Wet calcium phosphate porous body, wet calcium phosphate curable composition, and related materials

Abstract

[Problem] To provide a wet apatite porous body and a wet apatite curable composition exhibiting excellent bone conduction and bone replacement properties, and wet apatite and related materials for regenerating cartilage. Another problem is to provide an apatite-based curable composition, a calcium phosphate composition, a calcium carbonate composition, supporting bodies, and the like necessary to provide the abovementioned, and related manufacturing methods. [Solution] This problem has been solved by discovering a wet apatite porous body, a wet apatite curable composition, a wet apatite composition and related materials for regenerating cartilage, and manufacturing methods for these.

Description

Wet-process calcium phosphate porous body, wet-process calcium phosphate hardening composition, and related materials

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

[0002] In medicine, artificial materials are often used for tissue reconstruction of hard and soft tissues. For example, artificial bones are sometimes used for reconstruction of bone defects. Recently, wet apatite has been produced by the dissolution-precipitation method (Patent Document 1) rather than dry apatite, which is produced by sintering or other methods. In particular, wet carbonate apatite, which has the inorganic composition of bone, exhibits excellent osteoconductivity and is replaced by new bone through bone remodeling. Wet carbonate apatite artificial bones are being clinically applied in Japan and the United States. To accelerate bone remodeling by cells, it is useful to make the wet apatite porous so that cells can penetrate the artificial bone. Note that osteoconduction depends on the surface composition of the artificial bone. On the other hand, bone replacement, the process following osteoconduction, also depends on the resorption of the artificial bone. Therefore, wet carbonate apatite-coated calcium carbonate has excellent osteoconductivity and can rapidly replace bone. While wet apatite is a brittle material, it has issues with mechanical strength, but these issues can sometimes be resolved by combining it with a support. Furthermore, hardenable compositions that harden by forming wet apatite are easy to handle (Patent Document 2). Furthermore, bones are bonded to soft tissues such as cartilage, and materials that regenerate cartilage or bond to soft tissues are also useful. Therefore, there is a demand for medical and related materials that satisfy these properties.

[0003] Patent No. 4854300 JP2021-037281

[0004] The problem to be solved by the present invention is to provide a wet-process apatite porous body or wet-process apatite hardening composition having excellent osteoconductivity and bone replacement properties, as well as wet-process apatite and related materials for regenerating cartilage.

[0005] As a result of extensive research, the present inventors have discovered a wet-process porous apatite body, a wet-process apatite hardening composition, a wet-process apatite composition for cartilage regeneration and related materials, as well as methods for producing these, and have completed the present invention.

[0006] <Definitions of Terms, etc.> In the present invention, terms are defined as follows. For simplicity, unless otherwise specified, the values ​​described below are used for the following items. <Apatite Composition> Apatite compositions are a type of calcium phosphate composition that exhibits an apatite structure. Apatite compositions are classified into dry apatite compositions and wet apatite compositions. Dry apatite compositions are produced by sintering, while wet apatite compositions are produced under wet conditions, such as in an aqueous solution. Dry apatite does not contain water of crystallization and has limited attached water. It also has characteristics such as high crystallinity. Wet apatite contains water of crystallization and attached water, but has low crystallinity. In the present invention, dry apatite compositions and wet apatite compositions are classified based on the content of water of crystallization and attached water for simplicity's sake. First, the apatite composition is dried at 80°C for 2 hours. The moisture content is then evaluated. Dry apatite compositions generally do not lose weight, while wet apatite compositions lose weight by 0.2% by mass or more. For this reason, in the present invention, an apatite composition that loses 0.2 mass% or more in weight when dried at 50°C for 2 hours and then heat-treated at 300°C for 2 hours is defined as a wet apatite composition. Apatite compositions are also classified into hydroxyapatite compositions that do not contain carbonate groups and carbonate apatite compositions that contain carbonate groups. The chemical formula, ignoring water of crystallization, is stoichiometric hydroxyapatite: [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 inconstant values). Apatite has bone composition or is similar to bone composition, and therefore is clinically used as artificial bone. Carbonated apatite is preferred because it undergoes bone remodeling and is replaced by new bone. In the present invention, apatite having 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 the present invention, a wet apatite composition is defined as a composition in which at least a portion of the surface is wet apatite. A composition in which the surface is wet apatite but the interior is not wet apatite, such as wet apatite-coated calcium carbonate, and a composite material 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. Furthermore, a composition that hardens by forming wet apatite is also a wet apatite composition because its surface is wet apatite.

[0008] <Dissolution-precipitation reaction> In the present invention, a wet carbonate apatite composition may be produced using a dissolution-precipitation reaction. A method for producing wet carbonate apatite from calcium carbonate by a dissolution-precipitation reaction will be outlined below. When CaCO3, a precursor of wet carbonate apatite, is immersed in an aqueous solution of Na2HPO4, etc., a small amount of CaCO3 dissolves and Ca 2+ and CO3 2- In aqueous solution, PO4 3- The solution becomes supersaturated with respect to carbonate apatite due to the presence of CaCO3, and carbonate apatite crystals precipitate on the surface of CaCO3. Since carbonate apatite is formed in water, the precipitated carbonate apatite is wet carbonate apatite. Due to the precipitation of carbonate apatite, the solution becomes undersaturated with respect to CaCO3, so a small amount of CaCO3 dissolves and Ca 2+ and CO3 2-The dissociation occurs, the solution becomes supersaturated with carbonate apatite, and wet carbonate apatite precipitates. This dissolution and precipitation reaction occurs continuously, converting the precursor, CaCO3, into wet carbonate apatite while maintaining its macroscopic structure. In the dissolution-precipitation method, wet carbonate apatite is formed on the surface of the precursor. Therefore, if the dissolution-precipitation method is interrupted before the precursor is completely converted into wet carbonate apatite, wet carbonate apatite-coated calcium carbonate is produced. The volume of wet carbonate apatite produced by the dissolution-precipitation reaction is larger than that of the precursor, CaCO3, probably because the crystals are intertwined. In other words, the composition exhibits the tendency to expand during the dissolution-precipitation reaction. Furthermore, wet carbonate apatite crystals are formed on the surface of the precursor during the dissolution-precipitation reaction. Therefore, when precursor powders or granules are brought into close contact with each other and a dissolution-precipitation reaction occurs, the wet carbonate apatite crystals formed on the surfaces of the powders or granules bond with each other and harden, producing wet carbonate apatite blocks or the like.

[0009] <Aspect Ratio> The aspect ratio is the value obtained by dividing the length of a crystal or fibrous composition by its maximum thickness. Accumulating crystals with an aspect ratio greater than 1 may increase porosity. In principle, an aspect ratio greater than 1 is useful for improving porosity, but from a practical standpoint, the present invention targets crystals with an aspect ratio of 1.5 or greater. An aspect ratio of 3 or greater is preferred, with 10 or greater being more preferred. An aspect ratio of 51 or greater may be even more preferred. Accumulations of crystals with a high aspect ratio have high porosity but low mechanical strength. Therefore, when mechanical strength is prioritized, crystals with an aspect ratio of 1.5 or greater but less than 3, or 50 or less, may be selected. When porosity is prioritized over mechanical strength, a large aspect ratio is preferred. There is no upper limit to the aspect ratio, but from the standpoint of operability, an aspect ratio of 200 or less is preferred, 100 or less is more preferred, and 50 or less may be even more preferred. The thickness of crystals with an aspect ratio of 1.5 or greater is not particularly limited. In the case of vaterite crystals, the thickness is generally 0.3 μm to 3 μm, but in the case of fibrous compositions, any thickness can be used by extrusion molding, etc. On the other hand, from the viewpoint of practicality, in the case of crystals or fibrous compositions having an aspect ratio of 1.5 or more, the thickness is preferably 0.3 μm or more and 1 mm or less.

[0010] <Sphericity> In the present invention, "sphericity" refers to Wadell's practical sphericity, which is the diameter of a circle equal to the projected area of ​​a material divided by the diameter of the smallest circle circumscribing the projected image of the material. <Accumulated Structure> In the present invention, an accumulated structure refers to a structure in which crystals and the like are accumulated, and is a structure that exhibits an accumulated structure. Note that an accumulated structure is a structure that does not break apart even when immersed in water and remains as a single mass, and is different from an aggregate that breaks apart when immersed in water. <Surface Roughness> In the present invention, the surface roughness (Ra) is the arithmetic mean surface roughness (Ra) specified in ISO 25178. <Bioabsorbable Polymer> 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, sebacic acid, malic acid, and hydroxycarboxylic acids, collagen, gelatin, chitin, chitosan, hyaluronic acid, chondroitin sulfate, fibronectin, vitronectin, and laminin.

[0011] <Hardenable Composition> Hardenable compositions are sometimes classified as hardening compositions in which a paste formed by kneading a powder portion with a liquid portion hardens, and hardening compositions in which a paste formed by kneading a powder portion with water hardens. The former is sometimes called a hardening kit. However, when the liquid portion contains a water-soluble salt and the powder portion contains a water-soluble salt, they harden by the exact same reaction when kneaded with water, and are therefore essentially the same. Since the liquid portion of the hardenable composition of the present invention is composed entirely of an aqueous solution of a water-soluble salt, the powder portion contains the water-soluble salt that is the liquid portion, and hardens by the exact same reaction when kneaded with water. Therefore, in the present invention, the two are not distinguished and are defined as hardenable compositions. Note that hardenable compositions and cement are the same. Furthermore, the powder portion may contain granules, and in that case, they are also defined as hardenable compositions.

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

[0013] <Porosity and pore volume of 10 μm or less> In the present invention, there are cases where the porosity and pore formation are increased to promote osteoconduction and bone replacement. Unless otherwise specified, the porosity is preferably 30% or more, more preferably 40% or more, and even more preferably 50% or more. Ideally, it is 60% or more. To promote osteoconduction and bone replacement, it is preferable that the pore volume of 10 μm or less is large. Unless otherwise specified, the pore volume of 10 μm or less is 0.2 cm 3 / g or more is preferable, and 0.4cm 3 / g or more is more preferable, and 0.6cm 3 / g or more is more preferable. 3 / g or more is ideal. In this invention, pore volume is measured by mercury intrusion porosimetry. Mercury intrusion porosimetry is a type of pore distribution measurement method that utilizes the high surface tension of mercury to apply pressure to force mercury into the pores of a powder, and determines the pore distribution from the pressure and the amount of mercury intruded. In this invention, pores are 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. The pore diameter is a value calculated based on the results of mercury intrusion porosimetry analysis, assuming that mercury is intruded into cylindrical pores, regardless of the pore shape.

[0014] <Volume Average Diameter> The volume average diameter is a value specified in JIS-Z8819-2:2019. If discrepancies occur between measurements, values ​​measured using the ELSZ-2000ZS Zeta Potential, Particle Size, and Molecular Weight Measurement System manufactured by Otsuka Electronics Co., Ltd. are used. <Liquid Mixing Ratio> The liquid mixing ratio is the mass ratio of the liquid to the solid when kneading a medical curable composition. For example, kneading 1 g of powder with 0.8 g of liquid results in a liquid mixing ratio of 0.8. <Scaly, Spherical, or Acicular Surface Morphology> A feature of the present invention is the surface morphology of wet apatite, which may exhibit a scaly, spherical, or acicular surface. Furthermore, a larger height from the bottom to the highest point of the surface morphology may be preferable. For simplicity, in this invention, the height from the bottom to the highest point of the surface morphology may be referred to as the surface morphology height for a morphology selected from the group consisting of scaly, spherical, and acicular.

[0015] The present invention is as follows: (Hereinafter, the following inventions [1] to

[0014] may be referred to as "Inventions [1] to

[0014] ") [1] A wet apatite composition characterized by satisfying at least one of the following conditions (A1) to (A5): (A1) A wet carbonate apatite powder or a wet carbonate apatite block having an integrated structure in which the wet carbonate apatite powder is bonded, which satisfies any one of the following conditions: an aspect ratio of 1.5 or more but less than 3, an aspect ratio of 3 or more, and a burr-like shape in which the needle-like crystals extend in multiple directions, and the surface has a shape selected from the group consisting of scale-like, spherical, and needle-like; or an aspect ratio of 1.5 or more and having a hollow structure; or a sphericity of 0.9 or more, and the surface has a shape selected from the group consisting of scale-like, spherical, and needle-like, and the height from the bottom to the highest point in the surface shape is 0.2 μm or more. (A2) A wet-apatite-coated support in which wet apatite covers at least a part of the support, or a wet-apatite-embedded support in which wet apatite exists inside the support, satisfying at least one of the following conditions (A21) to (A24): (A21) A support having an arithmetic mean surface roughness (Ra) of 1.0 μm or more, at least a portion of which is coated with a wet carbonate apatite layer, wherein the arithmetic mean surface roughness (Ra) of the wet apatite layer surface is 4 μm or more, the wet apatite layer has recesses with a depth of 10 μm or more, or the wet apatite layer has a hollow structure, or the wet apatite layer has a structure in which any wet apatite selected from the group consisting of an aspect ratio of 3 or more, a burr shape in which needle-like crystals are extended in multiple directions, and a sphericity of 0.9 or more penetrates the wet apatite layer, or the wet apatite layer has a porosity of 5% or more and a specific surface area of ​​3 m2 as determined by mercury intrusion porosimetry. 3 / g or more, or the pore volume of pores with a pore diameter product of 0.01 μm or more and 1 μm or less is 0.03 cm 3 / g or more. (A22) At least a portion of a support that is a bioabsorbable polymer is coated with a wet apatite layer, and the support is any one of a three-dimensional interconnected structure, a porous membrane, a membrane with holes, and a membrane comprising wet apatite. (A23) The support has a thread structure, and 5% or more of the height of the threads is coated with wet apatite, and / or at least one selected from the group consisting of a portion of the threads where the arithmetic mean surface roughness (Ra) is 1.0 μm or more, a concave or convex portion on the surface of the threads, a groove formed on the side of the threads, and a portion where a portion of the threads has been removed is coated with wet apatite. (A24) The inside of a support that does not have undercuts or the inside of a support that has undercuts has a porosity of 30% or more, and / or a pore volume of pores with a diameter of 10 μm or less of 0.2 cm 3 / g or more, and has fixed thereto wet apatite having a structure selected from the group consisting of a honeycomb structure with a plurality of through-holes extending in one direction, a structure with frost column-like pores, a three-dimensional interconnected structure with a plurality of through-holes extending in multiple directions, a sponge structure, a gyro structure, a porous structure, and an integrated structure. (A3) A curable composition that satisfies any one of the following conditions (A31) to (A33). (A31) The powder portion 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, or a mixture of calcium carbonate and tricalcium phosphate having an average particle size of less than 2 μm as set forth in the group (A312) below, a mixture of calcium carbonate and tricalcium phosphate having an average particle size of less than 2 μm as set forth in the group (A312) below, and a water-soluble phosphate, a mixture of calcium carbonate and calcium hydrogen phosphate as set forth in the group (A312) below, a mixture of calcium carbonate, calcium hydrogen phosphate, and a water-soluble phosphate as set forth in the group (A312) below, or a mixture of at least one selected from the group (A313) and one selected from the group consisting of tricalcium phosphate, a mixture of tricalcium phosphate and a water-soluble phosphate, calcium hydrogen phosphate, or a mixture of calcium hydrogen phosphate and a water-soluble phosphate, wherein the hardenable composition hardens to form wet apatite when the powder portion is exposed to an aqueous solution of a water-soluble phosphate or water. (A311) Calcium carbonate, calcite, aragonite, vaterite, amorphous calcium carbonate, calcium carbonate with an aspect ratio of 3 or more, calcium carbonate with a burr-like structure in which needle-like crystals are extended in multiple directions, calcium carbonate with a hollow structure, 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 a burr-like structure in which needle-like crystals are extended in multiple directions, hollow calcium carbonate, hollow calcium carbonate with an aspect ratio of 3 or more, amorphous calcium carbonate, volume of 5 x 10 -13 m 3 That's it, 2 x 10 -8 m 3 The following calcium carbonate aggregates, calcium carbonate with an aspect ratio greater than 51 (A32) and a volume of 5×10 -13 m 3 That's it, 2 x 10-8 m 3 The paste comprises the following wet carbonate apatite granules and a powder portion that hardens to form wet apatite, and when mixed with a phosphate aqueous solution or water, the paste hardens to form wet carbonate apatite, and at least a portion of the wet carbonate apatite granules are bridged by the wet carbonate apatite to form interconnected pores, and / or the hardened paste is a hardenable composition that is absorbed in the body more quickly than the wet carbonate apatite granules; or the volume of tricalcium phosphate powder or a mixed powder of tricalcium phosphate and calcium carbonate bound by calcium phosphate bridges is 5×10 -13 m 3 That's it, 2 x 10 -8 m 3 The hardenable composition comprises a granular portion which is the following granules, and a liquid portion which is at least one selected from the group consisting of water, an aqueous solution of a phosphate, and an aqueous solution of a polyvalent carboxylate, and when the granular portion and the liquid portion are mixed, the granular portion becomes wet apatite granules and the granules bond together. (A33) A hardenable composition having a volume of 5×10 -13 m 3 That's it, 2 x 10 -8 m 3A hardenable composition comprising the following tricalcium phosphate granules and a liquid portion which is a phosphate aqueous solution having a pH of 3.0 or more but less than 8.0, wherein when the granules are exposed to the liquid portion, they bond with each other to form wet apatite. (A4) A chemically synthesized wet apatite which, when implanted in a bone defect in the trochlear groove of a rabbit femur so as to form a recess 2.0 mm to 3.0 mm from the cartilage surface of the trochlear groove, bonds with the host bone and forms cartilage on the trochlear groove side surface, which bonds with the cartilage covering the trochlear groove. (A5) The surface of one 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 in that it contains 3% by mass or more, 5% by mass or more, or 7% by mass or more of carbonate groups. [3] The wet carbonate apatite composition according to [1], characterized in that it contains 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. [4] The wet carbonate apatite composition according to [2], characterized in that it comprises 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 that the wet carbonate apatite has a carbonate group content of 3% by mass or more, 5% by mass or more, or 7% by mass or more, and that the wet carbonate apatite has a hollow structure and / or an aspect ratio of 3 or more, and / or a surface form selected from the group consisting of scale-like, spherical, and acicular, or that presents an aggregate structure in which such powders are bound together. [5] The integrated structure to which the wet carbonate apatite powder described in (A1) is bonded is a honeycomb structure having a plurality of through holes extending in one direction, a three-dimensional porous body having a plurality of through holes extending in multiple directions, a gyroid structure, a sponge-like structure, a structure having frost column-like pores, a tetrahedron, a hexahedron, a cylinder, a sphere having a volume of 5 × 10 -7 m 3 and / or the integrated structure has a porosity of 30% or more, and / or the integrated structure has pores with diameters of 0.10 μm or more and 10 μm or less and a pore volume of 0.2 cm 3 / g or more, and / or the height from the bottom to the highest part of one shape selected from the group consisting of scale-like, spherical, and needle-like shapes that cover the integrated structure is 0.2 μm or more. [6] A method for producing a wet carbonate apatite powder that satisfies any one of the conditions selected from the group consisting of an aspect ratio of 1.5 to less than 3, an aspect ratio of 3 or more, a burr-shaped structure in which needle-like crystals are extended in multiple directions, and a hollow structure, or a wet carbonate apatite aggregate structure that exhibits a structure in which such wet carbonate apatite powder is accumulated, or a wet carbonate apatite structure with frost pillar-shaped pores, characterized by exposing the following to a phosphate aqueous solution: a calcium carbonate powder that satisfies any one of the conditions of an aspect ratio of 1.5 to less than 3, an aspect ratio of 3 or more, a burr-shaped structure in which needle-like crystals are extended in multiple directions, and a hollow structure, or an accumulated structure in which such powders are combined to exhibit an accumulated structure, or a calcium carbonate structure with frost pillar-shaped pores that is produced by lowering the temperature of a slurry consisting of calcium carbonate and an aqueous solution of a water-soluble polymer in one direction or all directions to grow ice in the form of frost pillars, and a step of removing the water-soluble polymer by heat treatment, in that order. [7] A method for producing a wet apatite-coated support, in which at least a portion of the surface of a support having an arithmetic mean surface roughness (Ra) of 1.0 μm or more is coated with a wet apatite layer, characterized in that either (B1) or (B2) below is satisfied:(B1) The method comprises the steps of: (a) applying, to the surface of a support, calcium carbonate having a form selected from the group consisting of an aspect ratio of 3 or more, a burr-like shape with needle-like crystals extending in multiple directions, and a sphericity of 0.9 or more, or a mixture of a pore-forming material and a calcium nitrate solution or a calcium carboxylate solution; (b) subsequently thermally decomposing the calcium nitrate in the presence of carbon dioxide or thermally decomposing the calcium carboxylate to fix calcium carbonate having at least one form selected from the group consisting of an aspect ratio of 3 or more, a burr-like shape with needle-like crystals extending in multiple directions, and a sphericity of 0.9 or more, to the surface of the support via a calcium carbonate layer; or (c) coating a support with calcium carbonate having a pore-forming material or from which the pore-forming material has been removed; and (d) subsequently exposing the product of the previous step to an aqueous phosphate solution to convert the calcium carbonate portion of the product into wet carbonated apatite. (B2) A step of applying at least one selected from the group consisting of calcium oxide, calcium hydroxide, calcium carbonate, and a hardenable composition that hardens to form wet apatite to recesses on the surface of a support modified with a polycarboxylic acid salt or a support not modified with a polycarboxylic acid, followed by (B21), (B23), and (B25) in this order in the case of calcium oxide, or (B22) and (B25) in this order, or (B23) and (B25) in this order in the case of calcium hydroxide, or (B24) and (B25) in this order in the case of calcium carbonate, or (B26) in the case of a hardenable composition that hardens to form wet apatite.(B21) A step of exposing to moisture and adding moisture; (B22) A step of exposing to moisture and carbon dioxide simultaneously and adding moisture and carbon dioxide; (B23) A step of exposing to carbon dioxide and adding carbon dioxide; (B24) A step of adding calcium carbonate to the recesses of the support by either method (B241) or (B242); (B241) A step of adding calcium carbonate powder to the recesses of the support; (B242) A step of adding a calcium carbonate solution or a calcium bicarbonate solution to the recesses of the support; (B25) A step of exposing to a phosphate aqueous solution to convert at least a portion of the calcium carbonate into wet carbonate apatite; (B26) A step of hardening the hardenable composition that hardens to form wet apatite. [8] A method for producing a wet carbonate apatite-embedded support having a wet carbonate apatite composition fixed inside the support, the method comprising the step of exposing, inside the support, 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-former, a mixture of a composition satisfying either (C1) or (C2) and a water-soluble phosphate, and a mixture of a composition satisfying either (C1) or (C2), a water-soluble pore-former, and a water-soluble phosphate: (C1) A calcium carbonate powder exhibiting a morphology 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, and a burr-like shape with needle-like crystals elongated in multiple directions, or one selected from the group consisting of aragonite, vaterite, calcite, and amorphous calcium carbonate. (C2) A calcium carbonate block exhibiting one structure selected from the group consisting of a honeycomb structure having a plurality of through-holes extending in one direction, a structure having frost column-like pores, a three-dimensional interconnected structure having a plurality of through-holes extending in multiple directions, a sponge structure, a gyro structure, and an integrated structure.[9] A hollow-structure wet-process calcium powder, or a hollow-structure wet-process calcium aggregate having a structure formed by an accumulation of said hollow-structure wet-process calcium powder, characterized in that the powder is one selected from the group consisting of calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, apatite, and octacalcium phosphate, and has an aspect ratio of 3 or more and a hollow structure, or is composed of calcium carbonate, has a hollow structure, and satisfies at least one of the following characteristics: an aspect ratio of 10 or more, a long axis length of 60 μm or more, a longest short axis length of 5 μm or more, and a shell thickness of 1 μm or more.

[0010] A method for producing a calcium carbonate powder, calcium phosphate powder, calcium hydrogen phosphate powder, tricalcium phosphate powder, apatite powder, or octacalcium phosphate powder having a hollow structure, or an aggregate having a structure formed by an accumulation of these powders, characterized in that the method comprises the step of exposing calcium sulfate having an aspect ratio of 3 or more to an aqueous carbonate solution or an aqueous phosphate solution.

[0011] A medical dispenser that dispenses a band-shaped paste that hardens to form apatite, and that satisfies any one 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 value obtained by dividing the maximum area of ​​the portion where the space through which the paste of the dispenser passes and a plane perpendicular to a line passing through the center of the discharge port and the center of the injection port overlap, by the area of ​​the discharge port, is greater than 1. (D3) The thickness of the space through which the paste of the dispenser 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 dispenser is equal to or less than the thickness of the discharge port plus 3 mm, and / or the width of the discharge surface of the dispenser is equal to or less than the width of the discharge port plus 3 mm. (D5) The maximum thickness of the outer surface of the dispenser where a plane perpendicular to a line passing through the center of the discharge port and the center of the injection port overlaps is not more than the value obtained by adding 3 mm to the thickness of the discharge port, and / or the maximum width is not more than the value obtained by adding 6 mm to the thickness of the discharge port. (D6) A length of 1 mm or more from the discharge port toward the injection port is transparent or translucent.

[0012] At least a portion of the surface of the support is coated with a wet apatite composition, and 1 cm is coated with wet apatite. 2A wet apatite-coated support characterized in that when its surface is pressed against 1 cm thick muscle tissue surrounding a rabbit femur at 30 kPa for 10 seconds and then peeled off from the muscle tissue, the muscle surface is elevated by 0.5 mm or more.

[0013] A medical composite characterized in that at least a part of the surface of the support has at least one selected from the group consisting of a sponge-like structure, an interconnected pore structure, and an uneven structure, and the interior of the sponge-like structure, the interior of the interconnected pore structure, and / or the recesses contain at least one selected from the group consisting of metallic silver, metallic silver and wet apatite, a silver compound, a silver compound and wet apatite, metallic copper, metallic copper and wet apatite, a copper compound, or a copper compound and wet apatite.

[0014] A medical composite characterized in that its composition is wet carbonate apatite and / or calcium carbonate, and it has a sphericity of 0.9 or more and / or a hollow structure and a volume of 5 × 10 -15 m 3 That's it, 5 x 10 -13 m 3 A medical calcium composition characterized by:

[0016] The present invention provides a wet-process apatite porous body and a wet-process apatite hardening composition that are useful in medical applications and have excellent osteoconductivity and bone replacement properties, a wet-process apatite composition provided with a support, a wet-process apatite composition that regenerates cartilage, and related materials, as well as methods for producing these.

[0017] 1 is an explanatory diagram of the names of the screw portion used in the present invention.

[0034] FIG. 1 is a conceptual diagram of a method of forming interconnected pores from the beginning by combining a hardenable composition that hardens to form wet carbonate apatite with wet carbonate apatite granules, and a method of forming bone up to the center by absorbing the hardened paste of the hardened composition in vivo. (A) is a conceptual diagram of a method of forming interconnected pores by the paste generally bridging the wet carbonate apatite granules. (B) is a conceptual diagram of a surgical procedure for an internal cavity, in which only the wet carbonate apatite granules on the cavity surface are bridged. (C) is a conceptual diagram of a method of forming bone up to the center by absorbing the hardened paste in vivo.

[0035] FIG. 1 is a conceptual diagram of a method of evaluating a wet apatite composition useful for cartilage regeneration.

[0036] FIG. 2 is a schematic diagram of a dispenser. (A) is a perspective view showing the discharge port face of the dispenser. (B) is a perspective view showing the injection port face of the dispenser. (C) A cross-sectional view perpendicular to the width direction of the outlet of the space through which the paste of the dispenser passes, heading from the center of the outlet toward the injection port. (D) The dispenser as seen from the discharge surface. SEM images of wet apatite blocks produced in Experimental Examples 2 and 3. (A) An SEM image of the wet apatite block of Example 2 produced at 40°C. (B) An SEM image of the wet apatite block of Example 2 produced at 80°C. (C) An SEM image of the wet apatite block of Example 3 produced at 40°C. (D) An SEM image of the wet apatite block of Example 3 produced at 80°C. SEM images of the product of Experimental Example 4. (A) An SEM image of burr-shaped aragonite in which needle-like crystals are extended in multiple directions. (B) An SEM image of a wet carbonate apatite block with a structure in which burr-shaped wet carbonate apatite in which needle-like crystals are extended in multiple directions is accumulated. (C) High-magnification SEM image of Figure 6(B). SEM images of the product of Experimental Example 5. (A) SEM image of wet-apatite-coated titanium with a structure 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 with a structure in which wet carbonate apatite with a sphericity of 1 penetrates the wet-apatite layer. μ-CT images and SEM images of the product of Experimental Example 11. (A) μ-CT image of a wet carbonate apatite honeycomb support with sponge-structured wet carbonate apatite fixed inside.(B) SEM image of wet carbonate apatite with a sponge structure formed inside a wet carbonate apatite honeycomb. SEM images of the product of Experimental Example 20. (A) and (B) Wet carbonate apatite compositions produced using aragonite as a raw material. (C) and (D) Wet carbonate apatite compositions produced using vaterite as a raw material. (E) and (F) Wet carbonate apatite compositions produced using calcite as a raw material. SEM images, mercury intrusion test results, and μCT images of Experimental Example 23. (A) and (B) SEM images of the hardened body produced in Experimental Example 23. (C) Pore distribution analysis results using mercury intrusion porosimetry, showing a graph of the cumulative pore volume for pores with diameters of 10 μm or less against the pore diameter. The results for CytoTrans granules are also shown with a dashed line. (D) μCT image of a rabbit femoral defect reconstructed with CytoTrans granules 4 weeks after surgery. (E) μCT image 4 weeks after surgery when a rabbit femur defect was reconstructed using the wet carbonate apatite granules produced in Experimental Example 23. Intraoperative photographs and HE-stained images from Reference Example 3 and Experimental Examples 26-28. (A) Intraoperative photograph when a bone defect was reconstructed using only a hardenable composition paste. (B) HE-stained image 12 weeks after surgery when a bone defect was reconstructed using a paste formed with Biopex. (C) HE-stained image 12 weeks after surgery when a bone defect was reconstructed using only a hardenable composition paste, which is an equimolar mixture of α-tricalcium phosphate powder and vaterite powder produced in Reference Example 3. (D) Intraoperative photograph when granules are bridged as shown in Figure 1(A). (E) Histopathological image 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) A histopathological image 4 weeks after reconstruction using the surgical procedure in Figure 11(F). (H) A histopathological image 12 weeks after reconstruction in Experimental Example 28. Macroscopic findings, μCT images, and Safranin O stained images 4 weeks after surgery in Experimental Example 30. (A) Macroscopic findings 4 weeks after reconstruction using a wet carbonate apatite honeycomb structure. (B) Macroscopic findings 4 weeks after reconstruction using a wet carbonate apatite gyroscopic structure. (C) Macroscopic findings 4 weeks after reconstruction using a wet carbonate block. (D) Macroscopic findings 4 weeks after surgery in the control.(E) μCT image 4 weeks after surgery after reconstruction using a wet carbonate apatite honeycomb structure. (F) μCT image 4 weeks after surgery after reconstruction using a wet carbonate apatite gyro structure. (G) μCT image 4 weeks after surgery after reconstruction using a wet carbonate block. (H) μCT image of the control 4 weeks after surgery. (I) Safranin O-stained image 4 weeks after surgery after reconstruction using a wet carbonate apatite honeycomb structure. (J) Safranin O-stained image 4 weeks after surgery after reconstruction using a wet carbonate block. SEM image of the calcium carbonate aggregate produced in Example 33. μCT image of the wet carbonate apatite composition having frost pillar pores according to Experimental Example 35. SEM image of a sponge-like interconnected porous body formed on the surface of a titanium alloy according to Experimental Example 45.

[0018] The present invention is described below. <1. Wet Apatite Composition> This invention relates to a wet apatite composition, and dry apatite compositions such as apatite sinters are outside the scope of this invention. Because the usefulness of a wet apatite composition is affected by its structure, in this invention [1], the wet apatite composition must satisfy at least one of the following conditions (A1) to (A5). Satisfying multiple conditions may be more preferable. <A1. Structure of Wet Apatite Composition> The structure of A1 is a wet carbonate apatite powder satisfying one of three conditions, or a wet carbonate apatite block exhibiting an integrated structure in which this wet carbonate apatite powder is bonded. The first group is a wet apatite having an aspect ratio of 1.5 or more but less than 3, an aspect ratio of 3 or more, and a burr-like shape with needle-like crystals elongated in multiple directions, and having a surface morphology selected from the group consisting of a scale-like, spherical, and needle-like shape. Wet carbonate apatite with an aspect ratio of 1.5 to less than 3, or an aspect ratio of 3 or greater, and a burr-shaped wet carbonate apatite with needle-like crystals elongated in multiple directions, has a large specific surface area, making it advantageous in terms of osteoconduction and bone replacement. Furthermore, if the surface of these wet carbonate apatites is scaly, spherical, or needle-like, it is easy for osteoclasts and osteoblasts to adhere, and is useful for increasing the amount of M-CSF and RANKL adsorbed, which promote cell proliferation and differentiation. The second group is wet apatite with an aspect ratio of 1.5 or greater and a hollow structure. Wet apatite with a hollow structure has a large specific surface area, allowing it to adsorb a large amount of factors that promote cell proliferation and differentiation, making it useful for DDS and other applications. Furthermore, an aspect ratio of 1.5 or greater enhances the DDS effect. The third group is wet apatite with a sphericity of 0.9 or more, a surface shape selected from the group consisting of scale-like, spherical, and needle-like, and a height of 0.2 μm or more. Wet apatite with a sphericity of 0.9 or more has a smaller specific surface area than carbonate apatite of the first group, but the specific surface area increases as the surface morphology height increases. The surface morphology height must be 0.2 μm or more, with 0.4 μm or more being preferred, and 0.6 μm or more being more preferred.In Groups 1 and 3, wet carbonate 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 mechanical strength is prioritized, an aspect ratio of 1.5 or more and less than 3 is preferred.

[0019] <A2 Wet apatite with a support> Wet apatite exhibits excellent tissue affinity, but because it is a brittle material, there are still issues with mechanical strength. A composite material of wet apatite and a support (wet apatite-coated support, wet apatite-embedded support) that satisfies at least one of the conditions (A21) to (A24) is a wet apatite composition that has both tissue affinity and excellent mechanical strength.

[0020] The common essential condition for (A21) is that at least a portion of the surface of a support having an arithmetic mean surface roughness (Ra) of 1.0 μm or greater is coated with a wet carbonate apatite layer. The wet carbonate apatite layer refers to the layer that coats the surface of the support. While the mechanism by which the wet apatite layer bonds to the support has not been elucidated, it is believed that the wet apatite layer peels off from a smooth support without irregularities. Conversely, when the arithmetic mean surface roughness (Ra) of the support is 1.0 μm or greater, the wet apatite layer bonds firmly to the support. Therefore, it is believed that the wet apatite bonds to the support through an interlocking force (Patent No. 7665186). Therefore, the arithmetic mean surface roughness (Ra) of the support must be 1.0 μm or greater. From the perspective of increasing the interlocking force, the arithmetic mean surface roughness (Ra) is preferably 1.3 μm or greater, more preferably 1.6 μm or greater, and even more preferably 2.0 μm or greater. If the arithmetic mean surface roughness (Ra) of the support is 1.0 μm or more, the wet apatite layer can be firmly bonded to the support surface, but it is the wet apatite layer and / or the wet apatite bonded to the wet apatite layer that comes 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 relates to the surface shape of the wet apatite layer. In order for the wet apatite layer to exhibit excellent osteoconductivity, it must satisfy one of the following conditions: the arithmetic mean surface roughness (Ra) is 4 μm or more, the wet apatite layer has recesses with a depth of 10 μm or more, or the wet apatite layer has 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. From the viewpoint of accelerating bone replacement, it is particularly preferable if the wet apatite layer comprises wet apatite with a hollow structure. The second group relates to wet apatite that penetrates the wet carbonate apatite layer.A wet apatite layer having a structure in which any wet apatite selected from the group consisting of an aspect ratio of 3 or more, a burr-like shape with needle-like crystals elongated in multiple directions, and a sphericity of 0.9 or more penetrates the wet apatite layer is preferable because the wet carbonate apatite of this form is integrated with the wet apatite layer, thereby increasing the specific surface area. Furthermore, since any wet apatite selected from the group consisting of an aspect ratio of 3 or more, a burr-like shape with needle-like crystals elongated in multiple directions, and a sphericity of 0.9 or more is integrated with the wet apatite layer, it can also be considered to have a structure in which a portion of the wet carbonate apatite with an aspect ratio of 3 or more, a burr-like shape with needle-like crystals elongated in multiple directions, and a sphericity of 0.9 or more is present on the surface of the wet apatite layer. The third group is the condition 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 porosimetry. 3 / g or more, and the pore volume of the pores having a diameter product of 1 μm or more and 10 μm or less is 0.1 cm 3 / g or more, not only will an uneven structure be formed on the surface, but the interior will also become porous, which is preferable because it will accelerate the osteoconduction and bone replacement of the wet apatite layer. The porosity is more preferably 10% or more, and even more preferably 15% or more. The specific surface area is 2m 3 / g or more is more preferable, and 3m 3 The pore volume of pores with a diameter product of 1 μm or more and 10 μm or less is more than 0.2 cm 3 / g or more is more preferable, and 0.3cm 3 Although there are no limitations on the bond strength between the support and the wet apatite layer, the bond strength is preferably 10 MPa or more, more preferably 15 MPa or more, and even more preferably 20 MPa or more.

[0021] (A22) shows the case where the bioabsorbable polymer is the support. Because bioabsorbable polymers exhibit flexibility, the wet carbonate apatite on the surface of the support breaks, resulting in the wet apatite-coated bioabsorbable polymer becoming flexible. Three-dimensional interconnected structures, such as sponges and three-dimensional woven fabrics, are useful for reconstructing defects because they are easy to form. Porous membranes, such as meshes and nonwoven fabrics, are resistant to wet apatite peeling because wet apatite is introduced into the support and combined with it. Membranes with holes are also resistant to peeling because the wet apatite is bonded at the holes. Membranes containing wet apatite are resistant to peeling because the wet apatite inside the support and the wet apatite coating the support are bonded. In the case of membranes, if the wet apatite on the surface of the support has notches, it will break at the notches when subjected to bending stress, reducing the force that tries to peel the wet apatite from the support. For this reason, it may be useful for the wet apatite on the surface of the support to have notches that divide the support vertically and horizontally like a checkerboard. Since the wet apatite is replaced by bone, etc., if the support is a bioabsorbable polymer, the entire composition will be replaced by bone, etc. Because 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 coverage of the support with the wet apatite is preferably 40% or more, more preferably 70% or more, and even more preferably 90% or more.

[0022] (A23) shows the case of a support having a thread structure. Although a screw may be called a thread, the two terms are the same. The names of the threaded portions used in the present invention are as shown in Figure 1. One condition is that the wet apatite covers at least 5% of the height of the thread from the root to the crest. The crest height is half the difference between the outer diameter and the inner diameter of the thread. The covering height is preferably at least 10% of the crest height, more preferably at least 20%, and even more preferably at least 30%. Even if it is less than 5%, it is effective in improving osteoconductivity, but the effect may be limited. This height is a height that covers the threaded portion, but is not a height that completely blocks the threaded portion. For the wet apatite layer to bond with the screw, it is preferable that the wet apatite cover at least one selected from the group consisting of a portion of the threaded portion having an arithmetic mean surface roughness (Ra) of 1.0 μm or more, a concave or convex portion on the surface of the threaded portion, a groove formed on the side of the crest of the threaded portion, and a portion of the crest of the threaded portion where part of the crest has been removed. It is believed that the bond strength increases due to the mechanism described in (A21) except for conditions where some of the thread crests are removed. On the other hand, when wet apatite covers the area where some of the thread crests have been removed, the wet carbonate apatite provided in the area where the thread crests have been removed is bonded to the wet apatite in the valleys, etc., which is thought to reduce the shear stress on the wet apatite in the valleys, etc., that occurs when the screw is embedded, and that the force that peels off the wet apatite due to the surrounding crests is not applied to the wet carbonate apatite provided in the area where the thread crests have been removed.

[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 an undercut. An undercut is a recess larger than the opening of the pores inside the support when viewed from the central axis direction of the pores. If a material with the same structure as the pores is provided in the pores of a support with an undercut, the material cannot be extracted from the support. During the process of forming wet apatite inside the support, precursors such as calcium carbonate honeycomb expand, and wet carbonate apatite of a specific structure is produced inside the support, so wet apatite can also be installed on supports with undercuts. Supports without undercuts can be installed tightly. Mechanical strength is ensured by the support, and wet apatite fulfills the functions of osteoconduction and bone replacement. A porosity of 30% or more and / or a pore volume of 0.2 cm with pore diameters of 10 μm or less is used. 3 One condition is that wet apatite with a porosity of 10 μm or less is fixed. The porosity is more preferably 40% or more, and even more preferably 50% or more. In addition, the pore volume of pores with a diameter of 10 μm or less is 0.2 cm 3 / g or more, but 0.3cm 3 / g or more is preferable, and 0.4cm 3 / g or more is more preferable, and 0.5cm 3 Furthermore, the wet apatite must have a structure selected from the group consisting of a honeycomb structure with a plurality of through-holes extending in one direction, a structure with frost column-like pores, a three-dimensional interconnected structure with a plurality of through-holes extending in multiple directions, a sponge structure, a gyro structure, a porous structure, and an integrated structure.

[0024] (A3) is a condition related to a specific hardenable composition that contains a water-soluble phosphate in the solid or liquid portion and hardens by forming wet apatite. Basically, a solid other than the water-soluble phosphate contained in the solid portion reacts with a phosphate aqueous solution to form wet apatite, which then hardens. When the solid portion contains a water-soluble phosphate, the water-soluble phosphate becomes a phosphate aqueous solution when the solid portion is exposed to water. As a result, the water-soluble phosphate reacts with a solid other than the water-soluble phosphate contained in the solid portion to form wet apatite, which then hardens. Therefore, both harden by essentially the same hardening mechanism. While the formation of wet carbonate apatite is a necessary condition, it is not necessary for the entire hardened body to become wet carbonate apatite. While the hardenable composition is basically composed of a solid portion and a liquid portion, (A32) is a hardenable composition composed of granules, a powder portion, a liquid portion, or granules only, or granules and a liquid portion.

[0025] Previously invented hardenable compositions that form and harden wet apatite required calcium phosphate as an essential component. Furthermore, hardenable compositions containing multiple calcium phosphates required particle size control of the calcium phosphate. Among (A31), the effective composition (A311) is essentially different from previously invented hardenable compositions. The calcium component required for wet apatite formation is supplied from calcium carbonate or calcium sulfate, and the phosphate component is supplied from a water-soluble phosphate. This facilitates control of the microstructure of the hardened body, eliminates the need to control the particle size of powders with different compositions, and reduces production costs. There are no restrictions on the polymorph of calcium carbonate; calcite, vaterite, aragonite, and amorphous calcium carbonate can be used. From the perspective of reactivity, metastable phases such as vaterite, aragonite, and amorphous calcium carbonate are preferred. Furthermore, from the perspective of microstructure control, calcium carbonate with an aspect ratio of 3 or more, a burr-like structure with needle-like crystals elongated in multiple directions, a hollow structure, or a sphericity of 0.9 or more is preferred when forming porous bodies. In the case of a hardenable composition that forms a wet hydroxyapatite composition and hardens, calcium sulfate that does not contain carbonate groups is preferred.

[0026] The hardenable composition according to (A312) is a hardenable composition that requires rapid hardening 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 of less than 2 μm. The powder portion may contain a water-soluble phosphate. Calcium phosphate with a small average particle size has a fast dissolution rate. Therefore, using tricalcium phosphate with a small average particle size or calcium hydrogen phosphate with a high solubility shortens the hardening time. Tricalcium phosphate with an average particle size of less than 2 μm has a fast dissolution rate and shortens the hardening time. The average particle size must be less than 2 μm, but 1.8 μm or less is more preferable, and 1.4 μm or less is even more preferable. The hardenable composition according to (A313) is a hardenable composition that achieves high porosity in the hardened 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 contain a water-soluble phosphate.

[0027] (A32) is a hardenable composition intended to harden or fix granules in a bone defect area, thereby rapidly forming bone up to the center of the bone defect area, as shown in Figure 2. The paste formed by mixing the powder part and the liquid part is a 5 x 10 volume as shown in Figure 2(A) or Figure 2(B). -13 m 3 That's it, 2 x 10 -8 m 3 At least a portion of the wet carbonate apatite granules described below can be bridged to form interconnected pores. This allows bone to be rapidly formed up to the center of the bone defect. Furthermore, even if the granules and paste are mixed as shown in Figure 2(C), if the wet carbonate apatite formed by the hardening paste is absorbed in the body more quickly than the wet carbonate apatite granules, bone will be rapidly formed up to the center of the bone defect. The absorption rate of the wet carbonate apatite formed by the hardening paste can be accelerated by increasing the porosity, for example.

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

[0029] (A33) is a hardenable composition composed of tricalcium phosphate granules and a phosphate aqueous solution of a specific pH. When tricalcium phosphate granules are exposed to a phosphate aqueous solution of a specific pH (pH 3 or higher but lower than 8), wet apatite crystals precipitate on the granule surfaces, and the granules harden due to the entanglement of the wet apatite crystals. The pH of the phosphate aqueous solution is preferably 3.3 or higher but lower than 6, and even more preferably 3.6 or higher but lower than 5. Alpha-tricalcium phosphate is preferred as the tricalcium phosphate. Although tricalcium phosphate hardens at a pH lower than 3, the pH must be 3 or higher because hemolysis occurs. It is essential that the hardened body ultimately forms wet apatite, but octacalcium phosphate or the like may also form immediately after the reaction. The tricalcium phosphate granules may be sintered bodies milled to a specific size or tricalcium phosphate powder bound with wet apatite.

[0030] (A4) is a chemically synthesized wet apatite composition involved in cartilage formation. The ability to regenerate cartilage was assessed by the presence or absence of cartilage regeneration in a bone defect in the trochlea of ​​a rabbit femur. If there was any doubt about the assessment, a 3.5 mm diameter tissue defect was created in the trochlea of ​​a rabbit femur, as shown in Figure 3, and the defect was reconstructed with wet apatite 2.0–3.0 mm below the surrounding hyaline cartilage. Four weeks after surgery, the tissue containing the tissue defect was excised and assessed for the presence or absence of bonding between the wet apatite and the surrounding bone, and the formation of cartilage on the surface of the wet apatite. Because this was an animal study, the test was conducted on both sides of four individuals. The ability was assessed if bonding with the surrounding bone and cartilage formation were observed in 50% or more of the samples. The mechanism by which wet apatite promotes cartilage regeneration has not been elucidated, but it is speculated that wet apatite induces the engraftment of bone marrow-derived mesenchymal stem cells supplied from the bone marrow and their differentiation into cartilage at the site of contact with the cartilage.

[0031] (A5) relates to a specific wet apatite-coated support composition. Wet apatite has excellent osteoconductivity, but simply soluble calcium carbonate may have better bioabsorbability. Therefore, wet apatite-coated calcium carbonate may exhibit the same osteoconductivity as a composition consisting of wet apatite alone, and may also have excellent bioabsorbability. Furthermore, dry hydroxyapatite and dry tricalcium phosphate, which are sintered bodies, have excellent mechanical strength. Therefore, wet apatite-coated dry apatite may exhibit the same osteoconductivity as a composition consisting of wet apatite alone, and may also have excellent 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 into wet apatite. Wet apatite-coated dry apatite may 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 Carbonate Apatite Composition> The present invention [2] is a wet carbonate apatite composition containing 3% by mass or more, 5% by mass or more, or 7% by mass or more of carbonate groups. The amount of carbonate groups is the content in the entire apatite composition. The composition may also contain components other than wet carbonate apatite. Perhaps because the inorganic composition of bone is carbonate apatite, wet carbonate apatite is superior in bone replacement properties compared to wet hydroxyapatite. In the present invention [2], the amount of carbonate groups is 3% by mass or more, 5% by mass or more, or 7% by mass or more. However, since the higher the amount of carbonate groups, the better the bone replacement properties generally are, carbonate apatite containing 7% by mass or more of carbonate groups is most preferred.

[0033] <3. Wet Apatite Comprising 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 metal salts, metals with a diameter of 1 μm or less, growth factors, drugs, and bioabsorbable polymers. Unlike dry apatite produced by sintering, wet apatite can be comprised of 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 Howship's cavity formed by osteoclasts, dissolving bone and replacing it with new bone in harmony with bone remodeling. Meanwhile, the site of infection also becomes a weakly acidic environment. Therefore, adding an antibacterial drug, an antibacterial metal such as silver or copper with a diameter of 1 μm or less, or an antibacterial metal salt such as a silver compound or copper compound to the wet apatite composition of the present invention [1] results in a wet apatite composition that is susceptible to infection. Furthermore, the inclusion of growth factors, strontium with a diameter of 1 μm or less, or strontium compounds can promote bone remodeling and wound healing. The wet apatite composition of the present invention [1] not only replaces new bone but also regenerates cartilage when implanted in a cartilage defect. To improve this function, it is extremely useful to add copper, copper compounds, or bioabsorbable polymers such as collagen, gelatin, and chondroitin sulfate. Compared to wet hydroxyapatite, wet carbonate apatite has greater solubility in the weakly acidic range. Therefore, the wet apatite composition of the present invention [3] is preferably a wet carbonate apatite composition rather than a wet hydroxyapatite composition. Furthermore, it is preferable that the entire composition be wet carbonate apatite.

[0034] 4. Wet Carbonated 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, exhibiting a specific structure, such as a hollow structure. The specific material must be at least one selected from the group consisting of metal salts with a solubility in water of 1 or less, metals with a diameter of 1 μm or less, growth factors, drugs, and bioabsorbable polymers. The specific 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 be a powder with a hollow structure, an aspect ratio of 3 or more, and / or a surface morphology selected from the group consisting of scale-like, spherical, and acicular, or an aggregate structure in which such powders are bonded. The specific structure is not limited to other structures such as powders, powder aggregates, and membrane-like structures. The wet apatite composition of the present invention [4] is not limited to any particular manufacturing method. However, to better understand 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 a silver nitrate aqueous solution, silver carbonate, which has a solubility in water of 0.0032, precipitates on the surface of the aragonite powder through a dissolution-precipitation reaction. Next, when the silver carbonate-loaded aragonite powder is immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C, the aragonite powder undergoes a compositional transformation into wet carbonate apatite powder through a dissolution-precipitation reaction. In this dissolution-precipitation reaction, Ca is removed from the aragonite. 2+ and CO3 2- In aqueous solution, PO4 3-Due to the presence of α-hydroxybenzoates, the solution becomes supersaturated with carbonate apatite, and wet carbonate apatite precipitates on the surface of the silver carbonate-loaded aragonite. Therefore, wet carbonate apatite with a carbonate group content of 3% by mass or more, 5% by mass or more, or 7% by mass or more is coated 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, all of which have a water solubility of 1 or less. Because the metal salts are coated with the wet carbonate apatite, they possess functionality different from simple mixtures. For example, antibacterial metallic silver, silver compounds, copper, and copper compounds exhibit pH values ​​that decrease with infection and are not exposed to biological tissues until the wet carbonate apatite dissolves. This results in a composition that is susceptible to infection.

[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. However, from the viewpoint of manufacturing efficiency, the solubility in water is limited to 1 or less. Although the solubility varies depending on the temperature, it is sufficient that the solubility in water is 1 or less at any temperature. In wet carbonate apatite, metal salts, etc. are coated on the centrifugal side from the central axis of the hollow structure, or on the centrifugal side from the center. When wet carbonate apatite coated with metal salts, etc. is absorbed by osteoclasts, etc., the metal salts, etc. are exposed to body fluids, etc. Therefore, it is extremely useful from the viewpoint of controlling the concentration of metal salts, etc.

[0036] <5. Integrated Structure of Specific Structure Bonded with Wet Carbonate Apatite Powder> The present invention [5] is a wet apatite composition in which the integrated structure bonded with wet carbonate apatite powder described in (A1) above exhibits a specific structure. The integrated structure bonded with wet carbonate apatite powder described in (A1) above exhibits a specific microstructure, and further exhibiting a specific structure may improve biological function. 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 column-like pores are useful for forming tissues such as bone within the structure because they have through-holes within the structure. On the other hand, the gaps between granules are useful for forming tissues such as bone in the center of a bone defect, etc. Tetrahedrons, hexahedrons, cylinders, and structures with a volume of 5 x 10 -7 m 3 Granules with a diameter of 1 / 4 or less have an excellent ability to form structures that adhere to each other and form tissues such as bone between the particles. Structures with multiple legs, such as tetrapods and hexapods, not only form tissues between granules but also fix the granules together, making them useful for reconstructing external defects. Cylinders are also useful when fitting to tissue defects standardized with drills, etc. Note that the composition of the present invention is a medical material, etc., and a structure useful for tissue formation is desired, so the structure of the composition is defined as an approximate shape. For example, the vertices of a tetrahedral structure do not need to be acute angles. Compositions with rounded vertices or edges of a tetrahedral structure are also defined as having a tetrahedral structure. Furthermore, compositions with a porosity of 30% or more and / or a pore volume of 0.2 cm3 with a pore diameter of 0.10 μm to 10 μm are also defined as having a tetrahedral structure. 3 An integrated structure having a surface roughness of 0.2 μm or more is useful for bone replacement and osteoconduction. Furthermore, although it is a requirement of the present invention [1] (A1) that the integrated structure be coated with wet carbonate apatite in one form selected from the group consisting of scale-like, spherical, and needle-like, a larger surface roughness is preferred. The surface roughness is preferably 0.2 μm or more, more preferably 0.4 μm or more, and even more preferably 0.6 μm or more. The surface roughness is measured using a scanning electron microscope photograph or the like.

[0037] <6. Specific Manufacturing Method for Wet Carbonated Apatite with a Specific Structure> This invention [6] is a manufacturing method that involves exposing calcium carbonate with a specific structure to a phosphate aqueous solution to convert the composition from calcium carbonate to wet carbonate apatite while maintaining the macrostructure. The manufacturing method for an integrated structure composed of bound calcium carbonate powders that satisfy any of the following conditions is not limited: an aspect ratio of 1.5 to less than 3, an aspect ratio of 3 or more, a burr-like structure in which needle-shaped crystals extend in multiple directions, or a hollow structure. For example, the powder may be sintered by heat treatment under a carbon dioxide gas flow. Calcium carbonate structures with frost-pillar-like pores are manufactured by forming frost-pillar-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 grow the ice into frost pillars, followed by heat treatment to remove the water-soluble polymer. When these calcium carbonates with specific structures are exposed to a phosphate aqueous solution, the composition is converted from calcium carbonate to wet carbonate apatite from the surface while maintaining the macrostructure. To produce wet carbonate apatite-coated calcium carbonate, exposure to a phosphate aqueous solution can be terminated before the calcium carbonate is completely converted to wet carbonate apatite. On the other hand, to produce a composition entirely composed of wet carbonate apatite, exposure to a phosphate aqueous solution can be continued until the calcium carbonate is completely converted to wet carbonate apatite. When calcium carbonate with a specific structure is exposed to a phosphate aqueous solution to convert the calcium carbonate to wet carbonate apatite, the wet carbonate apatite surface is coated with either scaly, spherical, or needle-shaped wet carbonate apatite crystals. The factors determining the microstructure of the wet apatite crystals formed on the surface are not fully understood, but it is believed that the microstructure is fundamentally determined by crystal nucleation and crystal growth. For example, wet carbonate apatite with low crystallinity, close to amorphous, has limited crystal growth, making it difficult to form scaly, spherical, or needle-shaped crystals, and even if they do form, the surface morphology height 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 the dissolution-precipitation method, crystal growth is limited at high temperatures, possibly because many crystal nuclei grow. Therefore, the temperature of the phosphate aqueous solution is preferably 0°C or higher but lower than 50°C, more preferably 5°C or higher but lower than 40°C, and even more preferably 10°C or higher but lower than 30°C.

[0038] The concentration of the phosphate solution also controls crystal growth. If the concentration of the phosphate solution is high, the degree of supersaturation with carbonate apatite increases, making it difficult to form crystalline morphologies such as scale, sphere, or needle, and even if they do form, the surface morphology height decreases. 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. Note that lowering the phosphate concentration increases the time required for composition conversion, requiring exposure to a large amount of phosphate solution; therefore, the balance between crystal growth and production time must be considered during production.

[0039] <7. Method for Producing a Specific Wet Carbonate Apatite-Coated Support> The manufacturing method of the present invention [7] is useful as a method for producing a wet apatite-coated support that satisfies the requirement of the present invention [1] (A2). (B1) is a manufacturing method in which a specific calcium carbonate layer is coated on the surface of a support, and then the specific calcium carbonate-coated support is exposed to a water-soluble phosphate to produce a specific wet carbonate apatite-coated support. To form a calcium carbonate layer on the surface of the support, a calcium carboxylate such as a calcium nitrate solution or a calcium acetate solution is used. Calcium nitrate becomes calcium carbonate when thermally decomposed in the presence of carbon dioxide, and calcium carboxylate becomes calcium carbonate when thermally decomposed. Since both are solutions, they are useful for forming calcium carbonate in recesses on the surface of the support. On the other hand, to form a specific structure such as unevenness on the surface of a wet calcium carbonate layer coating a support, a method of adding calcium carbonate with a specific structure to a calcium carbonate layer formed from a calcium nitrate solution or a calcium acetate solution, or a method of adding a pore-forming material to a calcium carbonate layer, is useful. In the former case, calcium carbonate having one form selected from the group consisting of an aspect ratio of 3 or more, a burr-like shape with needle-like crystals extending in multiple directions, and 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 greater by coating, dipping, or other methods, followed by drying as needed. The calcium nitrate or calcium carboxylate on the support surface is then thermally decomposed to convert it to calcium carbonate. While calcium carboxylate can be converted to calcium carbonate simply by thermal decomposition, calcium nitrate must be thermally decomposed in the presence of carbon dioxide to convert it to calcium carbonate. Calcium carbonate exhibiting a form selected from the group consisting of an aspect ratio of 3 or greater, a burr-like shape with needle-like crystals elongated in multiple directions, and a sphericity of 0.9 or greater is fixed to the support by a calcium carbonate layer formed by thermal decomposition. Furthermore, if the pore-forming agent is a polymer, the pore-forming agent is burned off during the heat treatment step. After the calcium carbonate coating step, the product is exposed to a phosphate aqueous solution to convert the calcium carbonate portion of the product to wet carbonate apatite. If the pore-forming agent is a water-soluble inorganic pore-forming agent such as sodium chloride, the pore-forming agent is eluted during this step. As explained in (A21), wet apatite is believed to be bound to the support by interlocking forces. The manufacturing method of wet carbonate apatite by exposing calcium carbonate to a phosphate aqueous solution is a dissolution-precipitation reaction, and generally, the precursor is peeled off from the support when it is dissolved. However, in the case of calcium carbonate, the dissolution reaction and precipitation reaction occur almost simultaneously, and the precipitated wet apatite expands, so it is believed to be firmly bound to the support, which has an arithmetic mean surface roughness (Ra) of 1.0 μm or more.

[0041] In (B1), the mechanism for the strong bond between the support and the wet carbonate apatite layer is an expansion reaction in the recesses on the support surface when wet carbonate apatite is formed from calcium carbonate. Therefore, by applying a wet apatite precursor to the recesses on the support surface, a wet apatite-coated support in which the wet apatite and the support are strongly bonded can be produced. In (B2), a solid wet apatite precursor is applied to the recesses on the support surface. Examples of wet carbonate apatite precursors that are useful include calcium oxide, calcium hydroxide, calcium carbonate, and hardenable compositions that harden to form wet carbonate apatite. Examples of wet hydroxyapatite precursors that are useful include hardenable compositions that harden to form wet hydroxyapatite. All materials other than (B242) are solids, making them more difficult to apply to the recesses than liquids. Therefore, methods such as applying them as a suspension or pressure welding are effective. Furthermore, modifying the support with a polycarboxylic acid salt can increase the bond strength because the polycarboxylic acid salt bonds with hydroxyl groups, etc., on the support and precursor surfaces. In the case of calcium oxide, when moisture is added, it becomes calcium hydroxide and expands. When carbon dioxide is added, calcium hydroxide becomes calcium carbonate and expands. When phosphate is added, calcium carbonate becomes wet carbonated apatite and expands. In the case of calcium carbonate, it is possible to apply 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 suitable. Since the calcium carbonate concentration of calcium carbonate solution is limited, calcium bicarbonate solution is more preferable. Calcium carbonate can be applied to the recesses of the support by drying or heating these solutions. Hardenable compositions that harden to form apatite expand during the hardening reaction.

[0042] <8. Method for Producing a Wet Carbonate Apatite-Incorporated Support> The manufacturing method of the present invention [8] is useful as a method for producing a wet apatite composition-incorporated support. Basically, calcium carbonate is exposed to a phosphate aqueous solution inside the support to form wet carbonate apatite through a dissolution-precipitation reaction. As described in the explanation of the term dissolution-precipitation reaction, the dissolution-precipitation reaction causes expansion and hardening reactions. Furthermore, in a composite material containing a wet carbonate apatite-coated calcium carbonate composition inside the support, as described above, a composite material containing wet carbonate apatite-coated calcium carbonate inside the support can be produced by interrupting the exposure to the phosphate aqueous solution before the calcium carbonate powder or calcium carbonate block is completely converted to wet carbonate apatite. The manufacturing method according to (C1) is a manufacturing method in which any one of the calcium carbonate powders of (C1) is converted into a wet carbonate apatite composition inside the support by utilizing the hardening reaction accompanying the dissolution-precipitation reaction, and then fixed to the support. When any of (C1) is mixed with a water-soluble pore-forming material or a water-soluble phosphate and subjected to dissolution-precipitation, the water-soluble pore-forming material or the water-soluble phosphate is dissolved, thereby imparting further pores to the wet carbonate apatite composition. The production method according to (C2) is useful when the external shape of any of the calcium carbonate blocks (C2) is approximately the same as but slightly smaller than the internal shape of the support. If any of the calcium carbonate blocks (C2) is converted into wet carbonate apatite inside the support by utilizing the expansion reaction accompanying the dissolution-precipitation reaction, the wet carbonate apatite is fixed to the support by the expansion accompanying the dissolution-precipitation reaction.

[0043] 9. Hollow Structures of Specific Compositions This invention [9] relates to hollow-structure wet-processed calcium powders or hollow-structure wet-processed calcium aggregates having a structure formed by the accumulation of hollow-structure wet-processed calcium powders. The requirements for the hollow structure vary depending on the composition. When the composition is one selected from the group consisting of calcium phosphate powder, calcium hydrogen phosphate powder, tricalcium phosphate powder, apatite powder, and octacalcium phosphate powder, the aspect ratio must be 3 or greater. On the other hand, when the composition is calcium carbonate, the following requirements must be met: an aspect ratio of 10 or greater, a major axis length of 60 μm or greater, a maximum minor axis length of 5 μm or greater, and a shell thickness of 1 μm or greater. These requirements are due to calcium carbonate's advantages, such as its greater solubility compared to hollow structures of other compositions. The shell thickness forming 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 greater, more preferably 1.5 μm or greater, and even more preferably 2 μm or greater.

[0044] 10. Method for Producing Hollow Structures of Specific Composition The present invention relates to a method for producing hollow wet-process calcium. When calcium sulfate, a precursor of specific conditions, is immersed in a carbonate aqueous solution, the calcium sulfate is converted into calcium carbonate by a dissolution-precipitation process while maintaining its macrostructure. Furthermore, this process converts calcium sulfate of a specific structure into calcium carbonate with a hollow structure. There are no limitations on the production method as long as the calcium sulfate has a specific structure. It can be produced by suspending calcium sulfate hemihydrate in water or by extrusion molding. Immersing hollow wet-process calcium carbonate in a weakly acidic phosphate salt produces hollow calcium hydrogen phosphate or hollow calcium-deficient hydroxyapatite. Heat-treating hollow calcium-deficient hydroxyapatite produces hollow tricalcium phosphate. Immersing hollow calcium hydrogen phosphate in a disodium hydrogen phosphate aqueous solution produces hollow octacalcium phosphate. Immersing hollow wet-process calcium carbonate in a sodium dihydrogen phosphate aqueous solution or the like produces hollow wet-process octacalcium phosphate. Immersing hollow wet-process calcium carbonate in a sodium dihydrogen phosphate aqueous solution produces hollow wet-process octacalcium phosphate.

[0045] <11. Dispenser> The present invention

[0011] is useful for forming an interconnected hardened body, such as that shown in Figure 2(B), in a bone defect or the like, using a hardenable composition such as that of the present invention [1](A3). When reconstructing an internal cavity, granules are filled into the cavity, and then a hardenable composition paste, which hardens to form wet apatite or the like, is applied to the granule surface using a cement spatula or the like. This hardening of the paste results in the formation of highly interconnected pores. However, attempting to seal the granule surface with the paste using a cement spatula or the like can result in the granules moving, making the process cumbersome, and increasing the thickness of the paste. On the other hand, using the dispenser shown in Figure 4 to dispense a strip of the paste onto the granule surface and then shaping it with a cement spatula or the like can seal the granule surface with a thin hardened body of the hardenable composition.

[0046] (D1) is a condition necessary for discharging a band of cement paste. Theoretically, if the value obtained by dividing the width of the discharge port by the thickness is greater than 1, the band of paste will be discharged, 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. Ideally, it should be 0.5 mm or less.

[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 portion where the space through which the paste passes and a plane perpendicular to a line passing through the center of the discharge port and the center of the injection port overlap by the area of ​​the discharge port is greater than 1, the paste dispensed from the discharge port is constricted, and a band of cement paste is stably dispensed from the entire surface of the discharge port. 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 for the thickness of the inner surface of the dispenser near the discharge port, which is the surface of the space through which the paste passes. If the length (f) from the discharge port where the thickness (t1) 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 (T1) of the discharge port is 0.3 mm or more, a band of cement paste is stably dispensed. 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. Ideally, it is 1.5 mm or more.

[0048] (D4) is a condition related 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 discharging the paste formed by the medical curable composition in a band shape, it is necessary to discharge it uniformly under direct vision of the bone defect area, etc., and to move the dispenser at a constant speed. It is also 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. Therefore, the thickness (T1) of the discharge surface of the dispenser must be equal to or less than the thickness (t1) of the discharge port plus 2 mm. This value is preferably equal to or less than 0.6 mm, more preferably equal to or less than 0.4 mm, and even more preferably equal to or less than 0.2 mm. The thickness of the discharge surface of the dispenser and the discharge port may be the same. Similarly, the width (L1) of the discharge surface of the dispenser must be equal to or less than the width (l1) of the discharge port plus 2 mm. This value is preferably equal to or less than 0.6 mm, more preferably equal to or less than 0.4 mm, and even more preferably equal to or less than 0.2 mm. The width of the ejection surface of the ejector and the width of the ejection opening may be the same. Although either one of the conditions regarding the thickness of the ejection surface of the ejector and the ejection opening, or the width of the ejection surface of the ejector and the ejection opening, is useful, it is preferable to satisfy both.

[0049] (D5) is a condition regarding the overall outer shape of the dispenser. As mentioned above, when discharging the paste formed by the medical curable composition in a band-like shape onto the surface of the granules, it is necessary to discharge it uniformly under direct vision of the bone defect area, etc., and to move the dispenser at a constant speed. It is also necessary to position the discharge port close to the granules so that the angle between the surface of the granule aggregate and the paste is small. Therefore, the dispenser must also satisfy certain conditions regarding its outer shape. That is, it is preferable that the maximum thickness of the outer surface of the dispenser, where a plane perpendicular to a line passing through the center of the discharge port and the center of the injection port overlaps, is equal to or less than the thickness of the discharge port plus 3 mm, and / or the maximum width is equal to or less than the thickness of the discharge port plus 6 mm.

[0050] (D6) is a condition regarding the transparency of the dispenser. In order to dispense the paste in a band on the granules, it is preferable that the paste inside the dispenser can be seen. Therefore, a length of 1 mm or more from the discharge port toward the injection port must be transparent or translucent. 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 translucent. In the present invention

[0011] , a dispenser is defined as transparent or translucent if the paste inside the dispenser can be visually observed, but if any doubt arises, measurement should be made using an absorptiometer. A dispenser is defined as translucent if the absorbance is 2 or less at any wavelength between 360 nm and 830 nm, which are visible light wavelengths.

[0051] 12. Wet apatite-coated support that adheres to soft tissue The present invention relates to a wet apatite-coated support that adheres to soft tissue such as muscle tissue. A wet apatite-coated support comprising a specific wet apatite adheres to soft tissue such as muscle tissue. The effectiveness is verified using muscle tissue, which is a representative soft tissue. For example, when measured by mercury intrusion porosimetry, the pore volume of a pore diameter product of 0.01 μm to 1 μm is 0.03 cm 3 / g or more, the wet apatite-coated 1cm 2When the surface of this film was pressed against a 1 cm thick piece of muscle tissue surrounding a rabbit femur at 30 kPa for 10 seconds and then peeled off, the muscle surface was elevated by 0.5 mm or more. Since the longer the elevation from the muscle surface, the stronger the adhesive strength between the wet apatite and the muscle tissue, an elevation length of 0.8 mm or more is preferable, and 1 mm or more is even more preferable. The mechanism by which wet apatite bonded to the support binds to soft tissues such as muscle tissue has not been elucidated, but titanium plates with arithmetic mean surface roughnesses of 1 μm and 5 μm did not elevate the muscle tissue, which is thought to be a characteristic of the wet carbonate apatite-coated support, which exhibits a specific interconnected pore structure.

[0052] 13. Medical Metal Material Carrying a Specific Antibacterial Composition on its Surface The present invention

[0013] provides a medical metal material containing a specific antibacterial composition within a specific surface structure. This material is useful for plates and screws used in artificial hip and knee joints, fracture fixation, and other applications. This medical metal material has at least one structure selected from the group consisting of a sponge-like structure, an interconnected porous structure, and a textured structure on its surface. This specific structure allows the specific antibacterial composition to be fixed to the surface of the medical metal material, thereby providing sustained antibacterial activity. The interior of this specific structure and / or the recesses of the textured structure contain at least one material selected from the group consisting of metallic silver, metallic silver and wet apatite, a silver compound, a silver compound and wet apatite, metallic copper, metallic copper and wet apatite, a copper compound, or a copper compound and wet apatite. The wet apatite inhibits the release of the antibacterial composition and enhances its binding to bone.

[0053] The medical metallic material may be metallic silver, a silver compound, metallic copper, or a copper compound, but is not limited to these. 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, and copper compounds. From the viewpoint of antibacterial properties, silver is preferred over copper. While the amount of silver supported is not specified, from the viewpoint of antibacterial properties and tissue affinity, the amount is preferably 0.01% by mass or more and 10% by mass or less, and more preferably 0.05% by mass or more and 5% by mass or less, in terms of silver equivalent mass.

[0054] 14. Specific Spherical Calcium Composition for Medical Use The present invention

[0014] is useful as a medical artificial bone or a cell carrier for treating lower limb ischemia. The composition is wet carbonate apatite and / or calcium carbonate. There is no limit to the carbonate group content as long as the wet carbonate apatite has carbonate groups, but from the perspective of usefulness, wet carbonate apatite with a carbonate group content of 2% by mass or more is preferred. Because calcium carbonate has high solubility, a mixture of wet carbonate apatite and calcium carbonate may also be used. For example, a core-shell structure in which wet carbonate apatite is the shell and calcium carbonate is the core may also be used.

[0055] The sphericity is 0.9 or more, preferably 0.92 or more, and more preferably 0.94 or more. Furthermore, in order to increase the porosity, it is preferable that the material has a hollow structure. It is sufficient to satisfy either the condition of a sphericity of 0.9 or more or a hollow structure, but it is more preferable that the sphericity is 0.9 or more and that the material has a hollow structure. The volume is 5×10 -15 m 3 That's it, 2 x 10 -8 m 3 The volume is 5 x 10 -15 m 3 That's it, 5 x 10 -13 m 3 It must be the following:

[0056] <Experimental Examples and Reference Examples> The present invention will be described in more detail below based on Experimental Examples and Reference Examples, but the scope of the present invention is not limited to the Experimental Examples. Note that, unless otherwise specified in the Experimental Examples and Reference Examples, raw materials, analyses, etc. were performed under the following conditions. For example, in the Examples and Reference Examples described as "vaterite powder," vaterite powder (Karumaru, manufactured by Sakai Chemical Industry Co., Ltd., average volume diameter: approximately 5 μm) was used as the raw material. <Calcium Carbonate> Calcium carbonate used included aragonite powder, calcite powder (Ube Material Industries, Ltd., average volume diameter: approximately 1 μm), vaterite powder (Karumaru, manufactured by Sakai Chemical Industry Co., Ltd., average volume diameter: approximately 5 μm), chestnut-shaped vaterite powder with needle-like crystals elongated in multiple directions (Callite-SA, manufactured by Shiraishi Kogyo Co., Ltd., aggregate particle diameter: 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 aqueous magnesium chloride solution and introducing 0.1 L of carbon dioxide per minute at 80 °C. The resulting aragonite powder had an aspect ratio of 20–40 and a diameter of 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 was 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 in liquid nitrogen, and freeze-drying. Calcite powder is cubic, while vaterite powder is spherical. The Wadell practical sphericity of this vaterite powder is 0.98 to 1.00, and since it is essentially 1, it is expressed as 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> Tricalcium phosphate powder was used, consisting of αTCP-B (manufactured by Taiheiyo Kagaku Sangyo Co., Ltd.) with an average volume diameter of approximately 5 μm and its pulverized product. <Support> Medical grade titanium type 2 plates (manufactured by T&I Co., Ltd.) were used as metal supports. The arithmetic surface roughness (Ra) was 0.7±0.1 μm. For the roughened metal supports, medical grade titanium type 2 plates were immersed in a mixed acid solution containing 50% sulfuric acid by volume and 7% hydrochloric acid by volume at 70°C for 30 minutes for acid etching, followed by rinsing with distilled water. The arithmetic surface roughness (Ra) of the resulting roughened titanium plates was 2.2±0.7 μm. <Analysis Method> The composition was analyzed using a BRUKER D8 ADVANCE powder X-ray diffractometer at 40 kV, 40 mA, and a CuKα (λ=0.15418 nm) X-ray source. In addition, samples suspected to have formed carbonate apatite were confirmed to be carbonate apatite using a JASCO 6200 Fourier transform infrared spectrophotometer, and the carbonate group content in the carbonate apatite was calculated as necessary. The carbonate group content in the carbonate apatite was also analyzed by elemental analysis in some cases. The structure was analyzed using a Hitachi High-Tech S3400N scanning electron microscope, an Olympus MVX10 stereo microscope, 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 reactions were evaluated by reconstruction of bone defects created in rabbit tibias or beagle mandibles. A set period after reconstruction, the specimens were excised en bloc with the surrounding tissue, and decalcified tissue sections were prepared using standard methods. Hematoxylin-eosin (HE) staining was performed for histopathological analysis. Common Features: The wet apatite compositions manufactured in the experimental examples lost approximately 0.5-0.8% by mass when dried at 50°C for 2 hours and then heat-treated at 300°C for 2 hours. The carbonate content was 9-12% by mass. Dry carbonate apatite was manufactured using the method described in Cells and Materials 7(2), 111-122, 1997. No weight loss was observed when dried at 50°C for 2 hours and then heat-treated at 300°C for 2 hours.

[0059] [Experimental Example 1] Aragonite powder with an aspect ratio of approximately 2, vaterite powder with a sphericity of 1, aragonite powder with an aspect ratio of 20-40, and vaterite powder with a burr-like shape with needle-like crystals elongated in multiple directions were suspended in a 0.1 mol / L Na2HPO4 aqueous solution at 40°C and stirred for 24 hours. As a result, 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 20-40, and powdered wet carbonate apatite with a burr-like shape with needle-like crystals elongated in multiple directions were produced. The surfaces of these powders were scaly. Some of the powders had a spherical morphology. The spherical morphology was a radial accumulation of needle-like crystals. Furthermore, powdered wet carbonate apatite compositions with an aspect ratio of approximately 2 and an aspect ratio of 20 to 40, each having a hollow structure, were also produced from aragonite powder with an aspect ratio of approximately 2 and from aragonite powder with an aspect ratio of 20 to 40. The wet carbonate apatite produced from aragonite powder with an aspect ratio of 20 to 40 had a higher proportion of hollow carbonate apatite compositions than the wet carbonate apatite produced from aragonite powder with an aspect ratio of approximately 2. The surface morphology height in all cases 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 NaHPO aqueous solution at a liquid / liquid ratio (L / P) of 1.6. The mixture was placed in a 6 mm diameter, 3 mm thick mold and initially cured at 40°C and 100% relative humidity for 24 hours. Cylindrical wet carbonate apatite-coated calcium carbonate blocks with hollow structures and flaky, spherical, or needle-like surfaces were produced. The surface morphology height of these blocks was 0.25 μm. When these wet carbonate apatite-coated calcium carbonate blocks were immersed in a 1 mol / L NaHPO aqueous solution and maintained at 40°C or 80°C for four days, cylindrical wet apatite blocks with an integrated structure of hollow wet carbonate apatite powder were produced. The surfaces of these blocks all exhibited flaky, spherical, or needle-like morphologies. Figures 5(A) and (B) show SEM images of wet apatite blocks manufactured at 40°C or 80°C using aragonite powder with aspect ratios of 20 to 40. As shown in Figure 5(A), the wet carbonate apatite coating on the product manufactured at 40°C exhibited a scaly surface with a surface morphology height of 0.25 μm. On the other hand, the wet carbonate apatite composition coating on the product manufactured at 80°C exhibited a spherical shape with radially accumulated needle-like crystals and a surface morphology height of 0.2 μm. This indicates that the wet carbonate apatite hollow structure blocks manufactured at 40°C had a higher surface morphology height than those manufactured at 80°C. When vaterite powder was used as the raw material, the wet carbonate apatite coating on the product manufactured at 40°C exhibited a surface morphology height of 0.2 μm. On the other hand, the wet carbonate apatite composition coating on the product manufactured at 80°C exhibited a surface morphology height of 0.17 μm, which is outside the scope of the present invention. Although the mechanism is unknown, the fact that the surface morphology height of the wet carbonate apatite composition that coats the surface of aragonite is greater than that of vaterite, which has the highest solubility, suggests that calcium carbonate, which has a slower dissolution rate, may have a larger surface morphology height.

[0061] [Experimental Example 3] Aragonite powder, vaterite powder, and 30% gelatin aqueous solution were mixed at a ratio of 1.0 and placed in a mold with a diameter of 5 mm and a height of 10 mm. After drying, the mixture was removed from the mold and degreased at 650 °C under an equal volume of oxygen and carbon dioxide. The mixture was then immersed in a 0.2 mol / L Ca(NO3)2 ethanol solution. After removing excess solution, the mixture was degreased at 550 °C under an equal volume of oxygen and carbon dioxide, allowing calcium carbonate to form between the powder particles. Immersion in a 1 mol / L Na2HPO4 aqueous solution at 40 °C or 80 °C for 7 days resulted in conversion to wet carbonate apatite under all conditions. Furthermore, the precursor macrostructure was maintained. Figures 5(C) and (D) show SEM images of cylindrical wet apatite blocks, exhibiting an integrated structure of bonded wet carbonate apatite powder, prepared from vaterite powder at 40 °C and 80 °C. The surface of both products was needle-like, 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.

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

[0063] [Experimental Example 5] Honeycomb and gyroid structures were fabricated from a suspension of aragonite powder and photocurable resin using a stereolithography 3D printer (Photon Mono 4K, manufactured by ANYCUBIC). Calcium carbonate honeycomb and gyroid structures were degreased at 800°C under a stream of equal volumes of carbon dioxide and oxygen. They were then immersed in a 0.2 mol / L Ca(NO)2 ethanol solution. After removing excess solution with filter paper, they were heat-treated at 550°C under a stream of equal volumes of carbon dioxide and oxygen to convert calcium nitrate to calcium carbonate. The calcium carbonate honeycomb and gyroid structures fabricated 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 and gyroid structures. The surfaces of the wet carbonate apatite gyroid structures exhibited needle-like structures. The gyroid structure is a three-dimensional porous body having a plurality of through-holes extending in multiple directions.

[0064] [Reference Example 1] 0.5 mol / L Ca(NO3)2 ethanol solution was applied to the roughened titanium surface at 8 μL / cm ２ The titanium was then heat-treated at 550°C for 5 hours in a carbon dioxide stream to produce calcium carbonate-coated titanium. The calcium carbonate-coated titanium was then immersed in a 0.2 mol / L NaHPO aqueous solution at 80°C for 7 days to produce wet-process 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 roughened titanium and the wet-process carbonate apatite layer was approximately 77 MPa. The wet apatite layer of this product has an arithmetic surface roughness (Ra) of less than 4 μm, does not have any recesses of 10 μm or more in depth, does not have a hollow structure in the wet apatite layer, and does not have a structure in which any wet apatite selected from the group consisting of an aspect ratio of 3 or more, a burr-like shape in which needle-like crystals are extended in multiple directions, and a sphericity of 0.9 or more penetrates the wet apatite layer. In mercury intrusion porosimetry analysis, the wet apatite layer has a porosity of 3.5% and a specific surface area of ​​2.5 m 3 / g or more, pore diameter product of 0.01 μm to 1 μm and pore volume of 0.2 cm 3 / g, and therefore this composition is outside the scope of the present invention.

[0065] [Experimental Example 6] The roughened titanium surface was dip-coated with a suspension prepared from a 2 mol / L Ca(NO)2 ethanol solution and aragonite powder at a ratio of 4.0, a suspension prepared from a 2 mol / L Ca(NO)2 ethanol solution and vaterite powder at a ratio of 0.5, a suspension prepared from a 2 mol / L Ca(NO)2 ethanol solution and NaCl powder with an average particle size of 18 μm at a ratio of 4.0, and a suspension prepared from a 2 mol / L Ca(NO)2 ethanol solution and chestnut-shaped aragonite powder with needle-like crystals elongated in multiple directions at a ratio of 0.5. The resulting suspensions were then dried at 40°C for 24 hours and heat-treated at 550°C for 5 hours under a carbon dioxide stream to produce calcium carbonate-coated titanium. The calcium carbonate-coated titanium was then 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, a structure was formed in which wet apatite with an aspect ratio of 3 or more penetrated the wet apatite layer, and when vaterite was used, a structure was formed in which wet apatite with a sphericity of 1 penetrated the wet apatite layer. It was also found that when burr-shaped vaterite powder, in which needle-like crystals were elongated in multiple directions, or NaCl powder with an average particle size of 18 μm was used, a structure was formed in which burr-shaped wet apatite, in which needle-like crystals were elongated in multiple directions, penetrated the wet carbonate apatite layer, and the wet apatite layer had recesses approximately 12 μm deep. The arithmetic surface roughness (Ra) of the wet carbonate apatite-coated titanium produced using aragonite powder, NaCl powder, and burr-shaped powder with needle-like crystals elongated in multiple directions, and the bond strength between the roughened titanium and the wet carbonate apatite layer, were 20 μm, 12 μm, and 4.2 μm, respectively, and 40 MPa, 52 MPa, and 35 MPa. Mercury intrusion porosimetry analysis of the wet carbonate apatite-coated titanium produced using vaterite powder revealed a porosity of 7% and a specific surface area of ​​5 m 3 / g, pore diameter product of 0.01 μm to 1 μm and pore volume of 0.1 cm 3A comparison of this experimental example with Reference Example 1 revealed that wet-process carbonate apatite-coated titanium, which was produced by preparing 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, was an excellent wet-process carbonate apatite-coated titanium with improved osteoconductivity due to its large arithmetic surface roughness (Ra).

[0066] [Experimental Example 7] CaO, prepared by heat-treating CaCO3 at 1000°C, was pressed onto the surface of roughened titanium, followed by the addition of water. A slurry prepared from Ca(OH)2 and water was also applied to the roughened titanium surface. After both samples were pressed between filter paper at approximately 50 MPa to remove excess water, the samples were carbonated for three days in a carbon dioxide atmosphere at 100% relative humidity to produce CaCO3-coated titanium. A slurry prepared from CaCO3 and a 1 mol / L Na2HPO4 aqueous solution was also applied to the surface, pressed between filter paper at approximately 50 MPa to remove excess water, and then cured at 100% relative humidity and 37°C for two days to produce partially phosphated CaCO3-coated titanium. The CaCO3-coated titanium and partially phosphated CaCO3-coated titanium were then immersed in a 0.2 mol / L Na2HPO4 aqueous solution at 80°C for seven days. All wet-process carbonate apatite-coated titanium samples had carbonate group contents of 9-11 mass%. The bond strength between the roughened titanium and the wet carbonate apatite layer was 30-35 MPa. 3 / g, and the specific surface area of ​​wet carbonate apatite is 5 to 8 m 3 / g, pore volume of pores with diameters between 0.01 μm and 1 μm is 0.05 to 1.0 cm 3 / g.

[0067] [Experimental Example 8] A paste made from α-tricalcium phosphate with a particle size of approximately 1-2 μm and water in a mixture ratio of 2 was applied to the surface of roughened titanium, and the mixture was pressed with filter paper at approximately 50 MPa to remove excess water. After curing for 48 hours at 37°C and 100% relative humidity, wet calcium-deficient hydroxyapatite was produced. The bond strength between the roughened titanium and the wet carbonate apatite layer was approximately 35 MPa. The specific surface area was 9 m 3 / g, and the specific surface area of ​​wet apatite is 6m 3 / g, pore volume of pores with diameters between 0.01 μm and 1 μm is 0.07 cm 3 / g. [Experimental Example 9] CaCO3-coated titanium was produced by adding dropwise an aqueous solution of carbon dioxide bubbling into a CaCO3 suspension for 3 hours so that the surface temperature of the roughened titanium was maintained between 60 and 80°C. The CaCO3-coated titanium was then 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 confirmed in part of the wet carbonate apatite layer. The bond strength between the roughened titanium and the wet carbonate apatite layer was approximately 30 MPa.

[0068] [Experimental Example 10] A jungle-gym-shaped calcium carbonate structure with an arithmetic mean surface roughness (Ra) of approximately 8 μm was used as a support. The term "jungle-gym-shaped" refers to a structure in which pores separated by a lattice are interconnected in three or more directions, and the structure is composed of trabeculae assembled in a three-dimensional lattice pattern. Aragonite powder was suspended in a 1 mol / L Ca(NO3)2 aqueous solution, and the jungle-gym-shaped calcium carbonate structure was immersed in the suspension to apply the aragonite powder to the trabecular surfaces of the jungle-gym-shaped calcium carbonate structure. Heat treatment at 550°C for 24 hours in an electric furnace under a carbon dioxide gas flow of 100 mL / min resulted in the formation of calcite-integrated structures with aspect ratios of 20 to 40 on the trabecular surfaces of the jungle-gym-shaped calcium carbonate structure. Subsequent immersion in a 1 mol / L Na2HPO4 aqueous solution at 80°C for 7 days resulted in the entire structure being converted to wet carbonate apatite containing approximately 11% carbonate groups. The porosity of the wet carbonate apatite deposits formed inside the trabecular bone is approximately 70%, and the pore volume of pores with a diameter of 10 μm or less is 1 cm 3 / g or more. The surface of the wet carbonate apatite exhibited a spherical morphology with an accumulation of needle-like crystals. We also confirmed that the wet carbonate apatite exhibited a hollow structure with an aspect ratio of at least 20.

[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 to achieve a polycaprolactone:vaterite ratio of 30:160. The suspension was introduced into the pores of a honeycomb structure composed of calcium carbonate and an organic binder, with a partition wall thickness of 0.8 mm and a pore minor axis of 0.8 mm. The structure was then maintained at -20°C for 5 hours, then at -80°C for 12 hours, and then freeze-dried. The honeycomb structure composed of calcium carbonate and an organic binder, when degreased, became a calcium carbonate honeycomb structure with an arithmetic mean surface roughness (Ra) of approximately 8 μm. After freeze-drying, the structure was heated at 650°C for 24 hours in an equal-volume carbon dioxide-oxygen gas flow. The heat treatment degreased the organic components, forming a sponge-like calcium carbonate structure within the calcium carbonate honeycomb. After immersion in a 1 mol / L Na2HPO4 aqueous solution and hydrothermal treatment at 120°C for 7 days, both the honeycomb structure and the sponge structure inside the honeycomb structure were converted to wet carbonate apatite containing approximately 6% by mass of carbonate groups. Figures 8(A) and 8(B) show μCT and SEM images of the carbonate apatite honeycomb and the sponge-like structure inside the honeycomb pores. 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 low, this issue was eliminated by placing it inside the honeycomb structure as a support, demonstrating its potential for use as artificial bones.

[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. Calcium hydroxide spheres that passed through a 200 μm sieve but not a 100 μm sieve were heated at 5°C per minute to 1000°C and calcined at 1000°C for 6 hours to produce CaO spheres. The sphericity was 0.99 and the average diameter was 1.6 × 10 －４ m, and the average volume is 1.6 × 10 －１２ m ３The CaO spheres were placed in a calcium carbonate honeycomb support (with square pores, pore sides 5 mm long, and trabecular width 5 mm) with an arithmetic mean surface roughness (Ra) of approximately 8 μm. When water was added, the CaO spheres expanded and became fixed in the support, forming calcium hydroxide. The calcium hydroxide was then exposed to carbon dioxide saturated with 90% isopropanol and 10% water, which carbonated it to form vaterite. The porosity of the vaterite in the calcium carbonate honeycomb was approximately 80%. The calcium carbonate honeycomb was then immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 24 hours. The vaterite composition was converted to wet carbonate apatite containing approximately 11% carbonate groups. The porosity of the wet carbonate apatite formed in 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 a support. A paste prepared by mixing aragonite powder with a 1 mol / L NaHPO aqueous solution at a liquid-liquid ratio of 1.75 was introduced into the pores of the support and stored at 0°C for 24 hours. After 24 hours, the honeycomb structure was reacted in a thermostatic chamber at 40°C and 100% relative humidity for 24 hours, then washed with water and dried. The composition formed inside the honeycomb structure was a wet carbonate apatite integrated structure exhibiting a hollow structure with an aspect ratio of 20 to 40. The carbonate group content was approximately 11% and the porosity was approximately 80%. Furthermore, scale-like wet carbonate apatite was formed on the surface of the wet carbonate apatite integrated structure. Perhaps due to the temperature distribution during fabrication, the honeycomb structure had frost-pillar-like pores near the pore openings, while the central portion had a sponge-like structure.

[0072] [Experimental Example 14] A 30 mass% gelatin aqueous solution at 70°C was dispensed from a syringe and dried to produce a porous two-dimensional membrane. The gelatin aqueous solution was then filled into a mold and dried to produce a two-dimensional membrane with holes spaced 2 mm apart. The gelatin was then heated under reduced pressure at 130°C for 24 hours to thermally crosslink the gelatin. Vaterite powder and a 1 mol / L Na2HPO4 aqueous solution were mixed at a liquid ratio of 0.5. The porous two-dimensional membrane was immersed in the paste and vibrated to penetrate the paste into the two-dimensional membrane. For two-dimensional membranes with holes, the paste was applied to the inside and periphery of the holes. Next, a mold was used to apply the paste to both sides to a thickness of approximately 0.5 mm, and notches were formed at 2 mm intervals. For two-dimensional membranes with holes, the notches were formed so that the holes and notches overlapped. After initial hardening for 3 hours at 100% relative humidity and 40°C, the sample was immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 3 days, producing a wet carbonate apatite gelatin film that covered the entire surface of the gelatin support.When the wet carbonate apatite-coated gelatin film was bent, the wet carbonate apatite cracked at the notches in all cases, but the wet carbonate apatite was generally fixed to the gelatin film.

[0073] Experimental Example 15: A plate-shaped wet carbonate apatite block made from aragonite, approximately 1 mm thick, was immersed in a 30 mass% gelatin solution at 80°C, and excess gelatin 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, producing an aragonite-gelatin composite film. Next, a paste made by mixing vaterite with a 1 mol / L NaHPO solution at a liquid-liquid ratio of 0.5 was applied to both sides of the aragonite-gelatin composite film. A mold was used to form notches at 2 mm intervals in the paste, adjusting the thickness to approximately 0.5 mm. After initial curing at 100% relative humidity and 40°C for 3 hours, the block was immersed in a 1 mol / L NaHPO solution at 40°C for 3 days, producing a wet carbonate apatite-gelatin film covering the entire surface of the gelatin support. When the wet carbonate apatite-coated gelatin film was bent, the wet carbonate apatite cracked at the notch, but the wet carbonate apatite was mostly fixed to the gelatin film.

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

[0075] [Experimental Example 17] Titanium self-tapping screws with the shape shown in Figure 1 were roughened using the same method as used to roughen two types of medical titanium plates, producing roughened screws with an arithmetic surface roughness (Ra) of approximately 2 μm. Screws were also produced with recesses formed by drilling 0.5 mm diameter, 0.5 mm deep holes at 1 mm intervals into the root surface of the screw. Threads were also produced with grooves 0.4 mm wide and 0.4 mm deep on the flanks of the threads. Furthermore, screws were produced with a V-shaped groove drilled from the thread to the root along the central axis of the screw. A control screw was used without these roughening processes. Calcium carbonate was applied to the threads by applying a 2 mol / L Ca(NO3)2 ethanol solution or by applying calcium hydroxide paste. In the former method, the threads were immersed in a 2 mol / L Ca(NO3)2 ethanol solution and then heat-treated at 550°C for 5 hours under a carbon dioxide stream to produce calcium carbonate-coated titanium screws. For some screws, the Ca(NO3)2 was removed from the crests at 5% of the length of the crests and roots before the calcium carbonate application process. For the calcium hydroxide paste application method, calcium hydroxide paste was applied to the threads and pressed to remove excess water. The screws were then exposed to carbon dioxide at 100% relative humidity to produce calcium carbonate-coated titanium screws. For some screws, the Ca(OH)2 was removed from the crests at 5% of the length of the crests and roots before exposure to carbon dioxide. Finally, the calcium carbonate-coated screws were immersed in a 0.2 mol / L Na2HPO4 aqueous solution at 80°C for 7 days to produce wet carbonate apatite-coated screws.

[0076] Compared with control screws without texture, all textured screws exhibited increased bond strength between the carbonate apatite and the screw. The roughened screws had the highest bond strength, followed by grooved and recessed screws. For screws with a partially milled root, bond strength perpendicular to the central axis was unaffected, but the retention of wet carbonate apatite was enhanced when a load was applied in the direction of screw rotation. When compared with screws coated with Ca(NO3)2 ethanol solution and calcium hydroxide paste, screws coated with calcium hydroxide paste produced thicker wet carbonate apatite films. However, the bond strength was higher with Ca(NO3)2 ethanol solution. When screws were implanted into simulated bone, the wet carbonate apatite on the crests tended to peel off, while the wet carbonate apatite on the valleys was retained. This suggests that it may be preferable not to coat some of the crests with a 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 undercuts. The inner surface of the pipe not in contact with the opening was cut off by approximately 0.3 mm to produce a support with undercuts. A wet carbonate apatite honeycomb structure with a diameter of 9.9 mm was inserted into both pipes, but was unable to be fixed. When a pressure of 20 kPa was applied, the wet carbonate apatite honeycomb structure was expelled from the pipes. On the other hand, when a wet calcium carbonate honeycomb structure with a diameter of 9.9 mm was inserted into a pipe without an undercut and a pipe with an undercut and immersed in a 0.2 mol / L NaHPO aqueous solution at 80°C for 7 days, the wet carbonate apatite honeycomb structure was fixed inside the pipe in both cases, and was not expelled from the pipes even when a pressure of 20 kPa was applied. The porosity of the produced wet carbonate apatite honeycomb was 65%, and the pore volume of pores with a diameter of 10 μm or less was 0.2 cm. 3 / g. When calcium carbonate honeycomb is exposed to a phosphate aqueous solution inside the support, the calcium carbonate honeycomb becomes a wet carbonate apatite honeycomb structure, and it was found that the wet carbonate apatite composition can be fixed inside the support regardless of the presence or absence of undercuts because it expands and comes into close contact with the support during this process. From a theoretical standpoint, it was inferred that not only is it limited to wet carbonate apatite honeycomb structures, but also structures with frost column-like pores, three-dimensional interconnected structures with multiple through-holes extending in multiple directions, sponge structures, gyro structures, porous structures, and integrated structures can be fixed inside the support.

[0078] Experimental Example 19: The inside of the support with undercuts produced in Experimental Example 18 was filled with a paste prepared by mixing aragonite powder and a 1.0 mol / L NaHPO aqueous solution at a liquid-liquid ratio of 1.6. After hardening for 3 hours at 40°C and 100% relative humidity, the pipe was immersed in a 1.0 mol / L NaHPO aqueous solution at 40°C for 7 days. The wet carbonate apatite composition hardened and fixed inside the pipe, and was not expelled from the pipe even when a pressure of 20 kPa was applied. The porosity of the produced 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 more, burr-shaped calcium carbonate powder with needle-like crystals elongated in multiple directions, hollow calcium carbonate powder, and calcium sulfate dihydrate powder were mixed with a 1 mol / L aqueous solution of water-soluble phosphate, placed in a mold with a 6 mm diameter and 3 mm height hole, and stored at 37°C for 4 hours. All samples hardened. FT-IR analysis of the hardened samples confirmed that wet hydroxyapatite had formed in the case of calcium sulfate dihydrate powder, and carbonate apatite had formed in the other cases. Because unreacted material remained in the hardened samples, they were removed from the mold and immersed in 100 mL of a 0.5 mol / L aqueous solution of NaHPO at 80°C for 3 days. Powder XRD analysis and elemental analysis confirmed that the hardened bodies formed with calcium sulfate dihydrate powder were wet hydroxyapatite, while the other hardened bodies were wet carbonate apatite with a carbonate group content of approximately 12% by mass or more. Figure 9 shows SEM images of the hardened bodies formed with aragonite, vaterite, and calcite. These images are for carbonate apatite produced from a medical hardenable composition containing aragonite (Figures 9(A) and (B)), carbonate apatite produced from a medical hardenable composition containing vaterite (Figures 9(C) and (D)), and carbonate apatite produced from a medical hardenable composition containing calcite (Figures 9(E) and (F)). All hardened bodies were found to have largely maintained the micromorphology of calcium carbonate. Wet carbonate apatite crystals were also confirmed to have formed on the surface.

[0080] [Experimental Example 21] Calcite powder, aragonite powder, vaterite powder, and the water-soluble phosphate NaHPO were mixed in a mass ratio of 4:3, and the powder was mixed with water, 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 all of the powder hardened. After washing with water and drying, composition analysis revealed that all of the powders had a carbonate group content of approximately 12 mass%.

[0081] [Experimental Example 22] Calcium hydroxide was suspended in a 90% methanol 10% water mixed solvent, and carbon dioxide was introduced to produce vaterite powder with a diameter of about 1 μm. The vaterite powder was then dissolved in 2.5 mol / L NaCl solution with a pH of about 3.6. 1.2 H 1.8 When mixed with a PO4 aqueous solution at a water ratio of 0.7, bubbles appeared. The mixture expanded and became porous. When stored at 37°C and 100% relative humidity, the hardening time was 35 minutes. 1.3 H 1.7 PO4 aqueous solution, Na 1.4 H 1.6 PO4 aqueous solution, Na 1.5 H 1.5 The pH values ​​of the PO4 aqueous solutions were approximately 5.7, 6.1, and 6.6, and slight bubbles were observed when mixed with vaterite powder at a water-to-water ratio of 0.7. The hardening times when stored at 37°C and 100% relative humidity were 15, 10, 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 were hardenable compositions that hardened to form wet carbonate apatite-coated calcium carbonate.

[0082] Experimental Example 23: A hardenable composition consisting of aragonite powder as the solid portion and a 1 mol / L NaHPO aqueous solution as the liquid portion 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, whereupon wet carbonate apatite was formed and hardened. The hardened body was removed from the mold and immersed in a 1 mol / L NaHPO aqueous solution at 40°C for 7 days, producing a hardened block exhibiting an aggregate structure of bound powder with an aspect ratio of 20 to 40. The porosity of the product was approximately 80%, and the carbonate group content was 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 covered with spherical wet carbonate apatite. The hardened body was a structure in which wet carbonate apatite with an aspect ratio of 10 to 40 was accumulated. Figure 10(C) shows the cumulative pore volume of the wet carbonate apatite hardened body produced in this experiment and a commercially available granular wet carbonate apatite artificial bone (GC, Cytotrans Granule M) with pore diameters of 10 μm or less, measured by mercury intrusion porosimetry. The cumulative pore volume of the wet carbonate apatite porous body of this experiment was 1.2 cm 3 / g, Cytotrans granules 0.1cm 3 / g.

[0083] The wet carbonate apatite hardened body produced in this experimental example was crushed and sieved to a size of 0.6 mm to 1.0 mm, the same size as CyTrans Granule M, and used to fill a 6 mm diameter, 5 mm deep bone defect in a rabbit femur. Figure 10(D) shows a CyTrans granule outside the scope of the present invention, and Figure 10(E) shows a μCT image of the granular wet carbonate apatite composition produced in this experimental example four weeks after implantation. Compared with the results for CyTrans granules, the granular wet carbonate apatite composition produced in this experimental example showed vigorous bone formation around it, and while many areas of the CyTrans granules were not resorbed, most of the granular wet carbonate apatite composition produced in this experimental example was replaced by new bone.

[0084] [Experimental Example 24] Aragonite powder with an aspect ratio of 20 to 40 and α-tricalcium phosphate powder with average volume diameters of approximately 5 μm, 2 μm, and 1.3 μm were mixed in equal molar ratios to produce a solid portion. In addition, a 1 mol / L NaH2PO4 aqueous solution and a 1 mol / L Na2HPO4 aqueous solution were mixed to a pH of 7.0 to produce a solid portion. 2-x H x An aqueous solution of PO4 (x approximately 0.1) was prepared as the liquid portion. A liquid portion was also prepared by adding disodium citrate to this phosphate aqueous solution to a concentration of 0.5 mol / L. The two were mixed to a liquid-liquid ratio of 0.60, placed in a mold with a hole 6 mm in diameter and 3 mm deep, and stored at 100% relative humidity and 37°C. Hardening was confirmed after 3 hours. When the phosphate aqueous solution was used, the medical curable composition containing tricalcium phosphate with a volume average particle size of approximately 1.3 μm hardened. The hardened product was carbonate apatite containing approximately 11% by mass of carbonate groups. The medical curable composition containing tricalcium phosphate with a volume average particle size of approximately 2 μm hardened slightly, and the medical curable composition containing tricalcium phosphate with a volume average particle size of approximately 5 μm hardened even less. On the other hand, when the phosphate aqueous solution containing disodium citrate was used, all of the α-tricalcium phosphate powder hardened regardless of its volume average particle size. This experimental example demonstrated that when calcium carbonate with an aspect ratio of 2 to 50 is included in the solid portion and mixed with a phosphate aqueous solution, it is preferable to mix it with tricalcium phosphate with a volume average diameter of less than 2 μm. Furthermore, when calcium carbonate with an aspect ratio of 2 to 50 is included in the solid portion, it was found that poor hardening can be prevented by using a phosphate aqueous solution containing disodium citrate. While the mechanism behind this has not been fully elucidated, it is presumed that this is due to the chelating bond between the water-soluble polycarboxylic acid and the calcium carbonate.

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

[0086] Reference Example 2 Aragonite powder with an aspect ratio of 20 to 40 was crushed in an alumina mortar and sieved to produce aragonite powder with an aspect ratio of approximately 5 and 10. This calcium carbonate was mixed with an equimolar amount of tricalcium phosphate with a volume average particle size of approximately 2 μm to produce a solid portion. The liquid portion was prepared using the same Na phosphate solution with a phosphate concentration of 1 mol / L as used in Experimental Example 23. 2-x H x The curable compositions were a 1.2 mol / L NaHPO4 (x approximately 0.1) aqueous solution and a 1.2 mol / L NaHPO4 aqueous solution. Therefore, this curable composition is a medical curable composition outside the scope of the present invention. When the solid and liquid parts were mixed at a mixing ratio of 0.8, 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 3 hours, curing was poor in both cases. Furthermore, the curable composition containing aragonite with an aspect ratio of approximately 5 cured less well than the curable composition containing aragonite with an aspect ratio of approximately 10. However, it cured after 24 hours. Comparison of this Reference Example with Experimental Examples 24 and 25 revealed that when using calcium carbonate with an aspect ratio of 2 to 50, it is necessary to use tricalcium phosphate with a volume average diameter of less than 2 μm or a polycarboxylic acid salt.

[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. The hardening time was approximately 10 minutes under conditions of 100% relative humidity and 37°C, and the main component of the hardened body after 24 hours was hydroxyapatite. Biopex Excellent is primarily composed of tricalcium phosphate and does not contain calcium carbonate. Therefore, this hardenable composition is a cement outside the scope of the present invention. Another hardenable composition was prepared whose solid portion was an equimolar mixture of α-tricalcium phosphate powder with an average volume diameter of approximately 1.5 μm and vaterite powder (Karumaru, manufactured by Sakai Chemical Industry Co., Ltd.; average volume diameter of approximately 5 μm), and whose liquid portion was an aqueous solution of hydroxypropyl cellulose dissolved in a 1 mol / L sodium phosphate solution at pH 7.0. The paste formed by mixing the solid and liquid components in the appropriate ratio hardened in approximately 5 minutes at 100% relative humidity and 37°C. After 24 hours, the hardened body consisted primarily of wet carbonate apatite with a carbonate content of 12% by mass. The porosity was 75%. This hardenable composition is also outside the scope of the present invention. A 6 mm diameter defect in a rabbit tibia was reconstructed using the hardenable composition paste, as shown in Figure 11(A). Figure 11(B) shows an HE-stained image of Biopex Excellent 12 weeks after surgery. The hardened body was completely replaced by bone. Figure 11(C) shows an HE-stained image of a hardenable composition consisting of an equimolar mixture of α-tricalcium phosphate powder and vaterite powder with an average volume diameter of approximately 1.5 μm, 12 weeks after surgery. The hardened body was clearly replaced by bone. Comparison of the two revealed that when it is expected that the hardened body of the hardenable composition will be replaced by new bone, a hardenable composition that forms hydroxyapatite is unsuitable, and a hardenable composition that hardens to form wet carbonate apatite is preferable.

[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 wet carbonate apatite granules. The volume of the granules was approximately 2 × 10 -10 m 3The results were as follows. Using a paste prepared from a hardenable composition consisting of a mixture of α-tricalcium phosphate powder with an average volume diameter of approximately 1.5 μm (as produced in Reference Example 3) and vaterite powder, wet carbonate apatite granules were partially bridged to form an interconnected structure, as shown in Figure 2(B), and a 6 mm diameter defect in a rabbit tibia was reconstructed as shown in Figure 11(D). Figure 11(E) shows an HE-stained image four weeks after surgery. Even four weeks after surgery, bone was found to have formed up to the center of the interconnected porous structure. Comparison of this experimental example with Reference Example 2 demonstrated that the paste formed by mixing the powder and liquid components and hardening to form wet carbonate apatite is extremely useful. This paste bridges at least some of the wet carbonate apatite granules to form an interconnected porous structure.

[0089] Experimental Example 27: The wet carbonate apatite granules used in Experimental Example 26 were implanted into a 6-mm diameter defect in a 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-like shape. This bridged the wet carbonate apatite granules on the surface of the bone defect, forming an interconnected structure, as shown in Figure 2(C) (Figure 11(F)). An HE-stained image four weeks after surgery is shown in Figure 11(G). It was found that bone had formed up to the center of the interconnected porous structure, even four weeks after surgery. Comparison of this Experimental Example with Reference Example 2 demonstrated that the curable composition, which bridges at least a portion of the wet carbonate apatite granules to form an interconnected porous structure, is extremely useful.

[0090] Experimental Example 28: The wet carbonate apatite granules used in Experimental Example 26 were mixed with a paste and implanted in the mandibular tooth extraction socket of a beagle dog. Therefore, no interconnected pores were formed in the hardened body. Figure 11(H) shows an HE-stained image 6 months after surgery. It can be seen that the hardened paste was absorbed, and new bone was formed around the bioabsorbable granules in the center of the bone defect. The porosity of the hardened paste was 75%, while that of the bioabsorbable granules was 34%. Therefore, when the porosity of the hardened body produced by mixing at the standard mixture ratio was 30% or higher and the porosity of the hardened body was greater than that of the bioabsorbable granules, the hardened paste of the hardenable composition was absorbed over time after surgery, and bone formed in the center.

[0091] [Experimental Example 29] Tricalcium phosphate powder (αTCP-B, manufactured by Taihei Chemical Industry Co., Ltd.) was uniaxially pressed at 100 MPa, heated in an electric furnace at 10°C per minute to 1200°C, heat-treated at 1200°C for 12 hours, and then cooled in the furnace to produce an α-tricalcium phosphate block. The block was crushed and sieved to obtain a block with a volume of approximately 7 × 10 -11 m 3 The same tricalcium phosphate powder was mixed with an aqueous sodium phosphate solution with a phosphate concentration of 1.7 mol / L and a pH of 7.0 at a mixing ratio of 0.6, and the mixture was freeze-dried after hardening for 5 minutes. The freeze-dried product was crushed and sieved to a volume of approximately 7 × 10 -11 m 3 α-tricalcium phosphate aggregates were produced. 1 mol / L of disodium hydrogen phosphate and 1 mol / L of phosphoric acid were mixed to produce aqueous sodium hydrogen phosphate solutions with pH values ​​of 1, 3, 5, 6, 7, and 8. When tricalcium phosphate and water containing the water-soluble phosphate were mixed at a liquid-liquid ratio of 1.5, the pH of the mixtures was 1, 3, 5, 6, 7, and 8, respectively. α-tricalcium phosphate granules or aggregates were mixed with aqueous sodium hydrogen phosphate solutions at a liquid-liquid ratio of 0.4, placed in a mold with a hole 6 mm in diameter and 3 mm in height, and the setting time was measured at a relative humidity of 37°C. The setting times of the α-tricalcium phosphate granules were within 20 minutes, 1 to 2 hours, 6 to 24 hours, 6 to 24 hours, 24 to 48 hours, and 48 to 72 hours, respectively. The setting times of the α-tricalcium phosphate aggregates were within 2 minutes, 30 minutes, 50 minutes, 60 minutes, 90 minutes, and 6 to 24 hours, respectively. Furthermore, sodium hydrogen phosphate aqueous solution with a pH of 1 exhibited hemolysis. It was confirmed that in both cases, part of the composition of the two hardened bodies was wet apatite. Since medical hardenable compositions are required to not exhibit hemolysis and to have an appropriate hardening time, it was thought that the pH of the sodium hydrogen phosphate aqueous solution should be between 3 and 8. The mechanism by which the pH of the sodium hydrogen phosphate aqueous solution affects the hardening of α-tricalcium phosphate granules has not been elucidated, but one possible reason is thought to be that mixing with a low-pH phosphate aqueous solution dissolves α-tricalcium phosphate, increasing the calcium ion and phosphate ion concentrations.

[0092] [Experimental Example 30] The wet carbonate apatite honeycomb structure and wet carbonate apatite gyroid structure produced in Experimental Example 5, and the wet carbonate apatite block produced at 40°C in Experimental Example 2 were implanted into the trochlear groove of a rabbit femur, forming a 2 mm space from the cartilage on the trochlear groove surface, as shown in Figure 3. The control group was a group without a block implant. In Figure 12, (A), (E), and (I) represent the wet carbonate apatite honeycomb composition, (B) and (F) represent the wet carbonate apatite gyroid composition, (C), (G), and (J) represent the wet carbonate apatite block, and (D) and (H) represent the control. (A) to (D) are macroscopic findings, (E) to (H) are μCT images, and (D) and (H) are images stained with safranin O. Macroscopic findings four weeks after surgery revealed cartilage formation in all cases except the control. Furthermore, μCT images and Safranin O staining images taken four weeks after surgery showed that all, except for the control, had bonded to the host bone, and that cartilage had formed on the surface of the trochlear groove that bonded to the cartilage covering the trochlear portion.

[0093] Experimental Example 31: Silver phosphate, silver carbonate, copper phosphate, and copper carbonate were used as metal salts; silver nanoparticles as metals with diameters of 1 μm or less; alizarin red as a growth factor and drug simulant; and lactic acid-glycolic acid copolymer as a bioabsorbable polymer. All of the metal salts were decomposed at 750°C, the temperature used for dry carbonate apatite production. Alizarin red and lactic acid-glycolic acid copolymer were also incinerated. Therefore, it was found that incorporating these elements into the dry apatite composition was virtually impossible. The same process as in Experimental Example 7 was performed, except that 1% by mass of silver phosphate, silver carbonate, copper phosphate, copper carbonate, silver nanoparticles, alizarin red, and lactic acid-glycolic acid copolymer were added to the Ca(OH)2 produced in Experimental Example 7. Wet carbonate apatite-coated titanium containing silver phosphate, silver carbonate, copper phosphate, copper carbonate, silver nanoparticles, alizarin red, and lactic acid-glycolic acid copolymer was produced.

[0094] In addition, the aragonite powder produced in Experimental Example 21 was mixed with NaHPO at a mass ratio of 4:3, and 1% by mass of silver phosphate, silver carbonate, copper phosphate, copper carbonate, silver nanoparticles, alizarin red, and lactic acid-glycolic acid copolymer was added. This powder was kneaded with a 1 mol / L NaHPO aqueous solution, 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. All samples hardened. After washing with water and drying, composition analysis revealed that all samples were wet carbonate apatite. These results confirmed that the wet apatite composition of the present invention [1] can be produced by incorporating at least one element selected from the group consisting of metal salts, metals with a diameter of 1 μm or less, growth factors, drugs, and bioabsorbable polymers.

[0095] [Experimental Example 32] Aragonite powder was immersed in a 1 mol / L AgNO3 aqueous solution. The white aragonite powder turned yellow immediately after immersion. Silver carbonate was precipitated on the surface of the aragonite powder at 2.3 mass% silver equivalent. The silver carbonate-loaded aragonite powder was mixed with a medical curable composition consisting of a solid portion and a liquid portion of a 1 mol / L Na2HPO4 aqueous solution 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. Carbonated apatite with a carbonate group content of 2 mass% or more was formed and hardened. It was also confirmed that both silver carbonate and silver phosphate were loaded. The hardened material was removed from the mold and immersed in a 1 mol / L Na2HPO4 aqueous solution at 40°C for 7 days. The hardened material after immersion had a porosity of approximately 80% and a silver-loaded carbonate apatite with a carbonate group content of approximately 12 mass%. A hollow structure was 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, the surface of the hollow structure was covered with scaly wet carbonate apatite, which indicated that silver phosphate and other substances were also covered with scaly 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. Excess calcium nitrate was removed with filter paper. The aragonite aggregate was then 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 entire composition was calcite. As shown in Figure 13, a calcium carbonate aggregate with a porosity of 82% was produced, in which calcite particles with aspect ratios of 10 to 20 were bonded at their contact points. When the calcium carbonate aggregate with a porosity of 82% was immersed in a 1 mol / L aqueous AgNO3 solution, the calcium carbonate aggregate, which was white immediately after immersion, turned yellow. Silver carbonate was precipitated on the surface of the calcium carbonate aggregate, equivalent to 2.6 mass% silver. At a porosity of 82%, silver loading did not affect the porosity. The produced calcium carbonate aggregate and silver-loaded calcium carbonate aggregate were crushed and sieved to produce granules of 300-600 μm. The granules were placed in a mold with a hole 6 mm in diameter and 3 mm deep, filled with a 1 mol / L NaHPO aqueous solution, and stored at 40°C for 24 hours, resulting in hardening. The hardened product was then removed from the mold and immersed in a 1 mol / L NaHPO aqueous solution at 40°C for 72 hours. When calcium carbonate aggregate without silver loading was used as the solid portion, a medical calcium composition was produced, which consisted of carbonate apatite containing approximately 12% carbonate groups by mass, and had an integrated structure with an aspect ratio of 10-20 and a porosity of approximately 90%, in which contacting whiskers were bonded together. Furthermore, scaly wet carbonate apatite crystals were precipitated on the surface of the composition, and some compositions were confirmed to have a hollow structure. When silver-loaded calcium carbonate aggregate was used as the solid portion, a carbonate apatite aggregate structure containing approximately 12 mass% carbonate groups and loaded with silver carbonate and silver phosphate was produced, but no differences were observed in the medical calcium compositions produced other than those loaded with silver.

[0097] [Experimental Example 34] To verify the coating of specific compositions and the formation of specific structures with wet carbonate apatite, aragonite powder was coated with silver carbonate, silver nanoparticles (AGCN30, Funakoshi Co., Ltd.) as a metal with a diameter of 1 μm or less, Alizarin Red S (Fujifilm Wako Pure Chemical Industries, Ltd.) as a growth factor and drug simulant, and lactic acid-glycolic acid copolymer (Taki Chemical Co., Ltd.) as a bioabsorbable polymer. Since complete coating of the aragonite powder with lactic acid-glycolic acid copolymer could prevent the dissolution-precipitation reaction, it was dissolved in dioxane and sprayed onto the powder to partially coat the aragonite powder. All of these have a water solubility of 1 or less. The powder was then immersed in a 1 mol / L NaHPO aqueous solution at 40°C for 7 days. Wet carbonate apatite powder with a hollow structure, an aspect ratio of 20-40, and a surface coated with scaly wet carbonate apatite was produced. That is, a wet carbonate apatite composition was produced in which silver carbonate and / or silver phosphate obtained by phosphorylating silver carbonate, and silver nanoparticles of alizarin red S lactic acid glycolic acid copolymer with a diameter of 1 μm or less were coated on wet carbonate apatite.

[0098] Experimental Example 35: The solid portion was aragonite powder, and the liquid portion was a freshly prepared 5 mol / L NaHPO aqueous solution. The aragonite powder was added to the liquid portion at a mixing ratio of 2 while vibrating with a vibrator, and the mixture was mixed to produce a slurry. The slurry was placed in a 5 mm thick silicone rubber hole with an 8.5 mm diameter through-hole 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. This operation cooled the vaterite slurry from one direction (toward the stainless steel plate). After 24 hours, the mixture was reacted in a thermostatic chamber at 40°C and 100% relative humidity for 24 hours, then washed with water and dried. The product was carbonate apatite with approximately 11% carbonate groups and a porosity of approximately 80%. The surface was coated with a spherical wet carbonate apatite composition, with a height from the concave to the convex portion of 0.2 μm. The μCT image shown in FIG. 14 reveals that a wet apatite composition having frost column-like pores could be produced.

[0099] [Experimental Example 36] The slurry produced in Experimental Example 29 was placed in a stainless steel mold with a hole 6 mm in diameter and 3 mm in height, and the temperature of the slurry was cooled from all sides and stored at 0°C for 24 hours. After 24 hours, the slurry was reacted for 24 hours in a thermostatic chamber at 40°C and 100% relative humidity, then washed with water and dried. The product was a sponge-like structure of wet carbonate apatite containing approximately 11% carbonate groups and with a porosity of approximately 80%. The surface was covered with a spherical wet carbonate apatite composition, and the height from the recesses to the protrusions was 0.2 μm.

[0100] [Experimental Example 37] The calcium carbonate powder used in Experimental Example 1 was mixed with a 1 mol / L NaHPO aqueous solution at a liquid-liquid ratio (L / P) of 1.6, and the mixture was placed in a mold for a tetrahedron, a hexahedron, or a hexapod, which is a structure having multiple legs. After initial hardening for 24 hours at 40°C and a relative humidity of 100%, the mixture was kept at 40°C or 80°C for 4 days. As a result, a volume of approximately 2 × 10 -10 m 3 ~1×10 -9 m 3 Wet apatite blocks were fabricated as tetrahedrons, hexahedrons, and structures with multiple legs. All of these blocks exhibited a scaly surface, with a surface morphology height of 0.25 μm.

[0101] [Experimental Example 38] <9. Hollow Structure of Specific Composition> 0.4 mol / L sulfuric acid and 0.4 mol / L calcium chloride aqueous solution at 100°C were mixed 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 minor axis 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 with a minor axis 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 was produced. The hollow calcium carbonate particles were then immersed in solutions adjusted to pH 5 and pH 6 using a pH stat and 0.1 mol / L phosphoric acid for 24 hours. The hollow calcium carbonate particles were converted to hollow calcium hydrogen phosphate and hollow calcium-deficient apatite particles, respectively, while maintaining their macroscopic structure. Furthermore, hollow tricalcium phosphate was produced by firing the hollow calcium-deficient apatite particles at 1000°C, and hollow octacalcium phosphate was produced by immersing the hollow calcium hydrogen phosphate particles in a saturated octacalcium phosphate solution at pH 5.5.

[0102] [Experimental Example 39] A transparent dispenser was manufactured from acrylic resin. The width (l1) of the dispenser outlet was 10 mm, the thickness (t1) was 0.4 mm, the width (L1) of the dispenser surface was 10.6 mm, the thickness (T1) was 0.8 mm, the maximum width (l2) of the area where the space through which the paste of the dispenser passes overlaps with a plane perpendicular to a line passing through the center of the dispenser outlet and the center of the injection port was 12 mm, the maximum thickness (t2) was 2.4 mm, the maximum width (L2) of the area was 10.6 mm, the maximum thickness (T2) was 0.8 mm, and the length (f) of the space through which the paste of the dispenser passes from the center of the dispenser outlet toward the injection port was the same as the thickness of the dispenser outlet, was 2 mm. The value obtained by dividing the width (l1) of the dispenser outlet by the thickness (t1) was 25. A paste made by mixing a solid portion consisting of vaterite and tricalcium phosphate with a disodium hydrogen phosphate solution containing hydroxypropyl cellulose was injected into the injection port using a syringe. The paste spread in a band-like shape from the center of the outlet toward the injection port until it reached the area where the thickness of the space through which the paste passed was the same as the thickness of the outlet (hereinafter referred to as the parallel space). After passing through the parallel space, a band of paste approximately 10 mm wide and 0.4 mm thick was ejected from the outlet. The width of the ejection surface (L1) was the width of the outlet (l1) plus 0.6 mm, and the thickness of the ejection surface (T1) was the thickness of the outlet (t1) plus 0.4 mm, making it easy to predict the location of the paste ejection. The ejected band of paste covered the surface of the granules filling the internal cavity. By pressing the band of paste with a spatula, it was possible to bridge the granules on the surface of the internal cavity and easily coat the surface of the internal cavity, as shown in Figure 1(B).

[0103] [Reference Example 4] When the same paste as in Experimental Example 39 was ejected using an 18G needle with a length of 10 mm, the paste was ejected in a cylindrical spiral shape. When an attempt was made to cover the granules with the paste using a spatula, the granules rose up, making the coating difficult. Although the coating itself was possible, the thickness of the paste was uneven. A comparison of this Reference Example with Experimental Example 39 revealed that it was important to eject the paste in a band shape.

[0104] [Experimental Example 40] A dispenser identical to that of Experimental Example 39 was manufactured, except that the maximum width (l2) of the area where the space through which the paste passes and a plane perpendicular to a line passing through the center of the discharge port and the center of the injection port overlap was 10 mm and the maximum thickness (t2) was 0.4 mm. When the same paste as in Experimental Example 39 was injected, the center moved to the discharge port first, and the edge portions moved to the discharge port later. A band-shaped paste with a wavy center was dispensed from the discharge port. Comparing this Experimental Example with Experimental Example 39, it was found that the value obtained by dividing the maximum area of ​​the area where the space through which the paste passes and a plane perpendicular to a line passing through the center of the discharge port and the center of the injection port overlap by the area of ​​the discharge port is preferably greater than 1. When this maximum area is larger than the area of ​​the discharge port, the paste spreads in the width direction, where resistance is smaller, and the amount of paste dispensed at the center and edge of the discharge port is the same, resulting in a band-shaped paste being dispensed without wavy edges.

[0105] [Experimental Example 41] A dispenser similar to that of Experimental Example 38 was manufactured, except that a section where the thickness of the space through which the paste of the dispenser passes from the center of the discharge port toward the injection port was not formed was the same as the thickness of the discharge port. A strip of paste measuring approximately 10 mm in width and 0.4 mm in thickness was dispensed from the discharge port, but the strip of paste was dispensed in a wave-like manner. A comparison of this Experimental Example with Experimental Example 39 revealed that a dispenser having a section where the thickness of the space through which the paste of the dispenser passes from the center of the discharge port toward the injection port is the same as the thickness of the discharge port by a length of 0.3 mm or more.

[0106] [Experimental Example 42] A dispenser identical to that of Experimental Example 39 was manufactured, except that the width (L1) of the discharge surface was 16 mm and the thickness (T1) was 6.8 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, due to the large area of ​​the discharge surface, it was difficult to dispense the paste close to the granule surface under direct vision. Similarly, it was difficult to dispense the paste at a small angle with the granule surface. Comparing this Experimental Example with Experimental Example 39, it was found that the width (L1) of the discharge surface is preferably equal to or less than the width (l1) of the discharge port plus 3 mm, the thickness (T1) of the discharge surface is preferably equal to or less than the thickness (l1) of the discharge port plus 3 mm, and the thickness of the discharge surface is preferably equal to or less than the thickness (l1) of the discharge port 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 outlet surface and for the width of the inlet surface to be greater than the width of the outlet surface.

[0107] [Experimental Example 43] A dispenser identical to that of Experimental Example 39 was manufactured, except that the maximum width and maximum thickness of the outer surface of the dispenser, where the plane perpendicular to the line passing through the center of the discharge port and the center of the injection port, overlapped, were 20 mm and 10 mm, respectively. 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 discharge surface was difficult to see, it was difficult to dispense the paste near the granule surface under direct vision. Similarly, it was also difficult to dispense the paste so that the angle with the granule surface was small. A comparison of this Experimental Example with Experimental Example 39 revealed that the maximum thickness of the outer surface of the dispenser, where the plane perpendicular to the line passing through the center of the discharge port and the center of the injection port overlapped, was preferably no more than the thickness of the discharge port plus 3 mm, and / or no more than the thickness of the discharge port plus 6 mm.

[0108] [Experimental Example 44] A dispenser with the same structure as in Experimental Example 39 was manufactured using black opaque acrylic resin. A strip of paste approximately 10 mm wide and 0.4 mm thick was dispensed from the dispenser outlet, but because it was not possible to grasp the state in which the paste was being dispensed, it was found that the dispenser in Experimental Example 38 was clinically preferable. In order to grasp the paste being dispensed in advance, it was found that it was preferable for at least a length of 1 mm or more from the dispenser outlet toward the injection port to 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 rinsing with water, it was heated to 600°C at 5°C per minute, heat-treated at 600°C for 1 hour, and then furnace-cooled. As a result of this treatment, a sponge-like interconnected pore was formed on the titanium alloy surface (Figure 15). The surface was coated with a saturated silver nitrate solution followed by a saturated sodium chloride solution, and then rinsed with water. The plate was then 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 the formation of silver chloride and metallic silver. The silver chloride and metallic silver were surrounded by a sponge-like interconnected structure and were not peeled off even when rubbed with a fingernail, likely because they were fused and integrated. In contrast, when the surface of an untreated titanium alloy was coated with a saturated silver nitrate solution followed by a saturated sodium chloride solution, the powder formed at this stage flowed out. Comparison of the two confirmed the usefulness of the sponge-like interconnected pores formed on the titanium alloy surface.

[0110] [Experimental Example 46] When the medical metallic material produced in Experimental Example 45, in which silver chloride was integrated and provided inside the sponge-like interconnected pores on the surface of the titanium alloy, was immersed in a 0.1 mol / L Na2HPO4 aqueous solution, some of the silver chloride was converted into silver phosphate. The silver chloride and silver phosphate were surrounded by the sponge-like interconnected structure, and they did not peel off even when rubbed with a fingernail, probably because silver phosphate was precipitated on the surface of the molten and integrated silver chloride.

[0111] [Experimental Example 47] The surface of a type 2 titanium plate was polished with 800-grit SiC and anodized using a 0.1 mol / L aqueous solution of calcium glycerophosphate as the electrolyte using a DC stabilized power supply (Panasonic Precision Co., Ltd., PL-650-0.1) to form holes and produce a titanium substrate with a textured structure. A film of silver chloride was placed on the substrate and treated at 550°C in a vacuum for 1 hour. After returning 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 holes. The silver chloride in the holes could not be removed by polishing.

[0112] [Experimental Example 48] Two types of medical titanium (manufactured by T&I Co., Ltd.) were immersed in a mixed acid solution containing 50% by volume of sulfuric acid and 7% by volume of hydrochloric acid at 70°C for 30 minutes, and acid-etched to impart a textured structure to the surface. The arithmetic surface roughness (Ra) of the titanium with the textured structure was 2.2±0.7 μm. Next, 8 μL / cm of a 0.5 mol / L ethanol solution of Ca(NO3)2 was applied to the titanium surface. ２ The titanium dioxide solution was applied to the sample so that the coating was uniform, and the sample was heated to 550°C at a rate of 3°C per minute in an electric furnace under a carbon dioxide flow of 100 mL per minute. After heat treatment at 550°C for 5 hours, the sample was cooled in the furnace, producing 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, turning it yellow. When the surface was irradiated with light, silver nanoparticles were formed. When the sample was then immersed in a 0.2 mol / L Na2HPO4 aqueous solution for 7 days, the calcite was converted to carbonate apatite containing approximately 11% by mass of carbonate groups. The carbonate apatite-coated titanium was found to contain silver nanoparticles and silver phosphate.

[0113] [Experimental Example 49] A titanium alloy (Ti-6Al-4V) plate was sectioned with 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. The plate was then heated to 600°C at 5°C per minute, heat-treated at 600°C for 1 hour, and then furnace-cooled. As a result of this treatment, a sponge-like structure with interconnected pores was formed on the titanium alloy surface, separated by a metal surface lacking a sponge-like structure, an interconnected pore structure, or a textured structure. A saturated silver nitrate solution was applied to the titanium alloy surface, followed by a saturated sodium chloride solution, and then rinsed with water. At this stage, the silver chloride formed in the areas without the sponge-like structure was washed away. The plate was then 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 was formed within the sponge-like structure. The silver chloride was surrounded by a sponge-like interconnected structure, and perhaps because it had melted and become one with the rest, it did not peel off even when rubbed with a fingernail.

[0114] [Experimental Example 50] Calcium hydroxide sphericalized by spray drying was calcined at 800°C to produce calcium carbonate spheres. The sphericity was 0.98 and the volume was 6 x 10 -14 m 3 When calcium carbonate spheres were immersed in a 1 mol / L Na2HPO4 aqueous solution at 80°C for 7 days, they were converted into carbonate apatite with approximately 11% carbonate groups. The sphericity was 0.98, and the spheres had a hollow structure. The volume was 6 x 10 -14 m 3 When the hollow carbonate apatite spheres were mixed with glycerin, they could be easily discharged from an 18G syringe.

Claims

1. A wet apatite composition characterized by satisfying at least one of the following conditions (A1) to (A5): (A1) A wet carbonate apatite powder or a wet carbonate apatite block having an integrated structure in which the wet carbonate apatite powder is bonded, satisfying any one of the following conditions: an aspect ratio of 1.5 or more but less than 3, an aspect ratio of 3 or more, and a burr-like shape in which the needle-like crystals are elongated in multiple directions, and the surface exhibits a form selected from the group consisting of scale-like, spherical, and needle-like, or an aspect ratio of 1.5 or more and having a hollow structure, or a sphericity of 0.9 or more, the surface exhibits a form selected from the group consisting of scale-like, spherical, and needle-like, and the height from the bottom to the highest point in the surface form is 0.2 μm or more. (A2) A wet-apatite-coated support in which wet apatite covers at least a part of the support, or a wet-apatite-embedded support in which wet apatite exists inside the support, satisfying at least one of the following conditions (A21) to (A24): (A21) A support having an arithmetic mean surface roughness (Ra) of 1.0 μm or more, at least a portion of which is coated with a wet carbonate apatite layer, wherein the arithmetic mean surface roughness (Ra) of the wet apatite layer surface is 4 μm or more, the wet apatite layer has recesses with a depth of 10 μm or more, or the wet apatite layer has a hollow structure, or the wet apatite layer has a structure in which any wet apatite selected from the group consisting of an aspect ratio of 3 or more, a burr shape in which needle-like crystals are extended in multiple directions, and a sphericity of 0.9 or more penetrates the wet apatite layer, or the wet apatite layer has a porosity of 5% or more and a specific surface area of ​​3 m2 as determined by mercury intrusion porosimetry. 3 / g or more, or the pore volume of pores with a pore diameter product of 0.01 μm or more and 1 μm or less is 0.03 cm 3 / g or more. (A22) At least a portion of a support that is a bioabsorbable polymer is coated with a wet apatite layer, and the support is any one of a three-dimensional interconnected structure, a porous membrane, a membrane with holes, and a membrane comprising wet apatite. (A23) The support has a thread structure, and 5% or more of the height of the threads is coated with wet apatite, and / or at least one selected from the group consisting of a portion of the threads where the arithmetic mean surface roughness (Ra) is 1.0 μm or more, a concave or convex portion on the surface of the threads, a groove formed on the side of the threads, and a portion where a portion of the threads has been removed is coated with wet apatite. (A24) The inside of a support that does not have undercuts or the inside of a support that has undercuts has a porosity of 30% or more, and / or a pore volume of pores with a diameter of 10 μm or less of 0.2 cm 3 / g or more, and has fixed thereto wet apatite having a structure selected from the group consisting of a honeycomb structure with a plurality of through-holes extending in one direction, a structure with frost column-like pores, a three-dimensional interconnected structure with a plurality of through-holes extending in multiple directions, a sponge structure, a gyro structure, a porous structure, and an integrated structure. (A3) A curable composition that satisfies any one of the following conditions (A31) to (A33). (A31) The powder portion 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, or a mixture of calcium carbonate and tricalcium phosphate having an average particle size of less than 2 μm as set forth in the group (A312) below, a mixture of calcium carbonate and tricalcium phosphate having an average particle size of less than 2 μm as set forth in the group (A312) below, and a water-soluble phosphate, a mixture of calcium carbonate and calcium hydrogen phosphate as set forth in the group (A312) below, a mixture of calcium carbonate, calcium hydrogen phosphate, and a water-soluble phosphate as set forth in the group (A312) below, or a mixture of at least one selected from the group (A313) and one selected from the group consisting of tricalcium phosphate, a mixture of tricalcium phosphate and a water-soluble phosphate, calcium hydrogen phosphate, or a mixture of calcium hydrogen phosphate and a water-soluble phosphate, wherein the hardenable composition hardens to form wet apatite when the powder portion is exposed to an aqueous solution of a water-soluble phosphate or water. (A311) Calcium carbonate, calcite, aragonite, vaterite, amorphous calcium carbonate, calcium carbonate with an aspect ratio of 3 or more, calcium carbonate with a burr-like structure in which needle-like crystals are extended in multiple directions, calcium carbonate with a hollow structure, 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 a burr-like structure in which needle-like crystals are extended in multiple directions, hollow calcium carbonate, hollow calcium carbonate with an aspect ratio of 3 or more, amorphous calcium carbonate, volume of 5 x 10 -13 m 3 That's it, 2 x 10 -8 m 3 The following calcium carbonate aggregates, calcium carbonate with an aspect ratio greater than 51 (A32) and a volume of 5×10 -13 m 3 Spheres with a diameter of 98 μm or more, 2 × 10 -8 m 3 The paste comprises wet carbonate apatite granules that are spheres of 3.3 mm or less in diameter, and a powder portion that hardens to form wet apatite, and when mixed with a phosphate aqueous solution or water, the paste hardens to form wet carbonate apatite, and at least a portion of the wet carbonate apatite granules are bridged by the wet carbonate apatite to form interconnected pores, and / or the hardened paste is a hardenable composition that is absorbed in the body more quickly than the wet carbonate apatite granules, or the volume of tricalcium phosphate powder or a mixed powder of tricalcium phosphate and calcium carbonate bound by calcium phosphate bridges is 5×10 -13 m 3 That's it, 2 x 10 -8 m 3 The hardenable composition comprises a granular portion which is the following granules, and a liquid portion which is at least one selected from the group consisting of water, an aqueous solution of a phosphate, and an aqueous solution of a polyvalent carboxylate, and when the granular portion and the liquid portion are mixed, the granular portion becomes wet apatite granules and the granules bond together. (A33) A hardenable composition having a volume of 5×10 -13 m 3 That's it, 2 x 10 -8 m 3 A hardenable composition comprising the following tricalcium phosphate granules and a liquid portion which is a phosphate aqueous solution having a pH of 3.0 or more but less than 8.0, wherein when the granules are exposed to the liquid portion, they bond with each other to form wet apatite. (A4) A chemically synthesized wet apatite which, 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, bonds with the host bone and forms cartilage on the trochlear groove side surface that bonds with the cartilage covering the trochlear portion. (A5) The surface of one 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 claim 1, characterized in that it contains carbonate groups in an amount of 3 mass % or more, 5 mass % or more, or 7 mass % or more.

3. The wet carbonate apatite composition according to claim 1, characterized in that 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 is contained within the wet carbonate apatite composition.

4. The wet carbonate apatite composition according to claim 2, characterized in that 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, each having 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, and the wet carbonate apatite has a hollow structure and / or an aspect ratio of 3 or more, and / or a surface in a form selected from the group consisting of scale-like, spherical, and acicular, or presents an aggregate structure in which such powders are bonded together.

5. The integrated structure to which the wet carbonate apatite powder described in (A1) is bonded is a honeycomb structure having a plurality of through holes extending in one direction, a three-dimensional porous body having a plurality of through holes extending in multiple directions, a gyroid structure, a sponge-like structure, a structure having frost column-like pores, a tetrahedron, a hexahedron, a cylinder, a sphere having a volume of 5×10 -7 m 3 and / or the integrated structure has a porosity of 30% or more, and / or the integrated structure has pores with diameters of 0.10 μm or more and 10 μm or less and a pore volume of 0.2 cm 3 / g or more, and / or the height from the bottom to the highest part of one shape selected from the group consisting of scale-like, spherical, and needle-like shapes covering the integrated structure is 0.2 μm or more.

6. A method for producing a wet carbonate apatite powder that satisfies any one of the conditions selected from the group consisting of an aspect ratio of 1.5 to less than 3, an aspect ratio of 3 or more, a burr-shaped structure in which needle-like crystals are extended in multiple directions, and a hollow structure, or a wet carbonate apatite aggregate structure that exhibits a structure in which such wet carbonate apatite powder is accumulated, or a wet carbonate apatite structure with frost pillar-shaped pores, characterized by exposing to a phosphate aqueous solution calcium carbonate powder that satisfies any one of the conditions of an aspect ratio of 1.5 to less than 3, an aspect ratio of 3 or more, a burr-shaped structure in which needle-like crystals are extended in multiple directions, and a hollow structure, or an accumulated structure in which such powders are bonded together to exhibit an accumulated structure, or a calcium carbonate structure with frost pillar-shaped pores that is produced by lowering the temperature of a slurry consisting of calcium carbonate and an aqueous solution of a water-soluble polymer in one direction or all directions to grow ice in the form of frost pillars, and a step of removing the water-soluble polymer by heat treatment, in that order.

7. A method for producing a wet apatite-coated support, in which at least a portion of the surface of a support having an arithmetic mean surface roughness (Ra) of 1.0 μm or more is coated with a wet apatite layer, characterized in that either (B1) or (B2) below is satisfied: (B1) The method comprises the steps of: (a) applying, to the surface of a support, calcium carbonate having a form selected from the group consisting of an aspect ratio of 3 or more, a burr-like shape with needle-like crystals extending in multiple directions, and a sphericity of 0.9 or more, or a mixture of a pore-forming material and a calcium nitrate solution or a calcium carboxylate solution; (b) subsequently thermally decomposing the calcium nitrate in the presence of carbon dioxide or thermally decomposing the calcium carboxylate to fix calcium carbonate having at least one form selected from the group consisting of an aspect ratio of 3 or more, a burr-like shape with needle-like crystals extending in multiple directions, and a sphericity of 0.9 or more, to the surface of the support via a calcium carbonate layer; or (c) coating a support with calcium carbonate having a pore-forming material or from which the pore-forming material has been removed; and (d) subsequently exposing the product of the previous step to an aqueous phosphate solution to convert the calcium carbonate portion of the product into wet carbonated apatite. (B2) A step of applying at least one selected from the group consisting of calcium oxide, calcium hydroxide, calcium carbonate, and a hardenable composition that hardens to form wet apatite to recesses on the surface of a support modified with a polycarboxylic acid salt or a support not modified with a polycarboxylic acid, followed by (B21), (B23), and (B25) in this order in the case of calcium oxide, or (B22) and (B25) in this order, or (B23) and (B25) in this order in the case of calcium hydroxide, or (B24) and (B25) in this order in the case of calcium carbonate, or (B26) in the case of a hardenable composition that hardens to form wet apatite.(B21) A step of exposing to moisture and adding moisture; (B22) A step of exposing to moisture and carbon dioxide simultaneously and adding moisture and carbon dioxide; (B23) A step of exposing to carbon dioxide and adding carbon dioxide; (B24) A step of adding calcium carbonate to the recesses of the support by either method (B241) or (B242); (B241) A step of adding calcium carbonate powder to the recesses of the support; (B242) A step of adding a calcium carbonate solution or a calcium bicarbonate solution to the recesses of the support; (B25) A step of exposing to an aqueous phosphate solution to convert at least a portion of the calcium carbonate into wet carbonate apatite; (B26) A step of hardening the hardenable composition that hardens to form wet apatite.

8. A method for producing a wet carbonate apatite-embedded support having a wet carbonate apatite composition fixed inside the support, the method comprising the step of exposing, inside the support, 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-former, a mixture of a composition satisfying either (C1) or (C2) and a water-soluble phosphate, and a mixture of a composition satisfying either (C1) or (C2), a water-soluble pore-former, and a water-soluble phosphate: (C1) A calcium carbonate powder exhibiting a morphology 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, and a burr-like shape with needle-like crystals elongated in multiple directions, or one selected from the group consisting of aragonite, vaterite, calcite, and amorphous calcium carbonate. (C2) A calcium carbonate block exhibiting one structure selected from the group consisting of a honeycomb structure having a plurality of through-holes extending in one direction, a structure having frost column-like pores, a three-dimensional interconnected structure having a plurality of through-holes extending in multiple directions, a sponge structure, a gyro structure, and an integrated structure.

9. A hollow structure wet-process calcium powder, or a hollow structure wet-process calcium aggregate having a structure in which the hollow structure wet-process calcium powder is accumulated, characterized in that the hollow structure wet-process calcium powder is one selected from the group consisting of calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, apatite, and octacalcium phosphate, and has an aspect ratio of 3 or more and a hollow structure, or the hollow structure wet-process calcium aggregate is calcium carbonate, has a hollow structure, and satisfies at least one of the following group: an aspect ratio of 10 or more, a long axis length of 60 μm or more, a longest short axis length of 5 μm or more, and a shell thickness of 1 μm or more.

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 having a structure formed by the accumulation of these powders, characterized by including a step of exposing calcium sulfate having an aspect ratio of 3 or more to a carbonate aqueous solution or a phosphate aqueous solution.

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