Silica-calcium phosphate composite block body, and method for manufacturing silica-calcium phosphate composite block body

Abstract

To provide a silica-calcium phosphate composite block body that has high strength and does not collapse in water, and further exhibits excellent bone productivity.SOLUTION: A silica-calcium phosphate composite block body that is a composite block body that is hardened by chemical bonding of inorganic components, or entanglement or fusion of crystals of inorganic components, contains calcium phosphate containing silicic acid in its crystal structure, and has a volume of 2.0 mm3 or more, and having a DTS strength of 0.1 MPa or more.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a silica-calcium phosphate composite block and a method for producing the silica-calcium phosphate composite block. [Background technology]

[0002] Octacalcium phosphate (Ca8(HPO4)2(PO4)4·5H2O; OCP) has excellent biocompatibility and is composed of calcium and phosphate, which are widely present in the body. Therefore, it is not only the main component of immature bone, but also an attractive material that can serve as the core of new biomaterials. In particular, its excellent bone replacement ability makes it useful as a bone substitute (e.g., Non-Patent Document 1).

[0003] The bone remodeling process, which is bone metabolism, controls the rate of bone replacement by bone substitutes. Osteocytes and immune cells play essential and central roles in the bone remodeling process. By controlling these cells, the bone remodeling process can be promoted and bone formation can be promoted (e.g., Non-Patent Document 2).

[0004] Silicate ions are known to enhance osteoblast activity and increase bone production (Non-Patent Documents 3 and 4). ORTHOREBIRTH Co., Ltd. sells a cotton-shaped artificial bone filler called ReBOSSIS as a commercially available product. This product is characterized by its cotton-shaped form and its main ingredients being β-TCP (β-tricalcium phosphate), bioabsorbable polymer, and SiV (silicon-containing calcium carbonate), which promotes bone formation.

[0005] When silica is supported on calcium phosphate or calcium carbonate, organic silica is usually used as the silica source (Non-Patent Document 5). However, the organic molecules that remain after the hydrolysis of organic silica are a major concern in commercialization.

[0006] On the other hand, it is known that silica-supported calcium phosphate crystals can be easily produced by using silicate as an inorganic silica source (Patent Document 1). In Patent Document 1, silica-supported calcium phosphate crystals are obtained by hydrolyzing a ceramic containing at least one of calcium and phosphoric acid in an aqueous solution containing silicate. In addition, the silica-supported calcium phosphate crystals obtained in Patent Document 1 can be made into the form of a powder composition, a block material, or a porous body by a conventional method. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] J. Biomed. Mater. Res., 59, 29-34 (2002) [Non-Patent Document 2] BMC Med.,9, 66-75 (2011) [Non-Patent Document 3] Acta Biomater., 5, 57-62 (2008) [Non-Patent Document 4] Mater. Sci. Eng.: C, 42, 672-680 (2014) [Non-Patent Document 5] J. Mater. Chem. B, 2, 1250 (2014) [Patent documents]

[0008] [Patent Document 1] Patent Publication No. 2022-080165 Summary of the Invention [Problem to be solved by the invention]

[0009] However, when silicic acid-containing calcium phosphate crystals are obtained in the form of a powder composition, the powder is likely to scatter in tissues, and the scattered powder is likely to cause inflammation. Furthermore, when silicic acid-containing calcium phosphate crystals are obtained in the form of a block material or a porous body, the resulting block material or porous body has room for improvement in strength, and is likely to disintegrate in tissues and turn into powder.

[0010] The present invention has been made to solve the above problems, and has as its object to provide a silica-calcium phosphate composite block that has high strength, does not disintegrate in water, and exhibits excellent bone-producing ability. [Means for solving the problem]

[0011] As a result of investigations aimed at solving the above-mentioned problems, the inventors have found that the above-mentioned problems can be solved by mixing a ceramic (A) containing calcium and / or phosphate with an aqueous solution (B) containing a silicate and further containing calcium and phosphate that are not contained in the ceramic (A) in a weight ratio (water-mixing ratio) of the aqueous solution (B) to the ceramic (A) of 0.30 or more and 6.00 or less to obtain a mixed mud containing silicic acid-containing calcium phosphate, and reacting the mixed mud in a mold, thereby completing the present invention.

[0012] That is, the present invention relates to the following [1]-

[15] . [1] A composite block hardened by chemical bonding of inorganic components or by entanglement or fusion of crystals of inorganic components, It contains calcium phosphate with silicic acid in its crystal structure and has a volume of 2.0 mm 3 The silica-calcium phosphate composite block is characterized by having the above-mentioned properties and a DTS strength of 0.1 MPa or more. [2] The composite block according to [1], wherein the calcium phosphate comprises octacalcium phosphate. [3] The composite block according to [2], wherein the water-containing layer of the octacalcium phosphate is replaced with silicic acid. [4] The composite block according to any one of [1] to [3], wherein the calcium phosphate contains carbonate apatite or hydroxyapatite. [5] The composite block according to any one of [1] to [4], characterized in that the calcium phosphate contains a tricalcium phosphate α phase or a tricalcium phosphate β phase. [6] The composite block according to any one of [1] to [5], wherein the calcium phosphate further contains at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids. [7] The composite block material according to any one of [1] to [6], wherein the calcium phosphate further contains at least one selected from the group consisting of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and complexes thereof, and quaternary ammonium salts. [8] The composite block according to any one of [1] to [7], which is a porous body. [9] A mixed mud preparation step of mixing a ceramic (A) containing calcium and / or phosphoric acid with an aqueous solution (B) having a silicate concentration of 10 mass% or more and further containing calcium and phosphoric acid that are not contained in the ceramic (A) such that the weight ratio (mixed water ratio) of the aqueous solution (B) to the ceramic (A) is 0.30 or more and 6.00 or less to obtain a mixed mud containing silicic acid-containing calcium phosphate; A composite block preparation step in which the mixed mud is reacted in a mold; A method for producing a silica-calcium phosphate composite block containing silicic acid-containing calcium phosphate, comprising:

[10] The method according to [9], wherein the ceramic (A) is calcium phosphate.

[11] The method according to [9] or

[10] , characterized in that the silicic acid-containing calcium phosphate obtained in the mixed mud preparation step contains silicic acid-containing octacalcium phosphate.

[12] A method for producing a silica-calcium phosphate composite block, comprising the step of immersing the composite block obtained by the method according to any one of [9] to

[11] in a solution containing carbon dioxide, thereby causing a phase transition of the silicic acid-containing calcium phosphate to a silicic acid-containing carbonate apatite phase.

[13] A method for producing a silica-calcium phosphate composite block, comprising the step of immersing the composite block obtained by the method according to any one of [9] to

[11] in a solution not containing carbonate, thereby causing a phase transition of the silicic acid-containing calcium phosphate to a silicic acid-containing hydroxyapatite phase.

[14] The manufacturing method according to any one of [9] to

[13] , characterized in that in the mixed mud preparation step, a compound containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, quaternary ammonium salts, and dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and salts thereof is further mixed to prepare a mixed mud containing the compound.

[15] The method according to any one of [9] to

[14] , wherein the composite block is a porous body. Effect of the Invention

[0013] According to the present disclosure, it is possible to provide a silica-calcium phosphate composite block that has high strength, does not disintegrate in water, and further exhibits excellent bone production ability. [Brief description of the drawings]

[0014] [Figure 1] 1 is a photograph of a composite block obtained in Example 1 (a photograph substituting a drawing). [Diagram 2] FIG. 2 is a diagram showing the results of XRD analysis of the composite block obtained in Example 1. [Diagram 3] FIG. 2 is a graph showing the results of measuring the DTS intensity of the composite block obtained in Example 1. [Figure 4] FIG. 2 is a diagram showing the results of FT-IR analysis of the composite block material obtained in Example 1. [Diagram 5]1 is a SEM photograph (drawing substitute photograph) of the composite block body obtained in Example 1 (using a sodium silicate solution with a concentration of 19 mass %). [Figure 6] FIG. 1 shows HE staining images showing the results of animal experiments of (A) an OCP block not composited with silica, (B) a carbonate apatite (CO3Ap) block, which is a bone-substitute type bone filler, and (C) the composite block obtained in Example 1 (using a sodium silicate solution with a concentration of 19% by mass). [Figure 7] 1 is a photograph of a composite block obtained in Example 2 (a photograph substituting a drawing). [Figure 8] FIG. 1 is a graph showing the results of measuring the DTS intensity of the composite block obtained in Example 2. [Figure 9] FIG. 2 is a diagram showing the results of XRD analysis of the composite block obtained in Example 2. [Figure 10] FIG. 2 is a diagram showing the results of FT-IR analysis of the composite block material obtained in Example 2. [Figure 11] FIG. 1 is a graph showing the carbon dioxide content of the composite block material obtained in Example 2. [Figure 12] 2 is a SEM photograph (a photograph substituting a drawing) of the composite block obtained in Example 2. [Figure 13] 1 is a photograph of a composite block obtained in Example 3 (a photograph substituting a drawing). [Figure 14] FIG. 1 is a diagram showing the results of XRD analysis of the composite block obtained in Example 3. [Figure 15] 1 is a photograph (drawing substitute photograph) showing the results of an antibacterial test of the composite block material obtained in Example 3. [Figure 16] 1 is a photograph of a composite block obtained in Example 4 (a photograph substituting a drawing). [Figure 17] FIG. 1 is a diagram showing the results of XRD analysis of the composite block obtained in Example 4. [Figure 18] FIG. 1 shows the results of FT-IR analysis of the composite block obtained in Example 4. [Figure 19] 1 is a photograph (drawing substitute photograph) showing the results of an antibacterial test of the composite block material obtained in Example 4. [Figure 20] 1 is a photograph of a composite block obtained in Example 5 (a photograph substituting a drawing). [Figure 21] FIG. 1 is a diagram showing the results of XRD analysis of the composite block obtained in Example 5. [Figure 22] 1 is a photograph of a composite block obtained in Example 6 (a photograph substituting a drawing). [Figure 23] FIG. 1 is a diagram showing the results of XRD analysis of the composite block obtained in Example 6. [Figure 24] FIG. 1 shows the results of FT-IR analysis of the composite block material obtained in Example 6. [Diagram 25] 1 is a SEM photograph (a photograph substituting a drawing) of the composite block obtained in Example 6. [Figure 26] 1 is a photograph of a composite block obtained in Example 7 (a photograph substituting a drawing). [Figure 27] FIG. 1 shows the results of XRD analysis of the composite block obtained in Example 7. [Figure 28] FIG. 1 shows the results of FT-IR analysis of the complex block material obtained in Example 7 (0.6 g of thiomalic acid added). [Figure 29] 1 is a SEM photograph (a photograph substituting a drawing) of the composite block obtained in Example 7. [Diagram 30] 1 is a photograph of a composite block obtained in Example 8 (a photograph substituting a drawing). [Diagram 31] FIG. 1 is a diagram showing the results of XRD analysis of the composite block obtained in Example 8. [Diagram 32] 1 is a photograph of a composite block obtained in Example 9 (a photograph substituting a drawing). [Diagram 33] FIG. 13 is a graph showing the results of measuring the DTS intensity of the composite block obtained in Example 9. [Diagram 34] FIG. 1 shows the results of XRD analysis of the composite block obtained in Example 9. [Diagram 35] 1 shows photographs of the silica-supported OCP powder and block body obtained in Comparative Example 1, and the block body before and after immersion in water (photographs substituting drawings). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The description of a numerical range such as "XX to YY" or "XX to YY" means a numerical range including the lower and upper limits, unless otherwise specified. When a numerical range is described in stages, the upper and lower limits of each numerical range can be arbitrarily combined.

[0016] [Silica-calcium phosphate composite block] The silica-calcium phosphate composite block (hereinafter, simply referred to as the "composite block"), which is one embodiment of the present invention, is a composite block hardened by chemical bonding of inorganic components or by entanglement or fusion of crystals of inorganic components, and contains calcium phosphate containing silicic acid in its crystal structure. 3 The composite block is preferably obtained by the method for producing a silica-calcium phosphate composite block described below, and has a DTS strength of 0.1 MPa or more.

[0017] Examples of calcium phosphate contained in the composite block (hereinafter simply referred to as "calcium phosphate") include octacalcium phosphate (Ca8(HPO4)2(PO4)4·5H2O; OCP), hydroxyapatite (HAp), carbonate apatite (CO3Ap), tricalcium phosphate α-phase (α-TCP), and tricalcium phosphate β-phase (β-TCP).

[0018] When the calcium phosphate contains octacalcium phosphate, it is preferable that the water-containing layer of the octacalcium phosphate is replaced with silicic acid. Note that, as described later, a composite block containing octacalcium phosphate can be obtained by adjusting the silicate concentration of the aqueous solution (B) used in the manufacturing method of the silica-calcium phosphate composite block.

[0019] The composite block preferably has a silicic acid content of 10 atomic % or more, more preferably 1 It is 2 atomic % or more, more preferably 15 atomic % or more, while it is preferably less than 50 atomic %, more preferably 30 atomic % or less, and even more preferably 25 atomic % or less. Note that, as the stoichiometric composition of calcium phosphate, the ratio of Ca to PO4 is more than 50 atomic % in a single compound.

[0020] The calcium phosphate may contain an apatite phase, and when the calcium phosphate contains an apatite phase, the calcium phosphate may contain carbonate apatite or hydroxyapatite. Conventional apatite is in powder form, but the present invention makes it possible to obtain apatite as a composite block with silica.

[0021] The composite block containing carbonate apatite can be obtained by a manufacturing method for a silica-calcium phosphate composite block, which includes a step of immersing a silica-calcium phosphate composite block in a solution containing carbon dioxide, as described below.

[0022] The composite block containing hydroxyapatite can be obtained by a manufacturing method for a silica-calcium phosphate composite block, which includes a step of immersing a silica-calcium phosphate composite block in a solution not containing carbonate, as described below.

[0023] The calcium phosphate may comprise tricalcium phosphate alpha phase or tricalcium phosphate beta phase. A composite block containing tricalcium phosphate α-phase or tricalcium phosphate β-phase can be obtained by a method for producing a silica-calcium phosphate composite block, which includes a step of firing a silica-calcium phosphate composite block, as described below.

[0024] The calcium phosphate may further contain at least one element selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids in its crystal structure. Conventional bone filling materials have concerns about postoperative infection and incomplete bone formation. Among the above elements, silver, copper, and gallium are antibacterial elements, strontium, magnesium, and zinc are bone-activating elements, and lanthanoids have complex system performance with antibacterial molecules. Supporting the above elements leads to improved function of the composite block as a bone filling material.

[0025] The lanthanides referred to here include lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium, as well as yttrium, scandium, and hafnium, which behave similarly as rare earth elements.

[0026] When calcium phosphate further contains at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids in its crystal structure, the lower limit of the total content of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids in the composite block is preferably 0.01 atomic % or more, more preferably 0.1 atomic % or more, and even more preferably 0.5 atomic % or more. On the other hand, the upper limit of the total content of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids in the composite block is preferably 15 atomic % or less, more preferably 10 atomic % or less, and even more preferably 5 atomic % or less. When the total content of the above elements is within the above range, the function of the composite block as a bone filling material can be further improved.

[0027] The calcium phosphate may further contain at least one selected from the group consisting of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and complexes thereof in its crystal structure or on its crystal surface. When the aqueous layer contains at least one selected from the group consisting of carboxylic acids, tetracarboxylic acids, polycarboxylic acids, and complexes thereof, the aqueous layer can support at least one selected from the group consisting of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and complexes thereof. Examples of dicarboxylic acids include maleic acid, malic acid, succinic acid, itaconic acid, malonic acid, adipic acid, iminodiacetic acid, tartaric acid, thiomalic acid, oxalic acid, malonic acid, dithioglycolic acid, dithiodiacetic acid, and pyridinedicarboxylic acid. Examples of tricarboxylic acids include citric acid, trimesic acid, isocitric acid, aconitic acid, and tricarballylic acid. Examples of tetracarboxylic acids include ethylenediaminetetraacetic acid (EDTA), ethylenetetracarboxylic acid, 1,2,3,4-cyclobutanetetracarboxylic acid, pyromellitic acid, 4,4'-carbo nyldiphthalic acid, 1,2,4,5-cyclohexanetetracarboxylic acid, 4,4'-(ethyne-1,2-diyl)diphthalic acid, naphthalene-1,4,5,8-tetracarboxylic acid, 3,4,9,10-perylenetetracarboxylic acid, 4,4'-oxydiphthalic acid, 4,4'-(hexafluoroisopropylidene)diphthalic acid, 4,4'-(4,4'-isopropylidenediphenoxy)diphthalic acid, dicyclohexyl-3,4,3',4'-tetracarboxylic acid, Examples of the polycarboxylic acid include polyacrylic acid, polycitric acid, alginic acid, and polymannuronic acid. For example, since thiomalic acid is a precursor of antirheumatic drugs, when calcium phosphate contains thiomalic acid, the composite block as a bone filling material can be endowed with the function of a precursor of an antirheumatic drug.

[0028] When calcium phosphate further contains at least one selected from the group consisting of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and complexes thereof in the crystal structure or on the crystal surface, the lower limit of the total content of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and complexes thereof in the composite block is preferably 0.1 atomic % or more, more preferably 0.2 atomic % or more, and even more preferably 0.5 atomic % or more. On the other hand, the upper limit of the total content of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and complexes thereof in the composite block is preferably 10 atomic % or less, more preferably 5 atomic % or less, and even more preferably 2 atomic % or less. When the total content of the dicarboxylic acid, tricarboxylic acid, tetracarboxylic acid, polycarboxylic acid and complexes thereof is within the above range, the function of the composite block as a bone filling material can be further improved.

[0029] Calcium phosphate may further contain a quaternary ammonium salt in its crystal structure or on the crystal surface.When calcium phosphate further contains a quaternary ammonium salt, the quaternary ammonium salt can be supported in the water-containing layer.Examples of the quaternary ammonium salt include benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetylpyridinium chloride, cetrimonium, dophanium chloride, polydronium chloride, tetraethylammonium bromide, didecyldimethylammonium chloride, domiphen bromide, lecithin, phosphatidylcholine, glycerophosphorylcholine, choline chloride, trimethylglycine, acetylcholine, edrophonium, ergothioneine, tetramethylammonium gold, safranine, betanine, pentolinium, miltefosine, meldonium, and Janus Green. Since quaternary ammonium salts have antibacterial properties, when calcium phosphate contains a quaternary ammonium salt, antibacterial properties can be imparted to the composite block used as a bone filling material.

[0030] When calcium phosphate further contains a quaternary ammonium salt in its crystal structure or on the crystal surface, the lower limit of the content of the quaternary ammonium salt in the composite block is preferably 0.01 atomic % or more, more preferably 0.1 atomic % or more, and even more preferably 0.5 atomic % or more, whereas the upper limit of the content of the quaternary ammonium salt in the composite block is preferably 10 atomic % or less, more preferably 5 atomic % or less, and even more preferably 3 atomic % or less. When the content of the quaternary ammonium salt is within the above range, the antibacterial properties of the composite block as a bone filling material can be further improved.

[0031] The block body further containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids, the block body further containing at least one selected from the group consisting of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and complexes thereof, and the block body further containing a quaternary ammonium salt are preferably obtained by a method for producing a silica-calcium phosphate composite block body, in which a compound further containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, quaternary ammonium salts, and dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and salts thereof is mixed in a mixed mud preparation step described below, to prepare a mixed mud containing the compound.

[0032] The composite block has a DTS strength (diametral tensile strength) of 0.1 MPa or more, preferably 0.15 MPa or more, and more preferably 0.2 MPa or more. The upper limit of the DTS strength of the composite block is not particularly limited, but is usually 10 MPa or less. When the DTS strength is equal to or greater than the lower limit, the block does not disintegrate even when pinched firmly with tweezers, facilitating transplantation into bone defects in vivo. Furthermore, the block does not disintegrate within the tissue after transplantation and can remain stable. In addition, in the method for producing a silica-calcium phosphate composite block described below, a composite block having a DTS strength of 0.1 MPa or more can be obtained by setting the weight ratio (water-mixing ratio) of the aqueous solution (B) to the ceramic (A) to 0.30 or more and 6.00 or less.

[0033] The shape of the composite block depends on the shape of the mold used when filling the mixed mud, but since it has a certain strength, it can be processed into a specific shape. For example, it can be processed into a cube, rectangular parallelepiped, cylinder, cone, truncated cone, sphere, octahedron, tetrahedron, etc. In addition, in the manufacturing method of the silica-calcium phosphate composite block described later, by setting the weight ratio (water-mixing ratio) of the aqueous solution (B) to the ceramic (A) to be 0.30 or more and 6.00 or less, it is possible to obtain a block having a volume of 2 mm 3 The above composite block can be obtained. The volume of the composite block is 2 mm 3 There is no particular limitation as long as it is equal to or larger than 5 mm, but it is preferably 5 mm 3 More preferably, 10 mm 3 More preferably, 30 mm 3 The composite block having a volume equal to or larger than the above lower limit is easily immobilized in tissue. Moreover, such a large composite block can be produced by the method for producing a silica-calcium phosphate composite block described later. 3 If the temperature exceeds this range, there is a concern that the strength may decrease.

[0034] In the present invention, a composite block refers to a block in which the crystals of inorganic substances such as OCP, which are constituents of the inorganic component, are hardened and maintain their shape by chemical bonding or by entanglement or fusion of the crystals, without any intervening substances such as collagen between them. In addition, in the method for producing a silica-calcium phosphate composite block described below, by setting the weight ratio (water-mixing ratio) of the aqueous solution (B) to the ceramic (A) to be 0.30 or more and 6.00 or less, a composite block that is hardened by chemical bonding of the inorganic components or by entanglement or fusion of the crystals of the inorganic components can be obtained.

[0035] In the present invention, the chemical bond means that there is one or more chemical bonds classified as covalent bonds, ionic bonds, chelate bonds, or hydrogen bonds between crystals constituting an inorganic component.

[0036] In the present invention, the entanglement of crystals means that, microscopically, a plurality of crystals constituting a composite block are in contact with each other via their crystal faces.

[0037] In the present invention, fusion of crystals refers to the fact that the multiple crystals constituting the composite block are in contact with each other at their crystal faces or the like with no gaps in between, and the grain boundaries in these areas are unclear and cannot be observed.

[0038] The aforementioned intertwining of crystals and fusion of crystals can be easily identified by observing the microstructure of the composite block. For example, a scanning electron microscope (SEM) is used to observe the microstructure. In this case, in order to ensure the conductivity of the sample, an ion sputtering device may be used to pretreat the sample with osmium (Os), carbon (C), or other ions, using a method used in normal SEM observation, before observation.

[0039] A composite block that has hardened due to chemical bonding of inorganic components or entanglement or fusion of inorganic component crystals will retain its shape without disintegrating even when immersed in water for at least one hour. This is because the bonding between the crystals is stronger than the surface tension of the crystals, so the block will not disintegrate even if water or other substances get into the gaps between the crystals. Therefore, calcium phosphate compacts, which are formed by compressing calcium phosphate powder, are not included in this category, because no such bonding is expected between the particles that make up the powder.

[0040] The phrase "retains its shape without disintegrating even when immersed in water for 1 hour" means that the composite block clearly maintains its shape even after being immersed in distilled water for 1 hour, can be picked up and removed with tweezers, and has a mass loss of 20% or less by mass compared to the mass before immersion after being picked up and removed with tweezers and dried. The composite block does not disintegrate even when immersed in water for one hour, so that the block does not disintegrate within the tissue after transplantation and can remain stable.

[0041] Crystallographic information of calcium phosphate crystals can be obtained by standard methods, for example, by X-ray diffraction (XRD). An example of the apparatus is MiniFlex600 (Rigaku Corporation, Japan). Note that the term "crystal" refers to particles that show clear diffraction peaks in the XRD pattern of a powder sample and that exhibit a unique external shape due to the crystal structure when grown in a free space that does not inhibit crystal growth.

[0042] The element contents in the crystals can be evaluated in accordance with a conventional method, for example, by X-ray fluorescence analysis (XRF) using an apparatus such as SEA2210 (Seiko Instruments Technology Inc., Japan).

[0043] The chemical oscillation scheme of the crystal can be evaluated by, for example, Fourier transform infrared spectroscopy (FT-IR) in a conventional manner using an apparatus such as Nicolet NEXUS670 (Thermo Fisher Scientific, Inc., USA).

[0044] The microstructure of the crystal can be evaluated by a field emission scanning electron microscope (FE-SEM) according to a conventional method. An example of the apparatus is JSM-6700F (JEOL Ltd., Japan). In order to prevent charge accumulation on the surface of the crystal, the crystal may be sputter-coated with Os or the like.

[0045] The composite block may be a porous body. The shape of the pores of the porous body is not particularly limited. Usually, the porous body has interconnected pores, is isolated pores, or is a honeycomb structure. The porosity is not particularly limited, but is preferably 30% or more, more preferably 50% or more, and particularly preferably 70% or more. The pore size is not particularly limited, but is preferably 10 μm or more and 1000 μm or less, particularly preferably 100 μm or more and 700 μm or less, and more preferably 200 μm or more and 500 μm or less.

[0046] [Method of manufacturing silica-calcium phosphate composite block] A method for producing a silica-calcium phosphate composite block, which is one embodiment of the present invention (hereinafter, also simply referred to as a "composite block production method"), includes a mixed mud preparation step of mixing a ceramic (A) containing calcium and / or phosphate with an aqueous solution (B) having a silicate concentration of 10 mass% or more and further containing calcium and phosphate that are not contained in the ceramic (A) such that the weight ratio (water-mixing ratio) of the aqueous solution (B) to the ceramic (A) is 0.30 or more and 6.00 or less, thereby obtaining a mixed mud containing silicic acid-containing calcium phosphate, and a composite block preparation step of reacting the mixed mud in a mold.

[0047] The composite block body is preferably produced by the composite block body production method of the present embodiment. Each step in the composite block body production method will be described below.

[0048] (Mixed mud preparation process) The mixed mud preparation step is a step for obtaining a mixed mud containing silicic acid-containing calcium phosphate. In order to obtain the mixed mud containing silicic acid-containing calcium phosphate, a ceramic (A) containing calcium and / or phosphoric acid is mixed with an aqueous solution (B) having a silicate concentration of 10 mass% or more and containing a composition in which the ceramic (A) does not contain calcium and phosphoric acid, so that the weight ratio (water-mixing ratio) of the aqueous solution (B) to the ceramic (A) is 0.30 or more and 6.00 or less.

[0049] The ceramic (A) containing calcium and / or phosphate (hereinafter also simply referred to as "ceramic (A)") used in the mixed mud preparation process may be a ceramic containing calcium and phosphate, may be a ceramic containing calcium but not phosphate, or may be a ceramic containing phosphate but not calcium.

[0050] The ceramic containing calcium and phosphoric acid is calcium phosphate, and examples of the calcium phosphate that can be used include calcium hydrogen phosphate dihydrate (DCPD), calcium hydrogen phosphate anhydrate, calcium dihydrogen phosphate hydrate (MCPM), calcium dihydrogen phosphate anhydrate, tricalcium phosphate α phase, tricalcium phosphate β phase, tetracalcium phosphate (TTCP), amorphous calcium phosphate (ACP), hydroxyapatite, carbonate apatite, sodium-substituted hydroxyapatite, etc. These may be used alone or in combination in any ratio.

[0051] The ceramic containing calcium and not containing phosphate can use calcium inorganic salts or calcium organic salts. Examples of calcium inorganic salts include calcium carbonate, calcium hydroxide, calcium oxide, calcium chloride, calcium fluoride, calcium bromide, calcium iodide, calcium phosphide, calcium sulfate, calcium sulfate hemihydrate, calcium sulfate dihydrate, calcium oxalate anhydrate, calcium oxalate monohydrate, calcium oxalate dihydrate, calcium oxalate trihydrate, calcium sulfite, calcium silicate, calcium pyrophosphate, calcium tungstate, calcium molybdate, etc. Examples of calcium organic salts include calcium acetate, calcium succinate, calcium citrate, calcium malate, calcium thiomalate, calcium benzoate, calcium lactate, calcium stearate, etc. These may be used alone or in combination in any ratio.

[0052] Examples of ceramics that contain phosphoric acid but do not contain calcium include sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, triammonium phosphate, ammonium magnesium phosphate, and magnesium phosphate. These may be used alone or in combination in any desired ratio.

[0053] The aqueous solution (B) (hereinafter, also referred to simply as "aqueous solution (B)") used in the mixed mud preparation step, which has a silicate concentration of 10 mass% or more and further contains a composition in which, among calcium and phosphate, the ceramic (A) does not contain, may be an aqueous solution containing only silicate, an aqueous solution containing silicate and calcium, or an aqueous solution containing silicate and phosphate, so long as a mixed mud containing silicic acid-containing calcium phosphate is obtained by mixing with the ceramic (A).

[0054] When the ceramic (A) is a ceramic containing calcium and phosphoric acid, the aqueous solution (B) may be an aqueous solution containing only silicate, an aqueous solution containing silicate and calcium, or an aqueous solution containing silicate and phosphoric acid.

[0055] When the ceramic (A) is a calcium-containing, phosphate-free ceramic, the aqueous solution (B) is an aqueous solution containing a silicate and a phosphate. When the ceramic (A) is a ceramic containing phosphate and not containing calcium, the aqueous solution (B) is an aqueous solution containing silicate and calcium.

[0056] The aqueous solution (B) may be an aqueous solution further containing a compound containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, quaternary ammonium salts, and dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and salts thereof, which will be described later.

[0057] Examples of silicates that can be used in the aqueous solution (B) include water glass (Na2SiO3), potassium silicate, cesium silicate, and ammonium hexafluorosilicate. Among these, water glass is preferred because the sodium ion, which is the counter cation, induces the formation of octacalcium phosphate. Compounds other than the silicate solution to be supported on the block body may also be added. In this case, the compounds must be uniformly dispersed in the form of a solution or colloidal particles.

[0058] The calcium used in the aqueous solution (B) may be, for example, the compounds listed above as the "ceramic containing calcium and not containing phosphate". The phosphoric acid used in the aqueous solution (B) may be, for example, phosphoric acid (H3PO4) or any of the compounds listed above as the "ceramic containing phosphoric acid and not containing calcium".

[0059] The concentration of the silicate in the aqueous solution (B) is not particularly limited as long as it is 10% by mass or more, and is usually 10% by mass or more and 50% by mass or less, preferably 15% by mass or more and 40% by mass or less, and more preferably 18% by mass or more and 30% by mass or less.

[0060] By adjusting the silicate concentration of the aqueous solution (B) to 18 to 23 mass %, a composite block having a single phase of octacalcium phosphate (OCP) can be obtained.

[0061] In the mixed mud preparation step, the ceramic (A) and the aqueous solution (B) are mixed to prepare the mixed mud. There are no particular limitations on the mixing method, but for example, the aqueous solution (B) can be added dropwise to the powder of the ceramic (A) and thoroughly mixed using a spatula or the like to prepare the mixed mud. When silicate comes into contact with phosphoric acid, it is immediately hydrolyzed to become silica hydrogel, and further kneading can form a complex of silica and calcium phosphate. In addition, vigorous foaming may occur during mixing, causing partial hardening, but it is possible to keep the mixture in the same state until the foaming reaction settles down. It is preferable to continue mixing.

[0062] The weight ratio (mixture ratio) of the aqueous solution (B) to the ceramic (A) is from 0.30 to 6.00, preferably from 0.50 to 5.00, and more preferably from 1.00 to 3.00.

[0063] When the weight ratio (mixture ratio) of the aqueous solution (B) to the ceramic (A) is within the above range, the ceramic concentration in the mixed mud is high, so that calcium phosphate crystals can be tightly entangled, and a composite block having a volume of 2.0 mm or more is formed, which is hardened by chemical bonding of the inorganic components or by entanglement or fusion of the inorganic component crystals. 3 In addition, a composite block having a DTS strength of 0.1 MPa or more can be produced. In addition, when the water ratio is within the above range, the mixed mud has an appropriate viscosity, so that a silica-calcium phosphate composite block that maintains the shape of the mold can be produced. On the other hand, the silica-supported calcium phosphate crystals disclosed in the examples of Patent Document 1 are produced with a weight ratio (water-mixing ratio) of the aqueous solution containing silicate to the ceramic being more than 6.00. Due to the high water-mixing ratio, the silica-supported calcium phosphate crystals of Patent Document 1 are obtained in the form of a powder, block material, or porous body that has room for improvement in strength and is easily disintegrated in water.

[0064] Examples of silicate-containing calcium phosphates obtained in the mixed mud preparation process include octacalcium phosphate (Ca8(HPO4)2(PO4)4·5H2O; OCP), hydroxyapatite (HAp), carbonate apatite (CO3Ap), tricalcium phosphate α-phase (α-TCP), and tricalcium phosphate β-phase (β-TCP).

[0065] In the mixed mud preparation step, a compound containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, quaternary ammonium salts, and dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and salts thereof may be further mixed to prepare a mixed mud containing the compound. The method of mixing the compound is not particularly limited, and the compound may be contained in the aqueous solution (B), or the compound may be mixed in the form of powder with the ceramic (A) and the aqueous solution (B).

[0066] The compound containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, quaternary ammonium salts, and dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and salts thereof is not particularly limited. For example, the compound containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids can be a nitrate, fluoride, chloride, bromide, iodide, sulfate, carbonate, chromate, acetate, etc. of each element. The quaternary ammonium salt can be the above-mentioned quaternary ammonium salt. The compound containing at least one selected from the group consisting of dicarboxylic acid, tricarboxylic acid, tetracarboxylic acid, polycarboxylic acid, and salts thereof can be the above-mentioned dicarboxylic acid, etc. and complexes thereof. These may be used alone or in combination in any ratio.

[0067] The mixing ratio of the ceramic (A) and the compound containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, quaternary ammonium salts, and dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and salts thereof is not particularly limited, but the amount of the compound added per 1 g of ceramic (A) can be 0.1 mmol or more and 1 mol or less.

[0068] (Composite block preparation process) In the composite block preparation step, the mixed mud obtained in the mixed mud preparation step is reacted in a mold. In the composite block preparation step (step in which calcium ions and phosphate ions react) in the method for producing a composite block according to the present embodiment, mixed mud having a water-mix ratio within a specific range is reacted in a mold, whereby calcium phosphate crystals composited with silica are precipitated, and the crystals become intricately entangled, thereby obtaining a block that maintains the shape of the mold, has high strength, and does not disintegrate in water. The mold to be used is not particularly limited, and for example, a silicon mold can be used.

[0069] The reaction temperature and reaction time may be appropriately set, and the reaction temperature may be preferably 5 to 95°C, more preferably 15 to 80°C. The reaction time may be preferably 2 to 120 hours, more preferably 6 to 96 hours. The reaction is preferably carried out in a sealed state. Carrying out the reaction in a sealed state refers to filling the mixed mud into a mold, further closing the mold with a lid, and proceeding the reaction while avoiding contact between the mixed mud and the outside air, but air may be present inside the mold. When the reaction is carried out in a sealed state, a load may be applied appropriately to the mixed mud. By carrying out the reaction in a sealed state, factors that inhibit the progress of the reaction, such as drying of the mixed mud, can be prevented, and the precipitated calcium phosphate crystals are firmly intertwined with each other, resulting in a composite block body with higher strength.

[0070] After the reaction, the mixture may be dried in a dryer, etc. After removal, if any unreacted components remain, it is preferable to wash and remove them with distilled water, etc.

[0071] (Phase transition to apatite phase) The method for producing a composite block body may further include a step of immersing the composite block body obtained in the composite block body preparation step in a solution containing carbon dioxide or a solution not containing carbon dioxide. By immersing the composite block body in a solution containing carbon dioxide, the metastable phase of the silicic acid-containing calcium phosphate can be phase-transferred to a silicic acid-containing carbonate apatite phase. Also, by immersing the composite block body in a solution not containing carbon dioxide, the metastable phase of the silicic acid-containing calcium phosphate can be phase-transferred to a silicic acid-containing hydroxyapatite phase.

[0072] When the composite block is immersed in a solution containing or not containing carbon dioxide to cause a phase transition to a silicic acid-containing carbonate apatite phase or a silicic acid-containing hydroxyapatite phase, the silicic acid-containing calcium phosphate is preferably silicic acid-containing octacalcium phosphate from the viewpoint of the reaction mechanism, particularly the adjustment of the carbonate content in the final product.

[0073] Examples of the carbonate source in the solution containing carbonate include carbon dioxide gas, ammonium carbonate, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, and lithium carbonate. These may be used alone or in combination. The concentration of carbonate in the solution containing carbonate is not particularly limited, but is preferably 0.001 mol / L or more and 10 mol / L or less, more preferably 0.05 mol / L or more and 5 mol / L or less, and even more preferably 0.1 mol / L or more and 3 mol / L or less.

[0074] The temperature and time for immersing the composite block in the solution containing carbonate or the solution not containing carbonate may be appropriately set, and the immersion temperature may be preferably 25 to 99° C., more preferably 37 to 95° C., and even more preferably 50 to 90° C. The immersion time may be preferably 30 minutes or more and 14 days or less, more preferably 1 hour or more and 10 days or less, and even more preferably 2 hours or more and 7 days or less.

[0075] The pH during immersion is not particularly limited, but is preferably 6.0 or more, more preferably 7.0 or more, and even more preferably 8.0 or more. To adjust the pH, sodium hydroxide is added to the solution. Addition of aqueous solutions, hydrochloric acid, etc. is a common possibility.

[0076] After immersion, the substrate may be dried using a dryer, etc. After removal, the substrate may be washed using distilled water, etc.

[0077] (Firing of composite blocks) The method for producing a composite block may further include a step of firing the composite block obtained in the composite block preparation step. By firing the composite block, a composite block containing tricalcium phosphate α phase or tricalcium phosphate β phase can be produced.

[0078] When producing a composite block containing tricalcium phosphate α phase, the firing temperature must be equal to or higher than the β-α transition temperature of 1180° C. It can be preferably set to 1200 to 1700° C., more preferably 1400 to 1600° C. The firing time can be preferably set to 2 to 72 hours, more preferably 5 to 24 hours. When producing a composite block containing tricalcium phosphate β phase, the firing temperature must be 1180° C. or less, and can be preferably 800 to 1180° C., and more preferably 900 to 1150° C. The firing time can be preferably 2 to 96 hours, and more preferably 6 to 48 hours.

[0079] The composite block obtained by the method for producing a composite block may be a porous body. The shape of the pores of the porous body is not particularly limited. Typical examples include a body with interconnected pores, a body with isolated pores, and a honeycomb structure. The porosity is not particularly limited, but is preferably 30% or more, more preferably 50% or more, and particularly preferably 70% or more. The pore size is not particularly limited, but is preferably 10 μm or more and 1000 μm or less, particularly preferably 100 μm or more and 700 μm or less, and more preferably 200 μm or more and 500 μm or less. EXAMPLES

[0080] The following description will be given based on examples. Note that the examples are merely examples, and the present invention is not limited to these examples. In other words, the present invention is limited only by the claims, and includes various modifications other than the examples included in the present invention.

[0081] The physical properties of the composite blocks obtained in the examples were evaluated using the following measuring devices and conditions. [DTS Strength] The diametral tensile strength (DTS strength) of the composite block was measured using a Shimadzu Corporation universal testing machine, AGS-J, at a head speed of 1 mm / min.

[0082] [X-ray diffraction analysis] XRD analysis of the composite block was carried out using an X-ray diffraction analyzer (MiniFlex600, Rigaku Corporation, Japan, target: Cu, wavelength: 0.15406 nm). The measurement conditions of XRD were accelerating voltage and amplitude of 40 kV and 15 mA, respectively, and the diffraction angle was continuously scanned at 2θ values ​​from 3° to 70° at a scanning speed of 2° / min for the characterization.

[0083] [FT-IR analysis] Fourier transform infrared spectroscopy (FT-IR: Nicolet NEXUS670, Thermo Fisher Scientific, Inc., USA) was used to measure the concentration of triglycine sulfate using an attenuated total reflection prism made of GeSe (32 scans, resolution 2 cm). -1 ) The chemical oscillatory scheme of the composite block was characterized. The atmosphere was considered as the background for carrying out the measurements.

[0084] [Electron microscope observation] The microstructure of the composite block was evaluated by a field emission scanning electron microscope (FE-SEM: JSM-6700F, JEOL Ltd., Japan). The accelerating voltage was 5 kV, and the samples were sputter-coated with Os to prevent charge accumulation on the surface.

[0085] [XRF analysis] The chemical composition of the composite block was evaluated by X-ray fluorescence analysis (XRF:SEA2210, Seiko Instruments Technology Inc., Japan) at an accelerating voltage of 15 kV.

[0086] [CHN analysis] The C, H, and N contents of the composite block were evaluated by CHN analysis (CHN: Yanako CHN Coder MT-6, Yanako Co., Ltd., Japan) using helium-oxygen mixed gas as the carrier gas.

[0087] [Animal experiments] Prior to the experiment, approval was obtained from the ethics committees of the National Institute of Advanced Industrial Science and Technology and Okayama University of Science (approval numbers: Do2021-0356 (AIST), E2020-096 (Okayama University of Science)). This animal experiment was conducted at the animal experiment facility of the Faculty of Veterinary Medicine, Okayama University of Science. We used 18-week-old male Japanese white rabbits purchased from Japan SLC Co., Ltd. After losing consciousness by inhaling 2% isoflurane, 4 mL of a ketamine-seractal mixed anesthetic solution was injected into the rump. The animal was placed under deep anesthesia by intramuscular injection. Respiration, pulse, body temperature, and oxygen concentration were monitored to confirm that the animal was under deep anesthesia. The hair on both knees was then shaved, and the affected areas were sterilized three times alternately with povidone-iodine and Hibiscrub solution. After confirming that the liquid had been applied sufficiently to the incision, the skin and muscle of the knee were incised with a scalpel, and the distal end of the femur was exposed. A bone defect of 6 mm in diameter and 3 mm in thickness was created on the inner side of the distal end of the femur using a trephine burr. Here, reconstruction was performed using a composite block, or as a reference sample, an OCP block not composited with silica, or a carbonate apatite (CO3Ap) block, which is a bone replacement type bone filler. The embedded blocks were all cylindrical, dense samples with a diameter of 6 mm and a thickness of 3 mm. After reconstruction of the bone defect, the muscle and skin were sutured, and after confirming that the rat had woken up from anesthesia, the rat was returned to a cage and kept in a normal cage. No additional procedures such as loading were performed. After one month of normal breeding, and after confirming that there was no sign of inflammation or tumor formation at the implant site, the rabbit was euthanized by administering an overdose of anesthetic to the ear vein. The implant site was immediately removed together with the surrounding tissue in a single mass, which was then fixed in neutral buffered formalin solution. Then, pathological specimens were prepared according to the usual procedure.

[0088] [Antibacterial test] Prior to the experiment, approval was obtained from the Ethics Committee of the National Institute of Advanced Industrial Science and Technology (Approval Number: Micro 2019-0110 (AIST)). A composite block molded into a disk shape with a diameter of 6 mm x 1 mm was placed on an agar medium coated with Staphylococcus aureus. The composite block was immersed in 70% ethanol and then thoroughly washed aseptically with PBS before use. After placing the composite block on the agar medium, it was left to stand in a 37°C incubator for one day.

[0089] [Example 1] Preparation of silica-OCP composite block As ceramic (A), 1 g of calcium hydrogen phosphate dihydrate (DCPD) and 1 g of phosphoric acid The ceramics (A) and 1 g of calcium dihydrogen hydrate (MCPM) were mixed in a mortar while being thoroughly ground to obtain a uniform mixed powder. 4.32 mL of sodium silicate solution with a concentration of 0 to 38 mass% as aqueous solution (B) was dropped into 2 g of this mixed powder and mixed. That is, the weight ratio (mixture ratio) of aqueous solution (B) to ceramic (A) was 2.16. The aqueous solution (B), which is a sodium silicate solution, was immediately hydrolyzed by contact with MCPM and DCPD to become silica hydrogel. By continuing to knead this, a complex consisting of silica hydrogel and calcium phosphate was formed. By continuing to mix further, the formation of silica hydrogel was induced by a hydrolysis reaction due to contact with calcium phosphate, and the whole was made into a uniform mixed mud.

[0090] The obtained mixed mud was filled into a silicon mold with a diameter of 6 mm and a thickness of 3 mm, and cured at 60°C for one day in a sealed state. After curing, it was dried at 40°C for 12 hours or more, and then the dried mixed mud was removed from the mold. It was then thoroughly washed with distilled water to remove any remaining unreacted components, and then dried again at 40°C for 24 hours or more.

[0091] Figure 1 shows a photograph of the composite block obtained in Example 1. It can be seen from Figure 1 that when the silicate aqueous solution was used, the composite block maintained the shape of the mold. In addition, the volume of the composite block obtained using the sodium silicate solution was 80 mm3 That was all.

[0092] Figure 2 shows the results of XRD analysis of the composite block obtained in Example 1. When a sodium silicate solution with a concentration of 19 mass% was used, the composite block had a single crystal phase of octacalcium phosphate (OCP). When the concentration of the sodium silicate solution at the time of mixing was varied, it was found that the composite block had a single OCP crystal phase when a sodium silicate solution with a concentration of 18 to 23 mass% was used.

[0093] 3 shows the measurement results of the DTS strength of the composite block obtained in Example 1. The DTS strength of all the composite blocks obtained using the sodium silicate solutions with silicate concentrations of 15 mass % or more was 0.1 MPa or more, and they did not crumble even when pinched with tweezers.

[0094] Figure 4 shows the FT-IR analysis results of the composite block obtained in Example 1 (using a sodium silicate solution with a concentration of 19% by mass). In addition to the absorption band of the phosphate group, a band of the silanol group was observed, and it was observed that the silica hydrogel was sufficiently formed. In other words, it was found that the composite block had a structure in which the silica hydrogel and OCP were composited.

[0095] FIG. 5 shows an SEM photograph of the composite block obtained in Example 1 (using a sodium silicate solution with a concentration of 19% by mass). The composite block obtained using the sodium silicate solution had a structure in which fine plate-like crystals were accumulated. In addition, it did not disintegrate even when immersed in water for 1 hour. In other words, it was found that the composite block obtained using the sodium silicate solution was a composite block that had hardened due to chemical bonding of the inorganic components, or entanglement or fusion of the crystals of the inorganic components.

[0096] FIG. 6 shows HE (hematoxylin-eosin) stained images showing the results of animal experiments using (A) an OCP block not composited with silica, (B) a carbonate apatite (CO3Ap) block, which is a bone-substitute type bone filler, and (C) the composite block obtained in Example 1 (using a sodium silicate solution with a concentration of 19% by mass). Note that for all samples, blocks with a diameter of 6 mm and a thickness of 3 mm were used. (A) An OCP block not composited with silica, and (B) a carbonate apatite (CO3Ap) block, which is a bone-substitute type bone filler. The details of the preparation method of each of the above are described in the following documents. ·Y Sugiura, K Ishikawa, “Fabrication of pure octacalcium phosphate blocks from dicalcium hydrogen phosphate dihydrate blocks via a dissolution-precipitation reaction in a basic solution”, Materials Letters, Vol. 239, March 2019, p.143-146 ·Y Sugiura, K Ishikawa, “Fabrication of carbonate apatite blocks from octacalcium phosphate blocks through different phase conversion mode depending on carbonate concentration”, Journal of Solid State Chemistry, Vol. 267, November 2018, p.85-91

[0097] (C) When the composite block obtained in Example 1 was implanted, no signs of inflammation or tumors were observed in the surrounding tissue. Furthermore, the composite block obtained in Example 1 was significantly reduced in size after implantation, and very active bone formation was observed in the surrounding area of ​​the implantation. Approximately 30% of the volume of the composite block was absorbed. This indicates that the composite block was absorbed by the body through the bone remodeling process, and that active bone formation was occurring. On the other hand, (A) the OCP block not composited with silica and (B) the carbonate apatite (CO3Ap) block, which is a bone substitute, showed almost no change in shape after implantation and was observed to be directly bonded to the bone tissue at the periphery. In other words, it was found that the composite block obtained in Example 1 exhibited excellent properties by being composited with silica.

[0098] [Example 2] Preparation of silica-apatite composite block Ten composite blocks obtained in Example 1 (using a sodium silicate solution with a concentration of 19% by mass) were immersed in an ammonium carbonate solution with a concentration of 0 to 2 mol / L contained in a 50 mL centrifuge tube, sealed, and reacted in a thermostatic chamber at 80° C. for three days. The composite blocks did not collapse even when immersed in the solution, and maintained their shape. After the reaction, the composite block was washed several times with distilled water to remove the solution that had permeated inside, and then left to stand in a thermostatic bath at 80° C. for 12 hours or more to dry.

[0099] Figure 7 shows a photograph of the composite block obtained in Example 2. It can be seen from Figure 7 that the composite block maintained its shape before immersion in the solution. The volume of each of the composite blocks obtained was 80 mm 3 That was all.

[0100] Figure 8 shows the measurement results of the DTS strength of the composite block obtained in Example 2. The DTS strength of the composite block tended to decrease with increasing concentration of the ammonium carbonate solution used for treatment, but even the composite block treated with the most concentrated concentration had a DTS strength of 0.1 MPa or more, and did not crumble even when pinched with tweezers.

[0101] 9 shows the results of XRD analysis of the composite block obtained in Example 2. It was found that the obtained composite block was entirely composed of a single phase of apatite.

[0102] FIG. 10 shows the FT-IR analysis results of the composite block obtained in Example 2. From FIG. 10, in addition to the absorption band of the phosphate group observed in the composite block before immersion in the solution, a band of the silanol group was observed, and it was observed that the silica hydrogel remained sufficiently and underwent a phase transition to a single phase apatite. Furthermore, with an increase in the concentration of the ammonium carbonate solution used in the treatment, a band of the carbonate group was observed in addition to the bands of the phosphate group and the silanol group. Therefore, when treated with a solution not containing carbonate, it was observed that it became hydroxyapatite, and when treated with a solution containing carbonate, it was observed that it became carbonate apatite, and it was found that the silica hydrogel and these apatites were composited.

[0103] 11 shows the results of the carbon dioxide content by CHN analysis of the composite block material obtained in Example 2. It was found that the carbon dioxide content of the block material increased with increasing concentration of the ammonium carbonate solution.

[0104] FIG. 12 shows an SEM photograph of the composite block obtained in Example 2. As in Example 1, it had a structure in which fine plate-like crystals were accumulated. No evidence of elution of a specific component of the composite block (silica-OCP composite block) before immersion in the solution was observed inside the composite block. In addition, it did not disintegrate even after immersion in water for 1 hour. In other words, it was found that the obtained composite block was a composite block that had hardened due to chemical bonding of the inorganic components, or entanglement or fusion of the crystals of the inorganic components.

[0105] [Example 3] Preparation of Ag-containing silica-OCP composite block A composite block was obtained in the same manner as in Example 1, except that a mixture of 2.16 mL of a sodium silicate solution with a concentration of 38 mass% and 2.16 mL of a silver nitrate aqueous solution with a concentration of 0 to 200 mmol / L was dropped and kneaded as the aqueous solution (B) to obtain a mixed mud. That is, the water-mix ratio was 2.16, and the silicate concentration in the aqueous solution (B) was 19 mass%. A white composite block was obtained under the condition that the concentration of the silver nitrate aqueous solution was less than 50 mmol / L. On the other hand, a yellowish-white composite block was obtained under the condition that the concentration of the silver nitrate aqueous solution was 50 mmol / L or more, and it changed to brown and black over time.

[0106] Figure 13 shows a photograph of the composite block obtained in Example 3. The composite block maintained the shape of the mold, and the volume of each was 80 mm. 3 The DTS strength of the composite block obtained in Example 3 was 0.2 MPa or more, and the composite block did not disintegrate when pinched with tweezers or immersed in water for 1 hour. In other words, it was found that the obtained composite block was a composite block hardened by chemical bonding of the inorganic components or by entanglement or fusion of the crystals of the inorganic components.

[0107] 14 shows the results of XRD analysis of the composite block obtained in Example 3. It was found that OCP was formed at all Ag concentrations.

[0108] Figure 15 shows the results of the antibacterial test of the composite block obtained in Example 3. In the composite block containing Ag, areas around which bacteria did not exist were clearly observed. On the other hand, in the composite block not containing Ag, the sample was clearly observed to be in contact with bacteria.

[0109] [Example 4] Preparation of quaternary ammonium salt-containing silica-OCP composite block Aqueous solution (B) was prepared by mixing 2.16 mL of a 38% by mass sodium silicate solution and 2.16 mL of a 0 to 200 mmol / L cetylpyridinium chloride (CPC) aqueous solution. A composite block was obtained in the same manner as in Example 1, except that the water-mix ratio was 2.16 and the silicate concentration in the aqueous solution (B) was 19% by mass.

[0110] Figure 16 shows a photograph of the composite block obtained in Example 4. The composite block maintained the shape of the mold, and the volume of each was 80 mm. 3 The DTS strength of the composite block obtained in Example 4 was 0.36±0.12 MPa or more, and the composite block did not disintegrate when pinched with tweezers or immersed in water for 1 hour. In other words, it was found that the obtained composite block was a composite block hardened by chemical bonding of the inorganic components or by entanglement or fusion of the inorganic component crystals.

[0111] FIG. 17 shows the results of XRD analysis of the composite block obtained in Example 4. It was found that OCP was formed even at CPC concentrations of 0.01 to 0.01.

[0112] Figure 18 shows the FT-IR analysis results of the composite block obtained in Example 4. In addition to the absorption band of the phosphate group, a band of the silanol group was observed in Figure 18. In other words, it was found that the composite block has a structure in which silica hydrogel and OCP are composited.

[0113] Figure 19 shows the results of the antibacterial test of the composite block obtained in Example 4. In the composite block containing CPC, areas around which bacteria did not exist were clearly observed. On the other hand, in the composite block not containing CPC, the sample was clearly observed to be in contact with bacteria.

[0114] [Example 5] Preparation of lanthanide-containing silica-OCP composite block A composite block was obtained in the same manner as in Example 1, except that a mixture of 2.16 mL of a 38 mass% sodium silicate solution and 2.16 mL of a 10 mmol / L or 100 mmol / L lanthanoid (La, Ce, Y, or Pr) nitrate aqueous solution was added dropwise as aqueous solution (B) to obtain a mixed mud. That is, the water-mix ratio was 2.16, and the silicate concentration in aqueous solution (B) was 19 mass%.

[0115] Figure 20 shows a photograph of the composite block obtained in Example 5. The composite block maintained the shape of the mold, and the volume of each was 80 mm. 3 The DTS strength of the composite block obtained in Example 5 was 0.1 MPa or more, and the composite block did not disintegrate when pinched with tweezers or immersed in water for 1 hour. In other words, it was found that the obtained composite block was a composite block hardened by chemical bonding of the inorganic components or by entanglement or fusion of the crystals of the inorganic components.

[0116] 21 shows the results of XRD analysis of the composite block obtained in Example 5. It was found that OCP was formed at all CPC concentrations.

[0117] [Example 6] Preparation of silica-OCP composite block manufactured by mixing calcium carbonate, phosphate and silicate A composite block was obtained in the same manner as in Example 1, except that 0.7 g of calcium carbonate was used as the ceramic (A) and a mixture of 2 mL of a 4 mol / L phosphoric acid aqueous solution and 1.08 mL of a 38 mass% sodium silicate solution was used as the aqueous solution (B). That is, the water-mix ratio was 4.40, and the silicate concentration in the aqueous solution (B) was 13 mass%. Since the calcium carbonate powder foamed during mixing, the mixture was left to stand for a sufficient period of time after mixing to degas it.

[0118] Figure 22 shows a photograph of the composite block obtained in Example 6. The composite block maintained the shape of the mold, and the volume of each was 80 mm. 3The DTS strength of the composite block obtained in Example 6 was 0.97±0.17 MPa, which was about three times the strength of Example 1 in which calcium phosphate was used as the ceramic (A). In addition, it did not crumble even when pinched with tweezers.

[0119] 23 shows the results of XRD analysis of the composite block obtained in Example 6. It was found that OCP was formed even when calcium carbonate was used as the ceramic (A).

[0120] FIG. 24 shows the results of FT-IR analysis of the composite block obtained in Example 6. From FIG. 24, in addition to the absorption band of the phosphate group, a band of the silanol group was observed. In other words, it was found that the composite block has a structure in which silica hydrogel and OCP are composited. I did.

[0121] Fig. 25 shows an SEM photograph of the composite block obtained in Example 6. It was found that the inside of the composite block had a structure in which plate-like crystals were densely assembled and some of them were fused together. In addition, it did not disintegrate even after being immersed in water for 1 hour. In other words, it was found that the obtained composite block was a composite block that had hardened due to chemical bonding of the inorganic components, or entanglement or fusion of the crystals of the inorganic components.

[0122] [Example 7] Preparation of dicarboxylic acid-containing silica-OCP composite block A composite block was obtained in the same manner as in Example 6, except that 1.2 g of calcium carbonate was used as the ceramic (A) and 0 to 0.6 g of thiomalic acid was further added and mixed. That is, the water-mix ratio was 2.57, and the silicate concentration in the aqueous solution (B) was 13 mass%.

[0123] Figure 26 shows a photograph of the composite block obtained in Example 7. The composite block maintained the shape of the mold, and the volume of each was 80 mm. 3The DTS strength of the composite block obtained in Example 7 was 0.1 MPa or more, and the DTS strength of the composite block obtained by adding 0.6 g of thiomalic acid was 1.23±0.31 MPa, which was slightly higher than that of the composite block obtained without adding thiomalic acid (Example 6). In addition, the composite block did not crumble even when pinched with tweezers.

[0124] Figure 27 shows the results of XRD analysis of the composite block obtained in Example 7. It was found that the composite block obtained by adding 0.6 g of thiomalic acid was a single OCP phase. It was also observed that the d(100) peak of the OCP shifted from 4.7° to 4.2° toward the lower angle side. This revealed that thiomalic acid was contained between the layers of the OCP.

[0125] Figure 28 shows the results of FT-IR analysis of the composite block product (0.6 g of thiomalic acid added) obtained in Example 7. In addition to the absorption band of the phosphate group, bands of the silanol group and the carboxyl group were observed in Figure 28. In other words, it was found that the composite block product has a structure in which silica hydrogel, OCP, and carboxylic acid are composited.

[0126] Fig. 29 shows an SEM photograph of the composite block obtained in Example 7. It was found that the inside of the composite block had a structure in which plate-like crystals were densely assembled and some of them were fused together. In addition, it did not disintegrate even after being immersed in water for 1 hour. In other words, it was found that the obtained composite block was a composite block that had hardened due to chemical bonding of the inorganic components, or entanglement or fusion of the crystals of the inorganic components.

[0127] [Example 8] Preparation of silica-tricalcium phosphate composite block The composite block obtained in Example 1 (using a sodium silicate solution with a concentration of 19% by mass) and the composite block obtained in Example 6 were placed on an alumina baking dish and heated in an electric furnace at a heating rate of 5°C / min up to 1000°C, and then fired at 1000°C for 12 hours.

[0128] Figure 30 shows a photograph of the composite block obtained in Example 8. All composite blocks maintained the shape of the mold but had shrunk slightly. The volume of each composite block was 60 mm 3 The DTS strength of the composite block obtained in Example 8 was 0.1 MPa or more, and the composite block did not disintegrate when pinched with tweezers or immersed in water for 1 hour. In other words, it was found that the obtained composite block was a composite block hardened by chemical bonding of the inorganic components or by entanglement or fusion of the crystals of the inorganic components.

[0129] 31 shows the results of XRD analysis of the composite block obtained in Example 8. It was found that the composite block obtained by firing was a mixed phase of tricalcium phosphate β phase and cristobalite.

[0130] [Example 9] Preparation of polyacrylic acid-containing silica-OCP composite block A composite block was obtained in the same manner as in Example 6, except that a mixture of 2 mL of 4 mol / L phosphoric acid aqueous solution, 1 mL of 1 to 50 g / L sodium polyacrylate (PAA-Na) solution, and 1.08 mL of 38 mass% sodium silicate solution was used as the aqueous solution (B). That is, the water-mix ratio was 5.83, and the silicate concentration in the aqueous solution (B) was 10 mass%. Since the calcium carbonate powder foamed during mixing, the mixture was left to stand for a sufficient period of time after mixing to degas it.

[0131] Figure 32 shows a photograph of the composite block obtained in Example 9. The composite block maintained the shape of the mold, and the volume of each was 80 mm. 3 That was all.

[0132] Figure 33 shows the results of measuring the DTS strength of the composite block obtained in Example 9. All composite blocks had a strength of 0.1 MPa or more, and did not disintegrate even when pinched with tweezers. Furthermore, the composite block obtained in Example 9 did not disintegrate even when immersed in water for 1 hour. In other words, it was found that the obtained composite block was a composite block that had hardened due to chemical bonding of the inorganic components, or entanglement or fusion of the crystals of the inorganic components.

[0133] Fig. 34 shows the results of XRD analysis of the composite block material obtained in Example 9. A clear peak was observed around 4.7° in each of the obtained composite blocks, indicating that the composite block material contained OCP.

[0134] [Comparative Example 1] Preparation of silica-supported OCP powder Following Example 1 of Patent Document 1, a silica-supported OCP powder was obtained as follows. 2.39 g of calcium hydrogen phosphate dihydrate (DCPD) powder was used as ceramic (A), and 20 mL of 1 mol / L sodium silicate solution was used as aqueous solution (B). Ceramic (A) and aqueous solution (B) were reacted in a centrifuge tube, and the sample after the reaction was washed several times with distilled water and then completely dried in a dryer at 40°C to obtain silica-supported OCP powder. In other words, the water-mix ratio was 8.37. 0.1 g of the obtained powder was placed in a φ8 mm stainless steel uniaxial pressure mold and formed into a block by applying a load of 100 MPa using a hydraulic press. The block was then placed in distilled water and allowed to stand at room temperature for 30 minutes.

[0135] 35 shows photographs of the silica-supported OCP powder and block obtained in Comparative Example 1, as well as the block before and after immersion in water. The silica-supported OCP powder produced by the method described in Patent Document 1 became a tablet-shaped block when pressed, but disintegrated when immersed in distilled water due to the water-mix ratio exceeding 6.00 under the production conditions.

Claims

1. A composite block body that cures by chemical bonding of inorganic components, or entanglement or fusion of inorganic component crystals, A calcium phosphate containing silicic acid in its crystal structure, having a volume of 2.0 mm ３ or more, a DTS strength of 0.1 MPa or more, and the calcium phosphate containing octacalcium phosphate, characterized by being a silica-calcium phosphate composite block body.

2. The composite block body according to claim 1, wherein the water-containing layer of octacalcium phosphate is substituted with silicic acid.

3. The composite block body according to claim 1, wherein the calcium phosphate contains carbonated apatite or hydroxyapatite.

4. The composite block body according to claim 1, wherein the calcium phosphate contains α-phase tricalcium phosphate or β-phase tricalcium phosphate.

5. The composite block body according to any one of claims 1-4, wherein the calcium phosphate further contains at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids.

6. The composite block body according to any one of claims 1-4, wherein the calcium phosphate further contains at least one selected from the group consisting of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids and their complexes, and quaternary ammonium salts.

7. The composite block body according to any one of claims 1-4, which is a porous body.

8. The composite block body according to claim 5, which is a porous body.

9. The composite block body according to claim 6, which is a porous body.

10. A method for producing a silica-calcium phosphate composite block body, A ceramic (A) containing calcium ions and / or phosphate ions, and an aqueous solution (B) having a silicate concentration of 10% by mass or more and further containing a composition that does not contain the ceramic (A) among calcium ions and phosphate ions. A mixed mud preparation step of mixing the two so that the weight ratio (water-mixing ratio) of the aqueous solution (B) to the ceramic (A) is 0.30 or more and 6.00 or less to obtain a mixed mud containing calcium phosphate containing silicic acid, A composite block body preparation step of reacting the mixed mud in a mold, Including, The calcium phosphate containing silicic acid obtained in the mixed mud preparation step contains calcium phosphate octacalcium containing silicic acid, A method for producing a silica-calcium phosphate composite block body, characterized in that the DTS strength of the silica-calcium phosphate composite block body is 0.1 MPa or more.

11. The production method according to claim 10, wherein the ceramic (A) is calcium phosphate.

12. The method for producing a silica-calcium phosphate composite block further includes a step of immersing the composite block obtained by the production method according to claim 10 in a solution containing carbonic acid, and phase-transitioning the calcium octasilicate phosphate into a calcium silicate carbonate apatite phase.

13. The method for producing a silica-calcium phosphate composite block further includes a step of immersing the composite block obtained by the production method according to claim 10 in a solution not containing carbonic acid, and phase-transitioning the calcium octasilicate phosphate into a calcium silicate hydroxyapatite phase.

14. In the step of preparing the mixed mud, at least one compound selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, quaternary ammonium salts, and dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids and their salts is further mixed, and the mixed mud containing the compound is prepared. The production method according to any one of claims 10 to 13.

15. The production method according to any one of claims 10 to 13, wherein the composite block is a porous body.

16. The production method according to claim 14, wherein the composite block is a porous body.

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