymer with the Ca(OH)2 produced in Experimental Example 7, the same process as in Experimental Example 7 was carried out, and a wet carbonate apatite coated titanium comprising silver phosphate, silver carbonate, copper phosphate, copper carbonate, silver nanoparticles, alizarin red, and glycolic acid lactate copolymer was produced.

[0094] Furthermore, 1% by mass of silver phosphate, silver carbonate, copper phosphate, copper carbonate, silver nanoparticles, alizarin red, and glycolic acid lactate copolymer was added to the powder mixture prepared in Experimental Example 21, which was mixed with Na2HPO4 in a mass ratio of 4:3. This powder mixture was kneaded with a 1 mol / L aqueous solution of Na2HPO4, placed in a mold with a hole 6 mm in diameter and 3 mm in height, and stored at a relative humidity of 37°C for 48 hours, after which it all hardened. After washing and drying with water, compositional analysis revealed that it was all wet carbonate apatite. These results confirm that the wet apatite composition of the present invention [1] can produce a wet apatite composition that contains at least one selected from the group consisting of a metal salt, a metal with a diameter of 1 μm or less, a growth factor, a drug, and a bioabsorbable polymer.

[0095] [Experimental Example 32] Aragonite powder was immersed in a 1 mol / L AgNO3 aqueous solution. The aragonite powder, which was initially white, turned yellow immediately after immersion. 2.3% by mass of silver carbonate was precipitated on the surface of the aragonite powder. A medical-grade curable composition was prepared by mixing silver carbonate-supported aragonite powder as the solid part and a 1 mol / L Na2HPO4 aqueous solution as the liquid part, at a mixing ratio of 1.75. The paste was placed in a mold and held at 100% relative humidity and 40°C for 24 hours, at which point carbonate apatite with a carbonate group content of 2% by mass or more was formed and hardened. It was also found that both silver carbonate and silver phosphate were supported. The hardened body was removed from the mold and immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 7 days. The hardened body after immersion was silver-supported carbonate apatite with a porosity of approximately 80% and a carbonate group content of approximately 12% by mass. Hollow structures were observed in the hardened body, which exhibited an aggregate structure in which powders with an aspect ratio of 20 to 40 were bonded together. Furthermore, since the surface of the hollow structure was coated with flaky wet carbonate apatite, it was found that silver phosphate and other elements were also coated with flaky wet carbonate apatite. A comparison of this experimental example with experimental example 23 confirmed that silver salts can be easily supported on calcium carbonate and wet carbonate apatite, and that the supported silver salts do not affect the hardening reaction, etc.

[0096] [Experimental Example 33] Aragonite powder was immersed in a 1 mol / L aqueous calcium nitrate solution and removed, and excess calcium nitrate solution was removed using filter paper. Next, the aragonite aggregate was heat-treated in an electric furnace at 550°C for 24 hours under a carbon dioxide gas flow of 100 mL / min. Powder X-ray diffraction revealed that the composition was entirely calcite. As shown in Figure 13, a calcium carbonate aggregate structure with a porosity of 82% was produced, in which the contact points between calcite atoms with an aspect ratio of 10-20 were bonded. When a manufactured calcium carbonate aggregate with 82% porosity was immersed in a 1 mol / L AgNO3 aqueous solution, the calcium carbonate aggregate, which was white immediately after immersion, changed color to yellow. Silver carbonate, equivalent to 2.6% by mass, was precipitated on the surface of the calcium carbonate aggregate. The silver support did not affect the porosity of the 82% aggregate. The manufactured calcium carbonate aggregate and the silver-supported calcium carbonate aggregate were crushed and sieved to produce granules of 300-600 μm. These granules were placed in a mold with a hole 6 mm in diameter and 3 mm deep, filled with a 1 mol / L Na2HPO4 aqueous solution, and stored at 40°C for 24 hours until hardened. The hardened material was then removed from the mold and immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 72 hours. When a calcium carbonate aggregate without silver support was used as the solid portion, a medical-grade calcium composition was produced with a carbonate apatite composition containing approximately 12% by mass of carbonate groups, and an aggregate structure with a porosity of approximately 90%, where the contact points between whiskers with an aspect ratio of 10 to 20 were bonded. Furthermore, flaky wet carbonate apatite crystals precipitated on the surface of the composition, and hollow structures were also confirmed. When a silver-supported calcium carbonate aggregate was used as the solid portion, a carbonate apatite aggregate structure containing approximately 12% by mass of carbonate groups supported with silver carbonate and silver phosphate was produced. However, no differences were observed in the medical calcium compositions produced using materials other than silver-supported calcium carbonate.

[0097] [Experimental Example 34] To verify the coating of specific compositions and the formation of specific structures by wet-process carbonate apatite, aragonite powder was coated with silver carbonate, silver nanoparticles (AGCN30, manufactured by Funakoshi Co., Ltd.) with a diameter of 1 μm or less, Alizarin Red S (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a simulated composition of growth factors and drugs, and glycolic acid lactate copolymer (manufactured by Taki Chemical Co., Ltd.) as a bioabsorbable polymer. Since complete coating of the glycolic acid lactate copolymer with the aragonite powder may hinder the dissolution and extraction reaction, it was dissolved in dioxin and sprayed onto the powder to coat only a portion of the aragonite powder. All of these materials have a solubility in water of 1 or less. Next, the material was immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 7 days. A wet carbonate apatite powder was produced, which had a hollow structure, an aspect ratio of 20-40, and a surface coated with flaky wet carbonate apatite. Specifically, a wet carbonate apatite composition was produced in which silver carbonate and / or silver phosphate (silver carbonate phosphorylated), and silver nanoparticles with a diameter of 1 μm or less, and an alizarin red S lactate glycolic acid copolymer were coated onto the wet carbonate apatite.

[0098] [Experimental Example 35] The solid portion was aragonite powder, and the liquid portion was a 5 mol / L Na2HPO4 aqueous solution prepared immediately after preparation. Aragonite powder was added to the liquid portion while vibrating with a vibrator to achieve a mixing ratio of 2, and a slurry was prepared by mixing. The slurry was placed into a 5 mm thick silicone rubber hole with an 8.5 mm diameter through hole, which was placed on a stainless steel plate. The top of the hole was sealed with a 3 mm thick silicone rubber plate, and the mixture was stored at 0°C for 24 hours. In this operation, the vaterite slurry was cooled from one direction (towards the stainless steel plate). After 24 hours, the mixture was reacted in a constant temperature bath at 40°C with 100% relative humidity for 24 hours, then washed with water and dried. The product was carbonate apatite with a porosity of approximately 80% and containing approximately 11% carbonate groups. The surface was coated with a spherical wet carbonate apatite composition, and the height from the concave to the convex portion was 0.2 μm. From the μCT images shown in Figure 14, it was found that a wet apatite composition with frost-like pores can be produced.

[0099] [Experimental Example 36] The slurry prepared in Experimental Example 29 was placed in a stainless steel mold with holes 6 mm in diameter and 3 mm in height. The slurry was cooled from all directions and stored at 0°C for 24 hours. After 24 hours, it was reacted in a constant temperature bath at 40°C with 100% relative humidity for 24 hours, then washed with water and dried. The product was a sponge-like structure of wet carbonate apatite with a porosity of approximately 80% and containing approximately 11% carbonate groups. The surface was coated with a spherical wet carbonate apatite composition, and the height from the recess to the convex part was 0.2 μm.

[0100] [Experimental Example 37] The calcium carbonate powder used in Experimental Example 1 was mixed with a 1 mol / L Na2HPO4 aqueous solution at a mixing ratio (L / P) of 1.6. This mixture was placed in a mold for a hexapod, a structure comprising tetrahedra, hexahedrons, and multiple legs. Initial curing was performed at 40°C and 100% relative humidity for 24 hours, followed by 40°C or 80°C for 4 days. As a result, the volume of the aggregated structure formed by the bonding of wet carbonate apatite powder was approximately 2 × 10⁻¹⁶. -10 m 3 ~1 × 10 -9 m 3 Wet apatite blocks were manufactured, which were structures comprising tetrahedrons, hexahedrons, and multiple legs. All of these surfaces exhibited a scaly appearance, and the surface morphological height was 0.25 μm.

[0101] [Experimental Example 38] <9. Hollow structures with specific compositions> A 0.4 mol / L sulfuric acid solution and a 0.4 mol / L calcium chloride aqueous solution were mixed at 100°C and reacted at 100°C for 2 hours to produce calcium sulfate with an aspect ratio of 100 or more, and needle-shaped calcium sulfate with a maximum diameter of approximately 10 μm and a length of approximately 500 μm to 1000 μm. When the needle-shaped calcium sulfate was immersed in a 0.05 mol / L NaHCO3 aqueous solution at 4°C for 72 hours, hollow calcium carbonate was produced with a maximum diameter of approximately 12 μm and a length of approximately 500 μm to 1000 μm, an aspect ratio of approximately 4 to 80, and a shell thickness of approximately 5 μm. Next, the prepared hollow calcium carbonate was immersed in solutions prepared with a pH stat and 0.1 mol / L phosphoric acid to pH 5 and pH 6, and reacted for 24 hours. The hollow calcium carbonate maintained its macromorphology while undergoing compositional changes to hollow calcium hydrogen phosphate and hollow calcium-deficient apatite, respectively. Furthermore, when the hollow calcium-deficient apatite was calcined at 1000°C, hollow tricalcium phosphate was produced, and when the hollow calcium hydrogen phosphate was immersed in a saturated solution of octacalcium phosphate at pH 5.5, hollow octacalcium phosphate was produced.

[0102] [Experimental Example 39] A transparent dispenser was manufactured from acrylic resin with the following specifications: the width (l1) of the discharge port is 10 mm, the thickness (t1) is 0.4 mm, the width (L1) of the discharge surface is 10.6 mm, the thickness (T1) is 0.8 mm, the maximum width (l2) of the area where the space through which the paste passes in the dispenser overlaps with a plane perpendicular to the straight line passing through the center of the discharge port and the center of the inlet is 12 mm, the maximum thickness (t2) is 2.4 mm, the maximum width (L2) of this surface is 10.6 mm, the maximum thickness (T2) is 0.8 mm, and the length (f) of the space through which the paste passes in the dispenser from the center of the discharge port towards the inlet is the same as the thickness of the discharge port, which is 2 mm. The value obtained by dividing the width of the discharge port (l1) by the thickness (t1) is 25. When a paste prepared by kneading a solid portion consisting of vaterite and tricalcium phosphate with an aqueous solution of disodium hydrogen phosphate containing hydroxypropyl cellulose was injected through the injection port using a syringe, the paste spread in a band shape until it reached a point (hereinafter sometimes referred to as the parallel space) where the thickness of the space through which the paste passes in the dispenser, extending from the center of the discharge port towards the injection port, was the same as the thickness of the discharge port. Subsequently, after passing through the parallel space, a band of paste approximately 10 mm wide and 0.4 mm thick was discharged from the discharge port. The width of the discharge surface (L1) was the width of the discharge port (l1) plus 0.6 mm, and the thickness of the discharge surface (T1) was the thickness of the discharge port (t1) plus 0.4 mm, making it easy to predict the location of the discharged paste. The discharged strip-shaped paste covered the surface of the granules filled into the medial cavity, and by pressing the strip-shaped paste with a spatula, the granules on the surface of the medial cavity were bridged, making it possible to easily cover the surface of the medial cavity as shown in Figure 1(B).

[0103] [Reference example 4] When the same paste as in Experimental Example 39 was dispensed using a 10mm long 18G needle, the paste was dispensed in a cylindrical spiral shape. When attempting to cover the granules with the paste using a spatula, the granules floated to the surface, making coating difficult. Although coating itself was possible, the thickness of the paste was uneven. From a comparison between this reference example and Experimental Example 39, it was found that dispensing the paste in a strip shape is important.

[0104] [Experimental Example 40] A dispensing device identical to that used in Experimental Example 39 was manufactured, except that the maximum width (l2) of the area where the space through which the paste passes, the center of the dispensing port, and the center of the inlet overlap with a plane perpendicular to the straight line was set to 10 mm and the maximum thickness (t2) to 0.4 mm. When the same paste as in Experiment Example 39 was injected, the central part moved to the nozzle first, followed by the edges. A strip-shaped paste with a wavy center was dispensed from the nozzle. From a comparison between this experimental example and experimental example 39, it was found that it is preferable for the value obtained by dividing the maximum area of ​​the space through which the paste passes in the dispenser, the area perpendicular to the straight line passing through the center of the dispenser and the center of the inlet, by the area of ​​the dispenser, to be greater than 1. It was found that when this maximum area is greater than the area of ​​the dispenser, the paste spreads in the width direction where the resistance is small, so the amount of paste dispensed at the center and the edges of the dispenser is the same, and a band-shaped paste without waves is dispensed.

[0105] [Experimental Example 41] An extruder identical to that in Experimental Example 38 was manufactured, except that the thickness of the space through which the paste passes from the center of the discharge port toward the injection port was not the same as the thickness of the discharge port. A strip of paste approximately 10 mm wide and 0.4 mm thick was discharged from the discharge port, but the strip of paste was discharged in a wave-like pattern. From a comparison between this experimental example and experimental example 39, it was found that a dispensing device is preferable that has a portion of the space through which the paste passes from the center of the discharge port toward the injection port, where the thickness is 0.3 mm or more in length and the same as the thickness of the discharge port.

[0106] [Experimental Example 42] An extruder identical to that used in Experimental Example 39 was manufactured, except that the width (L1) of the extrusion surface was set to 16 mm and the thickness (T1) to 6.8 mm. When the same paste as in Experimental Example 30 was extruded, a strip-shaped paste approximately 10 mm wide and 0.4 mm thick was extruded from the nozzle. However, due to the large surface area of ​​the extrusion surface, it was difficult to extrude the paste directly near the granule surface. Similarly, it was difficult to extrude the paste at a small angle to the granule surface. From a comparison between this experimental example and experimental example 39, it was found that it is preferable for the width of the discharge surface (L1) to be less than or equal to the width of the discharge port (l1) plus 3 mm, and for the thickness of the discharge surface (T1) to be less than or equal to the thickness of the discharge port (l1) plus 3 mm. It was also found that it is preferable for the thickness of the inlet surface of the dispenser to be greater than the thickness of the discharge surface, and for the width of the inlet surface to be greater than the width of the discharge surface.

[0107] [Experimental Example 43] An identical dispenser to that used in Experimental Example 39 was manufactured, except that the maximum width of the outer surface of the dispenser, where a plane perpendicular to the straight line passing through the center of the discharge port and the center of the injection port overlapped, was set to 20 mm and the maximum thickness to 10 mm. When the same paste as in Experimental Example 30 was dispensed, a strip of paste approximately 10 mm wide and 0.4 mm thick was dispensed from the discharge port. However, because the dispensing surface was difficult to see, it was difficult to dispense the paste directly near the granule surface. Similarly, it was difficult to dispense the paste in such a way that the angle with the granule surface was small. From a comparison between this experimental example and experimental example 39, it was found that it is preferable that the maximum thickness of the outer surface of the discharger where a plane perpendicular to the straight line passing through the center of the discharge port and the center of the inlet port overlaps is less than or equal to the thickness of the discharge port plus 3 mm, and / or the maximum width is less than or equal to the thickness of the discharge port plus 6 mm.

[0108] [Experimental Example 44] An extruder with the same structure as in Experimental Example 39 was manufactured using black opaque acrylic resin. A strip-shaped paste approximately 10 mm wide and 0.4 mm thick was dispensed from the nozzle, but because the process of paste dispensing could not be observed, the extruder in Experimental Example 38 was found to be clinically preferable. It was found that, in order to predict the paste to be dispensed in advance, it is preferable that at least 1 mm of the dispenser from the dispensing port towards the injection port be transparent or semi-transparent.

[0109] [Experimental Example 45] A titanium alloy (Ti-6Al-4V) plate was immersed in a 5 mol / L NaOH aqueous solution and treated at 60°C for 24 hours. After washing with water, it was heated at 5°C per minute to 600°C, heat-treated at 600°C for 1 hour, and then furnace-cooled. As a result of this treatment, a sponge-like interconnected porous body was formed on the surface of the titanium alloy (Figure 15). A saturated silver nitrate solution was applied to the surface, followed by a saturated sodium chloride solution, and then washed with water. After that, it was heated in an electric furnace at 10°C per minute to 500°C, and heat-treated at 500°C for 10 hours. Powder XRD analysis revealed that silver chloride and metallic silver were formed. The silver chloride and metallic silver were surrounded by a sponge-like interconnected structure, and perhaps because they were fused together, they could not be removed even when scratched with a fingernail. On the other hand, when a saturated silver nitrate solution was applied to the surface of an untreated titanium alloy, followed by a saturated sodium chloride solution, the powder formed at that stage was washed away. A comparison of the two methods verified the usefulness of the sponge-like interconnected porous material formed on the surface of the titanium alloy.

[0110] [Experimental Example 46] When the medical metal material, in which silver chloride produced in Experimental Example 45 is integrated and contained within a sponge-like, interconnected porous structure on the surface of a titanium alloy, was immersed in a 0.1 mol / L Na2HPO4 aqueous solution, some of the silver chloride was converted to silver phosphate. The silver chloride and silver phosphate were surrounded by a sponge-like interconnected structure, and perhaps because the silver phosphate was deposited on the surface of the molten, integrated silver chloride, they could not be removed even when scratched with a fingernail.

[0111] [Experimental Example 47] Two types of titanium plates were polished with 800-grit SiC, and anodized using a 0.1 mol / L aqueous calcium glycerophosphate solution as the electrolyte and a DC stabilized power supply (PL-650-0.1, manufactured by Matsutei Precision Co., Ltd.) to form pores and produce a titanium substrate with an uneven surface. A film of silver chloride was placed on the substrate and treated at 550°C under vacuum for 1 hour. After it cooled to room temperature, the silver chloride adhering to the surface was removed by polishing. SEM-EDX observation confirmed that silver chloride had been introduced into the pores. The silver chloride in the pores could not be removed by polishing.

[0112] [Experimental Example 48] Two types of medical-grade titanium (manufactured by T&I Corporation) were acid-etched to create a surface texture by immersion in a mixed acid aqueous solution containing 50% sulfuric acid and 7% hydrochloric acid at 70°C for 30 minutes. The arithmetic surface roughness (Ra) of the manufactured titanium with the textured surface was 2.2 ± 0.7 μm. Next, 8 μL / cm³ of a 0.5 mol / L Ca(NO3)2 ethanol solution is applied to the titanium surface. 2 The material was applied in this manner, heated in an electric furnace at a rate of 3°C per minute to 550°C under a carbon dioxide flow rate of 100 mL per minute, and then heat-treated at 550°C for 5 hours before furnace cooling to produce calcite-coated titanium. When the calcite-coated titanium was immersed in a 0.1 mol / L AgNO3 aqueous solution, silver carbonate formed on the surface, causing the surface to turn yellow. When the surface was irradiated with light, silver nanoparticles were formed. Next, when immersed in a 0.2 mol / L Na2HPO4 aqueous solution for 7 days, the calcite underwent a compositional transformation into carbonate apatite containing approximately 11% by mass of carbonate groups. It was found that the carbonate apatite-coated titanium contained silver nanoparticles and silver phosphate.

[0113] [Experimental Example 49] A titanium alloy (Ti-6Al-4V) plate was separated using nail polish, then immersed in a 5 mol / L NaOH aqueous solution and treated at 60°C for 24 hours. After rinsing with water, the nail polish was removed with acetone. Subsequently, the plate was heated at 5°C per minute up to 600°C, heat-treated at 600°C for 1 hour, and then furnace-cooled. As a result of this treatment, a sponge-like, interconnected porous body was formed on the titanium alloy surface, separated by a metal surface that does not possess any of the following characteristics: a sponge-like structure, an interconnected porous body structure, or an uneven surface structure. A saturated silver nitrate solution was applied to the surface of a titanium alloy, followed by a saturated sodium chloride solution, and then washed with water. At this stage, silver chloride formed in areas where a sponge-like structure had not formed was washed away. Subsequently, the alloy was heated in an electric furnace at a rate of 10°C per minute up to 500°C, and then heat-treated at 500°C for 10 hours. Powder XRD analysis revealed that silver chloride had formed inside the sponge-like structure. The silver chloride was surrounded by a sponge-like interconnected structure and, possibly because it was molten and integrated, it could not be removed even when scratched with a fingernail.

[0114] [Experimental Example 50] Calcium carbonate spheres were produced by spray-drying spheroidized calcium hydroxide and then calcining it at 800°C. The sphericity was 0.98, and the volume was 6 × 10⁻⁶. -14 m 3 The results were as follows: When calcium carbonate spheres were immersed in a 1 mol / L Na2HPO4 aqueous solution at 80°C for 7 days, their composition was transformed into carbonate apatite containing approximately 11% carbonate groups. The sphericity was 0.98, and it exhibited a hollow structure. The volume was 6 × 10⁻⁶. -14 m 3 When the hollow carbonate apatite spheres were mixed with glycerin, they could be easily dispensed from an 18G syringe.

Claims

1. A block-shaped wet carbonate apatite composition exhibiting an aggregate structure formed by bonding wet carbonate apatite powders, each having a sphericity of 0.9 or higher, exhibiting a surface morphology selected from the group consisting of flaky, spherical, and needle-like shapes, and having a height of 0.2 μm or more from the base to the highest point in the surface morphology.

2. The block-shaped wet apatite composition according to claim 1, characterized in that it is a gyroid structure.

3. The block-shaped wet apatite composition according to claim 1 or 2, characterized in that, when implanted in a bone defect in the trochlear groove of a rabbit femur such that a recess of 2.0 mm to 3.0 mm is formed from the cartilage surface of the trochlear groove, the chemically synthesized wet apatite is such that it binds to the host bone and cartilage that binds to the cartilage covering the trochlear portion is formed on the trochlear groove side surface.

4. The block-shaped wet apatite composition according to claim 1 or 2, characterized in that it contains at least one selected from the group consisting of a metal salt, a metal with a diameter of 1 μm or less, a growth factor, a drug, and a bioabsorbable polymer within the wet carbonate apatite composition.

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