JP2024021585A - Silica-calcium phosphate composite block and method for producing silica-calcium phosphate composite block - Google Patents

Abstract

The present invention provides a silica-calcium phosphate composite block that has high strength, does not disintegrate in water, and exhibits superior bone production ability. [Solution] A composite block body that is hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components, includes calcium phosphate containing silicic acid in the crystal structure, and has a volume of 2 A silica-calcium phosphate composite block having a size of .0 mm3 or more and a DTS strength of 0.1 MPa or more. [Selection diagram] Figure 1

Description

The present invention relates to a silica-calcium phosphate composite block and a method for producing the silica-calcium phosphate composite block.

Octacalcium phosphate (Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) _{4.5H 2} O; OCP) has excellent biocompatibility and is composed of calcium and phosphate, which are widely present in living organisms. . Therefore, it is not only a main component of immature bone, but also an attractive material that can be used as the core of new biomaterials. In particular, its excellent bone replacement ability makes it useful as a bone substitute material (for example, Non-Patent Document 1).

The bone remodeling process, which is bone metabolism, controls the rate of bone replacement of bone substitutes. Osteocytes and immune cells play an essential and central role in the bone remodeling process. By controlling these cells, bone remodeling processes can be promoted and bone formation can be promoted (eg, Non-Patent Document 2).

Silicate ions are known to enhance osteoblast activity and increase bone production (Non-Patent Document 3, Non-Patent Document 4). As a commercial product, ORTHORE BIRTH Co., Ltd. sells a cotton-shaped artificial bone filling material called ReBOSSIS. This product is characterized by being cotton-shaped and containing β-TCP (β-tricalcium phosphate), a bioabsorbable polymer, and SiV (silicon-containing calcium carbonate), which promotes bone formation, as the main ingredients.

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

On the other hand, it is known that by using a silicate as an inorganic silica source, calcium phosphate crystals carrying silica can be easily produced (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 a silicate. Further, the silica-supported calcium phosphate crystal obtained in Patent Document 1 can be made into a powder composition, a block material, or a porous body by a conventional method.

J. Biomed. Mater. Res., 59, 29-34 (2002) BMC Med.,9, 66-75 (2011) Acta Biomater., 5, 57-62 (2008) Mater. Sci. Eng.: C, 42, 672-680 (2014) J. Mater. Chem. B, 2, 1250 (2014)

JP2022-080165

However, when silicic acid-containing calcium phosphate crystals are obtained in the form of a powder composition, there is a problem that the powder is easily scattered within the tissue, and furthermore, 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 porous material, there is room for improvement in the strength of the obtained block material or porous material, and furthermore, it is said that it is likely to disintegrate in the structure and turn into powder. There was an issue.

The present invention solves the above problems, and aims to provide a silica-calcium phosphate composite block that has high strength, does not disintegrate in water, and exhibits excellent bone production ability.

As a result of studies to solve the above problems, the present inventors found that ceramic (A) containing calcium and/or phosphoric acid, ceramic (A) containing silicate, and ceramic (A) containing calcium and/or phosphoric acid. Aqueous solution (B) containing a composition of The inventors have discovered that the above problems can be solved by obtaining a mixed mud containing calcium phosphate and reacting the mixed mud in a mold, and have completed the present invention.

That is, the present invention relates to the following [1] to [15].
[1] A composite block body that is hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components,
A silica-calcium phosphate composite block comprising calcium phosphate containing silicic acid in its crystal structure, having a volume of 2.0 mm ³ or more, and a DTS strength of 0.1 MPa or more.
[2] The composite block according to [1], wherein the calcium phosphate contains octacalcium phosphate.
[3] The composite block according to [2], wherein the water-containing layer of the octacalcium phosphate is replaced by 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], wherein the calcium phosphate contains a tricalcium phosphate α phase or a tricalcium phosphate β phase.
[6] 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. Composite block body described in.
[7] 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. , the composite block body according to any one of [1] to [6].
[8] The composite block body according to [1] to [7], which is a porous body.
[9] An aqueous solution (B) containing a ceramic (A) containing calcium and/or phosphoric acid, and a silicate concentration of 10% by mass or more, and further containing no ceramic (A) among calcium and phosphoric acid. ) in such a way 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 silicate-containing calcium phosphate. A mixed mud preparation process to obtain;
a composite block body 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, the method comprising:
[10] The manufacturing method according to [9], wherein the ceramic (A) is calcium phosphate.
[11] The production method according to [9] or [10], wherein the silicic acid-containing calcium phosphate obtained in the mixed mud preparation step contains silicic acid-containing octacalcium phosphate.
[12] The composite block obtained by the production method according to any one of [9] to [11] is further immersed in a solution containing carbonic acid, and the silicic acid-containing calcium phosphate is immersed in a solution containing carbonic acid. A method for producing a silica-calcium phosphate composite block, characterized by phase transition to a carbonate apatite phase.
[13] The composite block obtained by the production method according to any one of [9] to [11] is further immersed in a carbonic acid-free solution, and the silicic acid-containing calcium phosphate is immersed in a silicic acid-containing solution. A method for producing a silica-calcium phosphate composite block, characterized by phase transition to a hydroxyapatite phase.
[14] In the mixed mud preparation step, further from silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, quaternary ammonium salts, and dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids and their salts. The manufacturing method according to any one of [9] to [13], characterized in that a compound containing at least one selected from the group consisting of: is mixed to prepare a mixed mud containing the compound.
[15] The manufacturing method according to any one of [9] to [14], wherein the composite block body is a porous body.

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 exhibits excellent bone production ability.

It is a photograph of the composite block obtained in Example 1 (photograph substituted for a drawing). FIG. 3 is a diagram showing the results of XRD analysis of the composite block obtained in Example 1. 3 is a diagram showing the measurement results of DTS strength of the composite block obtained in Example 1. FIG. 3 is a diagram showing the results of FT-IR analysis of the composite block obtained in Example 1. FIG. This is a SEM photograph of the composite block obtained in Example 1 (using a sodium silicate solution with a concentration of 19% by mass) (a photograph substituted for a drawing). (A) OCP block that is not composited with silica, (B) carbonate apatite (CO ₃ Ap) block that is a bone replacement type bone prosthesis material, and (C) composite block obtained in Example 1. (Using a sodium silicate solution with a concentration of 19% by mass) is an HE staining image showing the results of an animal experiment. It is a photograph of the composite block obtained in Example 2 (photograph substituted for a drawing). 3 is a diagram showing the measurement results of DTS strength of the composite block obtained in Example 2. FIG. FIG. 3 is a diagram showing the results of XRD analysis of the composite block obtained in Example 2. 3 is a diagram showing the results of FT-IR analysis of the composite block obtained in Example 2. FIG. FIG. 3 is a diagram showing the carbonate content of the composite block obtained in Example 2. It is a SEM photograph of the composite block obtained in Example 2 (a photograph substituted for a drawing). It is a photograph of the composite block obtained in Example 3 (photograph substituted for a drawing). 3 is a diagram showing the results of XRD analysis of the composite block obtained in Example 3. FIG. It is a photograph showing the results of an antibacterial test of the composite block obtained in Example 3 (a photograph substituted for a drawing). It is a photograph of the composite block obtained in Example 4 (a photograph substituted for a drawing). FIG. 3 is a diagram showing the results of XRD analysis of the composite block obtained in Example 4. 3 is a diagram showing the results of FT-IR analysis of the composite block obtained in Example 4. FIG. It is a photograph showing the results of an antibacterial test of the composite block obtained in Example 4 (a photograph substituted for a drawing). It is a photograph of the composite block obtained in Example 5 (photograph substituted for a drawing). FIG. 7 is a diagram showing the results of XRD analysis of the composite block obtained in Example 5. It is a photograph of the composite block obtained in Example 6 (photograph substituted for a drawing). FIG. 7 is a diagram showing the results of XRD analysis of the composite block obtained in Example 6. FIG. 6 is a diagram showing the results of FT-IR analysis of the composite block obtained in Example 6. It is a SEM photograph of the composite block obtained in Example 6 (a photograph substituted for a drawing). It is a photograph of the composite block obtained in Example 7 (photograph substituted for a drawing). FIG. 7 is a diagram showing the results of XRD analysis of the composite block obtained in Example 7. FIG. 3 is a diagram showing the results of FT-IR analysis of the composite block obtained in Example 7 (added with 0.6 g of thiomalic acid). It is a SEM photograph of the composite block obtained in Example 7 (a photograph substituted for a drawing). It is a photograph of the composite block obtained in Example 8 (a photograph substituted for a drawing). FIG. 7 is a diagram showing the results of XRD analysis of the composite block obtained in Example 8. This is a photograph of the composite block obtained in Example 9 (photograph substituted for a drawing). FIG. 7 is a diagram showing the measurement results of DTS strength of the composite block obtained in Example 9. FIG. 7 is a diagram showing the results of XRD analysis of the composite block obtained in Example 9. These are photographs of the silica-supported OCP powder obtained in Comparative Example 1, the block body, and the block body before and after immersion in water (photographs substituted for drawings).

Unless otherwise specified, the expression "XX to YY" or "XX to YY" indicating a numerical range means a numerical range including the lower limit and upper limit, which are the endpoints. When numerical ranges are described in stages, the upper and lower limits of each numerical range can be combined arbitrarily.

[Silica-calcium phosphate composite block]
The silica-calcium phosphate composite block (hereinafter also simply referred to as "composite block"), which is an embodiment of the present invention, is hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components. A composite block body containing calcium phosphate containing silicic acid in its crystal structure, having a volume of 2.0 mm ³ or more, and a DTS strength of 0.1 MPa or more. Further, it is preferable to obtain a composite block by a method for producing a silica-calcium phosphate composite block described below.

Calcium phosphate (hereinafter also simply referred to as "calcium phosphate") contained in the composite block is, for example, octacalcium phosphate (Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) _{4.5H 2} O; OCP), hydroxyapatite ( HAp), carbonate apatite (CO ₃ Ap), tricalcium phosphate α phase (α-TCP), and tricalcium phosphate β phase (β-TCP).

When the calcium phosphate contains octacalcium phosphate, it is preferable that silicic acid replaces the water-containing layer of the octacalcium phosphate. Note that the composite block containing octacalcium phosphate can be obtained by adjusting the silicate concentration of the aqueous solution (B) used in the method for producing a silica-calcium phosphate composite block, as described below.

The composite block has a silicic acid content of preferably 10 atomic % or more, more preferably 1
The content is 2 atom % or more, more preferably 15 atom % or more, while preferably less than 50 atom %, more preferably 30 atom % or less, still more preferably 25 atom % or less. In addition, as for the stoichiometric composition of calcium phosphate, the ratio of Ca and PO ₄ in a single compound is more than 50 atomic %.

Calcium phosphate may contain an apatite phase. When calcium phosphate contains an apatite phase, calcium phosphate may contain carbonate apatite or hydroxyapatite. Conventional apatite is in powder form, but according to the present invention, apatite can be obtained as a composite block with silica.

A composite block containing carbonated apatite can be obtained by a method for producing a silica-calcium phosphate composite block, which includes a step of immersing the silica-calcium phosphate composite block in a solution containing carbonic acid, which will be described later.

A composite block containing hydroxyapatite can be obtained by a method for producing a silica-calcium phosphate composite block, which includes a step of immersing the silica-calcium phosphate composite block in a carbonate-free solution, which will be described later.

The calcium phosphate may include a tricalcium phosphate alpha phase or a tricalcium phosphate beta phase.
A composite block containing a tricalcium phosphate α phase or a 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, which will be described later. can.

Calcium phosphate may further contain, in its crystal structure, at least one member selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids. With conventional bone grafting materials, there have been 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 active elements, and lanthanoids have complex system performance with antibacterial molecules. Supporting the above elements leads to improvement in the function of the composite block as a bone replacement material.

The lanthanoids mentioned here include lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium, as well as yttrium and scandium, which have similar behavior as rare earth elements. , refers to hafnium.

When calcium phosphate further contains at least one member selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids in its crystal structure, silver, copper, gallium, and strontium in the composite block body. The lower limit of the total content of , magnesium, zinc, and lanthanoids 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, in the composite block body, the upper limit of the total content of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids is preferably 15 atom % or less, more preferably 10 atom % or less, and even more preferably 5 atoms. % or less.
When the total content of the above elements is within the above range, the function of the composite block as a bone grafting material can be further improved.

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 calcium phosphate further contains at least one selected from the group consisting of dicarboxylic acid, tricarboxylic acid, tetracarboxylic acid, polycarboxylic acid, and complexes thereof, dicarboxylic acid, tricarboxylic acid, tetracarboxylic acid, polycarboxylic acid is added to the water-containing layer. At least one member selected from the group consisting of and complexes thereof can be supported. Dicarboxylic acids include, for example, 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, pyridinedicarboxylic acid, etc. can be mentioned. Examples of tricarboxylic acids include citric acid, trimesic acid, isocitric acid, aconitic acid, and tricarballylic acid. Tetracarboxylic acids include ethylenediaminetetraacetic acid (EDTA), ethylenetetracarboxylic acid, 1,2,3,4-cyclobutanetetracarboxylic acid, pyromellitic acid, 4,4'-carbonyldiphthalic 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 Acid, 4,4'-oxydiphthalic acid, 4,4'-(hexafluoroisopropylidene)diphthalic acid, 4,4'-(4,4'-isopropylidene diphenoxy)diphthalic acid, dicyclohexyl-3,4,3 Examples include ',4'-tetracarboxylic acid. Examples of polycarboxylic acids include polyacrylic acid, polycitric acid, alginic acid, polymannuronic acid, and the like.
For example, thiomalic acid is a precursor of an anti-rheumatic drug, so when calcium phosphate contains thiomalic acid, the composite block used as a bone grafting material can be given a function as a precursor of an anti-rheumatic drug.

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

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 on the water-containing layer. Quaternary ammonium salts include, for example, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetylpyridinium chloride, cetrimonium, dophanium chloride, polydronium chloride, tetraethylammonium bromide, didecyldimethylammonium chloride, domiphene bromide, lecithin. , phosphatidylcholine, glycerophosphorylcholine, choline chloride, trimethylglycine, acetylcholine, edrophonium, ergothioneine, tetramethylammonium gold, safranin, betanin, pentolinium, miltefosine, meldonium, Janus green, and the like.
Since quaternary ammonium salts have antibacterial properties, when calcium phosphate contains a quaternary ammonium salt, antibacterial properties can be imparted to a composite block as a bone grafting material.

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, and more The content is preferably 0.1 atomic % or more, more preferably 0.5 atomic % or more. On the other hand, in the composite block, the upper limit of the quaternary ammonium salt content is preferably 10 atom % or less, more preferably 5 atom % or less, still more preferably 3 atom % 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 grafting material can be further improved.

Furthermore, a block body containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids, and further a group consisting of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and complexes thereof. A block body containing at least one selected from the following and a block body further containing a quaternary ammonium salt are further mixed with silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, Mixing a compound containing a quaternary ammonium salt and at least one selected from the group consisting of dicarboxylic acid, tricarboxylic acid, tetracarboxylic acid, polycarboxylic acid, and their salts to prepare a mixed mud containing the compound. It is preferable to obtain the silica-calcium phosphate composite block by a method for producing a silica-calcium phosphate composite block.

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 higher than the lower limit value, the material will not collapse even if it is forcefully pinched with tweezers, and therefore it can be easily transplanted into a bone defect in a living body. Furthermore, the block does not disintegrate within the tissue after transplantation and can exist stably. In addition, in the method for manufacturing 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, the DTS strength can be A composite block body having a pressure of .1 MPa or more can be obtained.

The shape of the composite block body depends on the shape of the mold used when filling the mixed mud, but since it has a certain strength, it is possible to process it into a specific shape. For example, it is possible to process it into a cube, rectangular parallelepiped, cylinder, cone, truncated cone, sphere, octahedron, tetrahedron, etc. 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, the volume can be reduced to 2 mm ³ The above composite block can be obtained.
The volume of the composite block body is not particularly limited as long as the volume is 2 mm ³ or more, but preferably 5 mm ³ or more, more preferably 10 mm ³ or more, still more preferably 30 mm ³ or more. When the volume of the composite block is greater than or equal to the above lower limit, the composite block is more likely to be immobilized within the tissue. Moreover, such a large-sized composite block can be manufactured by the method for manufacturing a silica-calcium phosphate composite block described later. On the other hand, if it exceeds 1000 mm ³ , there is a concern that the strength will decrease.

In the present invention, a composite block is defined as a structure in which crystals of an inorganic substance such as OCP, which is a constituent of an inorganic component, are chemically bonded to each other, or crystals are entangled or fused with each other, without intervening substances such as collagen. It refers to something that hardens and maintains its shape by fitting together. In addition, in the method for producing a 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, the chemical It is possible to obtain a hardened composite block by bonding or entanglement or fusion of crystals of inorganic components.

In the present invention, a chemical bond refers to the presence of one or more chemical bonds classified as covalent bonds, ionic bonds, chelate bonds, or hydrogen bonds between the crystals constituting the inorganic component.

In the present invention, the intertwining of crystals refers to a structure in which, microscopically, a plurality of crystals constituting a composite block are in contact with each other through crystal planes.

In the present invention, fusion of crystals means that there are parts where multiple crystals constituting a composite block are in contact with each other without gaps, such as crystal planes, and the grain boundaries are unclear in these parts. It means that it cannot be observed.

The above-mentioned entanglement between crystals and fusion between crystals can be easily determined by observing the fine structure of the composite block. For example, a scanning electron microscope (SEM) is used to observe the fine structure. At this time, in order to ensure the conductivity of the sample, the sample may be pretreated with osmium (Os), carbon (C), etc. by a method used in normal SEM observation using an ion sputtering device, and then observed. .

A composite block that is hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components maintains its shape without disintegrating even when immersed in water for at least one hour. This is because the bonding force between the crystals is stronger than the surface tension and will not collapse even if water or the like enters the gap due to the bonding between the crystals. Therefore, a calcium phosphate green compact formed by compacting calcium phosphate powder is not included in this category because it is not expected that the particles constituting the powder will be bonded to each other.

In addition, "maintains its shape without disintegrating even after being immersed in water for 1 hour" means that the composite block maintains its shape clearly even after being immersed in distilled water for 1 hour, and it is not necessary to pick it up with tweezers. It means that the composite block can be taken out, and that the mass loss of the composite block after being picked up with tweezers and dried is 20% by mass or less relative to the mass before immersion.
Since the composite block does not disintegrate even when immersed in water for one hour, the block does not disintegrate within the tissue after implantation and can stably exist.

Crystallographic information on calcium phosphate crystals can be obtained according to conventional methods, for example, by X-ray diffraction (XRD). An example of the device is MiniFlex600 (Rigaku Co., Ltd., Japan). Note that crystals refer to particles that have a clear diffraction peak in the XRD pattern of a powder sample and exhibit a unique external shape due to the crystal structure when grown in free space that does not inhibit crystal growth.

The element content in the crystal can be evaluated according to a conventional method using, for example, X-ray fluorescence analysis (XRF). Examples of the device include SEA2210 (Seiko Instruments Technology Co., Ltd., Japan).

The chemical vibrational scheme of a crystal can be evaluated according to a conventional method, for example, by Fourier transform infrared spectroscopy (FT-IR). Examples of the device include Nicolet NEXUS670 (Thermo Fisher Scientific, Inc., USA).

The crystal microstructure can be evaluated using, for example, a field emission scanning electron microscope (FE-SEM) according to a conventional method. Examples of the device include 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.

The composite block body may be a porous body. The shape of the pores of the porous body is not particularly limited. Usually, a continuous porous body, an isolated porous body, a honeycomb structure, etc. are mentioned.
Moreover, the porosity is not particularly limited. Preferably it is 30% or more, more preferably 50% or more, 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 even more preferably 200 μm or more and 500 μm or less.

[Method for manufacturing silica-calcium phosphate composite block]
A method for manufacturing a silica-calcium phosphate composite block (hereinafter also simply referred to as a "method for manufacturing a composite block"), which is an embodiment of the present invention, uses ceramic (A) containing calcium and/or phosphoric acid, An aqueous solution (B) having a salt concentration of 10% by mass or more and containing a composition that does not contain ceramic (A) among calcium and phosphoric acid is added to the aqueous solution (B) in a weight ratio of the aqueous solution (B) to the ceramic (A) ( A mixed mud preparation step for obtaining a mixed mud containing silicic acid-containing calcium phosphate by mixing the mud so that the mixing ratio (mixed water ratio) is 0.30 or more and 6.00 or less, and a composite block preparation step in which the mixed mud is reacted in a mold. including the manufacturing process.

The composite block body is preferably manufactured by the method for manufacturing a composite block body of this embodiment. Each step in the method for manufacturing a composite block body will be described below.

(Mixed mud preparation process)
The mixed mud preparation step is a step of obtaining a mixed mud containing silicate-containing calcium phosphate. The weight ratio of the aqueous solution (B) to the ceramic (A) (mixed water (ratio) is 0.30 or more and 6.00 or less.

The ceramic (A) containing calcium and/or phosphoric acid (hereinafter also simply referred to as "ceramic (A)") used in the mixed mud preparation process may be a ceramic containing calcium and phosphoric acid, and may be a ceramic containing calcium and/or phosphoric acid. It may be a ceramic that contains phosphoric acid and does not contain phosphoric acid, or a ceramic that contains phosphoric acid and does not contain calcium.

The ceramic containing calcium and phosphoric acid is calcium phosphate, such as calcium hydrogen phosphate dihydrate (DCPD), calcium hydrogen phosphate anhydrate, calcium dihydrogen phosphate hydrate (MCPM), dihydrogen phosphate Calcium hydrogen anhydrate, tricalcium phosphate α phase, or tricalcium phosphate β phase, tetracalcium phosphate (TTCP), amorphous calcium phosphate (ACP), hydroxyapatite, carbonate apatite, sodium-substituted hydroxyapatite, etc. Can be used. These may be used alone or in combination in any ratio.

For ceramics containing calcium but not phosphoric acid, calcium inorganic salts or calcium organic salts can be used. 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, and calcium sulfate dihydrate. Calcium oxalate anhydrate, calcium oxalate monohydrate, calcium oxalate dihydrate, calcium oxalate trihydrate, calcium sulfite, calcium silicate, calcium pyrophosphate, calcium tungstate, molybdate Calcium etc. can be used. As the calcium organic salt, for example, calcium acetate, calcium succinate, calcium citrate, calcium malate, calcium thiomalate, calcium benzoate, calcium lactate, calcium stearate, etc. can be used. These may be used alone or in combination in any ratio.

Ceramics containing phosphoric acid but not calcium include, for example, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, phosphoric acid Ammonium dihydrogen, diammonium hydrogen phosphate, triammonium phosphate, ammonium magnesium phosphate, magnesium phosphate, etc. can be used. These may be used alone or in combination in any ratio.

An aqueous solution (B) (hereinafter simply referred to as an "aqueous solution ( B)") may be an aqueous solution containing only silicate, as long as it is mixed with ceramic (A) to obtain a mixed mud containing silicate-containing calcium phosphate, or an aqueous solution containing silicate and calcium. It may be an aqueous solution or an aqueous solution containing silicate and phosphoric acid.

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

When the ceramic (A) is a ceramic containing calcium and not containing phosphoric acid, the aqueous solution (B) is an aqueous solution containing silicate and phosphoric acid.
When the ceramic (A) is a ceramic containing phosphoric acid and no calcium, the aqueous solution (B) is an aqueous solution containing silicate and calcium.

The aqueous solution (B) is selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, lanthanoids, quaternary ammonium salts, as well as dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and salts thereof, as described below. It may be an aqueous solution further containing a compound containing at least one selected species.

As the silicate used in the aqueous solution (B), for example, water glass (Na ₂ SiO ₃ ), potassium silicate, cesium silicate, ammonium hexafluorosilicate, etc. can be used. Among these, water glass is preferable because its countercation, sodium ion, induces the formation of octacalcium phosphate. Further, a compound other than the silicate solution to be supported on the block may be added. In that case, it is necessary to uniformly disperse it in a solution or colloidal particle state.

As the calcium used in the aqueous solution (B), for example, the compounds listed above as "ceramic containing calcium but not containing phosphoric acid" can be used.
As the phosphoric acid used in the aqueous solution (B), for example, phosphoric acid (H ₃ PO ₄ ), the compound mentioned above as "ceramic containing phosphoric acid and not containing calcium", etc. can be used.

The concentration of silicate in the aqueous solution (B) is not particularly limited as long as it is 10% by mass or more. Usually, the content is 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.

Note that by setting the silicate concentration of the aqueous solution (B) to 18 to 23% by mass, a composite block having a single phase of octacalcium phosphate (OCP) can be obtained.

In the mixed mud preparation step, the ceramic (A) and the aqueous solution (B) are mixed to form a mixed mud. Although there are no particular restrictions on the mixing method, for example, the aqueous solution (B) may be added dropwise to the powder of the ceramic (A) and mixed sufficiently using a spatula or the like to form a mixed mud. When silicate comes into contact with phosphoric acid, it immediately hydrolyzes to form a silica hydrogel, but by further kneading, a complex consisting of silica and calcium phosphate can be formed. Also, it may foam violently during mixing and partially harden, but until the foaming reaction subsides,
It is preferable to continue mixing.

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, preferably 0.50 or more and 5.00 or less, and more preferably 1.00. 3.00 or less.

When the weight ratio (mixed water ratio) of the aqueous solution (B) to the ceramic (A) is within the above range, the ceramic concentration in the mixed mud will be high, making it possible to firmly entangle calcium phosphate crystals and inorganic components. A composite block body that is hardened by chemical bonding or entanglement or fusion of crystals of inorganic components, and has a volume of 2.0 mm ³ or more and a DTS strength of 0.1 MPa or more. Block bodies can be manufactured. In addition, when the water mixing ratio is within the above range, the mixed mud has appropriate viscosity, so it is possible to produce a silica-calcium phosphate composite block that maintains the shape of the mold.
On the other hand, the silica-supported calcium phosphate crystals disclosed in the Examples of Patent Document 1 are manufactured by setting the weight ratio (water mixing ratio) of the aqueous solution containing the silicate to the ceramic to be more than 6.00. Due to the high water mixing ratio, the silica-supported calcium phosphate crystals of Patent Document 1 have room for improvement in strength and are obtained in the form of powder, block material, or porous material that easily disintegrates in water.

The silicic acid-containing calcium phosphate obtained in the mixed mud preparation process is, for example, octacalcium phosphate (Ca ₈ (HPO ₄ ) ₂ (PO ₄ ) _{4.5H 2} O; OCP), hydroxyapatite (HAp), carbonate apatite ( CO ₃ Ap), tricalcium phosphate α phase (α-TCP), and tricalcium phosphate β phase (β-TCP).

In the mixed mud preparation process, further 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. A mixed mud containing the compound may be prepared by mixing a compound containing at least one of the above compounds. 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 as a powder with the ceramic (A) and the aqueous solution (B).

Contains at least one member 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. The compound is not particularly limited.
For example, compounds containing at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids include nitrates, fluorides, chlorides, bromides, iodides, sulfates, Carbonates, chromates, acetates, etc. can be used. As the quaternary ammonium salt, the above quaternary ammonium salts and the like can be used. As the compound containing at least one selected from the group consisting of dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, polycarboxylic acids, and salts thereof, the above dicarboxylic acids and their complexes can be used. These may be used alone or in combination in any ratio.

Ceramic (A), 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. The mixing ratio of the compound containing at least one type of ceramic (A) is not particularly limited, but the amount of the compound added can be 0.1 mmol or more and 1 mol or less with respect to 1 g of ceramic (A).

(Composite block preparation process)
In the composite block body preparation step, the mixed mud obtained in the mixed mud preparation step is reacted in a mold. In the method for manufacturing a composite block body of the present embodiment, in the composite block body preparation step (step in which calcium ions and phosphate ions react), a mixture with a water mixing ratio within a specific range is prepared in a mold. By reacting the mud, calcium phosphate crystals containing silica are precipitated, and the crystals intertwine in a complex manner, making it possible to obtain a block with high strength that maintains the shape of the mold and does not disintegrate in water. The mold used is not particularly limited, but for example, a silicon mold can be used.

The reaction temperature and reaction time may be set appropriately, and the reaction temperature is preferably 5 to 95°C, more preferably 15 to 80°C. The reaction time can be preferably 2 to 120 hours, more preferably 6 to 96 hours. Note that the reaction is preferably carried out in a sealed state. Carrying out the reaction in a sealed state means filling the mixed mud into a mold and covering it with a lid to allow the reaction to proceed while avoiding contact between the mixed mud and outside air, but there is no air inside the mold. may be included. When the reaction is carried out in a sealed state, an appropriate load may be applied to the mixed mud. By conducting the reaction in a sealed state, it is possible to prevent factors that inhibit the progress of the reaction, such as drying of the mixed mud, and the precipitated calcium phosphate crystals are tightly intertwined with each other, resulting in a stronger composite block. is obtained.

After the reaction, it may be dried using a dryer or the like. Further, if unreacted components remain after taking out, it is preferable to wash and remove them using distilled water or the like.

(Phase transition to apatite phase)
The method for producing a composite block may further include the step of immersing the composite block obtained in the composite block preparation step in a solution containing carbonic acid or a solution not containing carbonic acid. By immersing the composite block in a solution containing carbonic acid, the silicic acid-containing calcium phosphate metastable phase can be phase-transformed into the silicic acid-containing carbonate apatite phase. Furthermore, by immersing the composite block in a solution that does not contain carbonic acid, the silicic acid-containing calcium phosphate metastable phase can be phase-transformed to the silicic acid-containing hydroxyapatite phase.

When the composite block is immersed in a carbonic acid-containing solution or a carbonic acid-free solution to cause a phase transition to a silicic acid-containing carbonated apatite phase or a silicic acid-containing hydroxyapatite phase, the reaction mechanism, especially the From the viewpoint of adjusting the carbonate content, the silicic acid-containing calcium phosphate is preferably a silicic acid-containing octacalcium phosphate.

Examples of the carbonic acid source in a solution containing carbonic acid include carbon dioxide gas, ammonium carbonate, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, lithium carbonate, and the like. These may be used alone or in combination. The concentration of carbonic acid in the solution containing carbonic acid 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 It is 0.1 mol/L or more and 3 mol/L or less.

The temperature and time when immersing the composite block in a solution containing carbonate or a solution not containing carbonate may be set as appropriate, and the immersion temperature is preferably 25 to 99°C, more preferably 37 to 95°C, More preferably, the temperature can be set to 50 to 90°C. The immersion time is preferably 30 minutes or more and 14 days or less, more preferably 1 hour or more and 10 days or less, and still more preferably 2 hours or more and 7 days or less.

The pH during immersion is not particularly limited, but is preferably 6.0 or higher, more preferably 7.0 or higher, and even more preferably 8.0 or higher. It is common to add an aqueous sodium hydroxide solution, hydrochloric acid, etc. to the solution for pH adjustment.

After dipping, it may be dried using a dryer or the like. Further, after taking out, it may be washed using distilled water or the like.

(Firing of composite block body)
The method for manufacturing a composite block body may further include a step of firing the composite block body obtained in the composite block body preparation step. By firing the composite block, a composite block containing a tricalcium phosphate α phase or a tricalcium phosphate β phase can be manufactured.

When producing a composite block containing tricalcium phosphate α phase, the firing temperature needs to be 1180° C. or higher, which is the β-α transition temperature. The temperature is preferably 1200 to 1700°C, more preferably 1400 to 1600°C. The firing time can be preferably 2 to 72 hours, more preferably 5 to 24 hours.
When manufacturing a composite block body containing tricalcium phosphate β phase, the firing temperature needs to be 1180° C. or lower. The temperature is preferably 800 to 1180°C, more preferably 900 to 1150°C. The firing time can be preferably 2 to 96 hours, more preferably 6 to 48 hours.

The composite block obtained by the method for manufacturing a composite block may be a porous body. The shape of the pores of the porous body is not particularly limited. Usually, a continuous porous body, an isolated porous body, a honeycomb structure, etc. are mentioned.
Moreover, the porosity is not particularly limited. Preferably it is 30% or more, more preferably 50% or more, 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 even more preferably 200 μm or more and 500 μm or less.

The following will explain based on examples. Note that this embodiment is just an example, and the present invention is not limited to these examples in any way. That is, the present invention is limited only by the scope of the claims, and includes various modifications other than the embodiments included in the present invention.

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

[X-ray diffraction analysis]
XRD analysis of the composite block was performed using an X-ray diffraction analyzer (MiniFlex600, Rigaku Co., Ltd., Japan, target: Cu, wavelength: 0.15406 nm). The XRD measurement conditions were an accelerating voltage and an amplitude of 40 kV and 15 mA, respectively, and for characteristic evaluation, the diffraction angle was continuously scanned at a 2θ value from 3° to 70° at an operating speed of 2°/min.

[FT-IR analysis]
Triglycine sulfate detector with attenuated total internal reflection prism made of GeSe (32 scans, resolution 2 cm ⁻¹ ) by Fourier transform infrared spectroscopy (FT-IR: Nicolet NEXUS670, Thermo Fisher Scientific Co., USA) The characteristics of the chemical vibrational scheme of the composite block were evaluated using The atmosphere was considered as the background to perform the measurements.

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

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

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

[Animal experimentation]
Prior to the experiment, approval was obtained from the Ethics Committee of the National Institute of Advanced Industrial Science and Technology and the Okayama University of Science (Approval number: D2021-0356 (National Institute of Advanced Industrial Science and Technology), 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.
An 18-week-old male Japanese white rabbit purchased from Japan SLC Co., Ltd. was used. After losing consciousness by inhaling 2% isoflurane, 4 mL of a ketamine-Seractal mixed anesthetic solution was injected intramuscularly into the buttocks to place them under deep anesthesia. Respiration, pulse, body temperature, and oxygen concentration were monitored to confirm that the animal was under deep anesthesia. Both knees were shaved, and the affected area was sterilized alternately three times with povidone-iodine and Hibiscrub solution.
After confirming that the drug solution had been sufficiently applied to the incision, the skin and muscles of the knee were incised with a scalpel, and the distal end of the femur was expanded. A bone defect with a diameter of 6 mm and a thickness of 3 mm was created on the medial side of the distal end of the femur using a trephine bar. Here, as a composite block or a reference sample, reconstruction was performed using an OCP block that was not composited with silica or a carbonate apatite (CO ₃ Ap) block that is a bone replacement type bone grafting material. The embedded blocks were all cylindrical dense samples with a diameter of 6 mm and a thickness of 3 mm. After reconstructing the bone defect, the muscles and skin were sutured, and after confirming that the animal had woken up from anesthesia, it was returned to the cage and reared normally. Note that no measures were taken to add load or the like.
After one month of normal rearing, and after confirming that there were no signs of inflammation or tumor formation at the implanted site, the rabbits were euthanized by excessive administration of anesthetic into the ear vein. Immediately, the implanted part of the block was removed together with the surrounding tissue and fixed in a neutral buffered formalin solution. Thereafter, pathological specimens were prepared according to customary procedures.

[Antibacterial test]
Prior to the experiment, approval was obtained from the Ethics Committee of the National Institute of Advanced Industrial Science and Technology (AIST) (approval number: Micro2019-0110 (National Institute of Advanced Industrial Science and Technology)). 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 thoroughly washed aseptically with PBS before use. The composite block was placed on an agar medium and then placed in a constant temperature bath at 37° C. for 1 day.

[Example 1] Preparation of silica-OCP composite block 1 g of calcium hydrogen phosphate dihydrate (DCPD) and 1 g of calcium dihydrogen phosphate hydrate (MCPM) were used as the ceramic (A). The mixture was thoroughly ground and mixed in a mortar to obtain a uniform mixed powder. To 2 g of this mixed powder, 4.32 mL of a sodium silicate solution having a concentration of 0 to 38% by mass was added dropwise as an aqueous solution (B) and mixed. That is, the weight ratio (mixed water ratio) of the aqueous solution (B) to the ceramic (A) was 2.16. The aqueous solution (B), which is a sodium silicate solution, was immediately hydrolyzed into a silica hydrogel by contacting with MCPM and DCPD. By continuously kneading this, a complex consisting of silica hydrogel and calcium phosphate was formed. Further, mixing was continued to induce the formation of silica hydrogel by a hydrolysis reaction upon contact with calcium phosphate, and the whole was made into a uniform mixed mud.

The obtained mixed mud was filled into a silicone mold with a diameter of 6 mm and a thickness of 3 mm, and the mold was cured at 60° C. for 1 day in a sealed state. After curing, the mixed mud was dried at 40° C. for 12 hours or more and then taken out from the mold. Thereafter, it was thoroughly washed with distilled water to remove remaining unreacted components, and then dried again at 40° C. for 24 hours or more.

FIG. 1 shows a photograph of the composite block obtained in Example 1. From FIG. 1, it can be seen that the composite block maintains the shape of the mold when the silicate aqueous solution is used. Moreover, the volumes of the composite blocks obtained using the sodium silicate solution were all 80 mm ³ or more.

FIG. 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% by mass was used, the crystal phase of the composite block was a single phase of octacalcium phosphate (OCP). In addition, when we verified by changing the concentration of the sodium silicate solution during mixing, we found that when a 18 to 23 mass% sodium silicate solution was used, the crystal phase of the composite block became an OCP single phase. Ta.

FIG. 3 shows the measurement results of the DTS strength of the composite block obtained in Example 1. The DTS strength of the composite blocks obtained using a sodium silicate solution with a silicate concentration of 15% by mass or more was 0.1 MPa or more, and did not disintegrate even when pinched with tweezers etc. .

FIG. 4 shows the results of FT-IR analysis of the composite block obtained in Example 1 (using a sodium silicate solution with a concentration of 19% by mass). From FIG. 4, in addition to the phosphoric acid group absorption band, a silanol group band was observed, indicating that the silica hydrogel was sufficiently formed. That is, it was found that the composite block had a structure in which silica hydrogel and OCP were combined.

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. Moreover, it did not disintegrate even after being immersed in water for 1 hour. That is, it was found that the composite block obtained using the sodium silicate solution was hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components.

FIG. 6 shows (A) an OCP block that is not composited with silica, (B) a carbonate apatite (CO ₃ Ap) block that is a bone replacement type bone grafting material, and (C) a block of OCP obtained in Example 1. The figure shows an HE (hematoxylin and eosin) stained image showing the results of an animal experiment using a composite block (using a sodium silicate solution with a concentration of 19% by mass). In addition, all the samples used block bodies with a diameter of 6 mm and a thickness of 3 mm. Details of the preparation methods for (A) an OCP block that is not composited with silica and (B) a carbonate apatite (CO ₃ Ap) block that is a bone replacement type bone grafting material 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

(C) When the composite block obtained in Example 1 was implanted, no findings of inflammation or tumor were observed in the surrounding tissue. Further, the composite block obtained in Example 1 showed a remarkable decrease in size after implantation, and furthermore, very active bone formation was observed in the area around implantation. Approximately 30% of the volume of the composite block was absorbed. This indicates that the composite block body is absorbed into the living body through the bone remodeling process, and bone new generation is actively occurring.
On the other hand, (A) an OCP block that is not composited with silica, and (B) a carbonate apatite (CO ₃ Ap) block that is a bone replacement type bone grafting material, there is almost no change in shape after implantation. It was observed that it was directly connected to bone tissue in the peripheral area. That is, it was found that the composite block obtained in Example 1 exhibited excellent properties by being composited with silica.

[Example 2] Preparation of silica-apatite composite block 10 composite blocks obtained in Example 1 (using a sodium silicate solution with a concentration of 19% by mass) were placed in a 50 mL centrifuge tube at a concentration of 0 to 0. It was immersed in a 2 mol/L ammonium carbonate solution, sealed, and reacted for 3 days in a constant temperature bath at 80°C. The composite block did not disintegrate and maintained its shape even when immersed in the solution.
After the reaction, the composite block was washed multiple times with distilled water to remove the solution that had penetrated inside, and then allowed to stand in a constant temperature bath at 80° C. for 12 hours or more to dry.

FIG. 7 shows a photograph of the composite block obtained in Example 2. From FIG. 7, it was found that the composite block body after being immersed in the solution maintained its shape before being immersed. Moreover, the volumes of the obtained composite blocks were all 80 mm ³ or more.

FIG. 8 shows the measurement results of the DTS strength of the composite block obtained in Example 2. The DTS strength of the composite block body tended to decrease as the concentration of the ammonium carbonate solution used for treatment increased, but even the composite block body treated with the highest concentration remained over 0.1 MPa, even when picked with tweezers. It was enough not to collapse.

FIG. 9 shows the results of XRD analysis of the composite block obtained in Example 2. It was found that all of the obtained composite blocks had a single phase of apatite.

FIG. 10 shows the results of FT-IR analysis of the composite block obtained in Example 2. From Figure 10, in addition to the phosphate group absorption band observed in the composite block before immersion in the solution, a silanol group band is observed, indicating that the silica hydrogel remains sufficiently and undergoes a phase transition to an apatite single phase. The situation was observed. Furthermore, as the concentration of the ammonium carbonate solution used for the treatment increased, a band of carbonate groups was observed in addition to bands of phosphoric acid groups and silanol groups. Therefore, when treated with a solution that does not contain carbonate, hydroxyapatite is observed, and when treated with a solution containing carbonate, carbonate apatite is observed, indicating that silica hydrogel and these apatites are composited. It turns out that it has become.

FIG. 11 shows the results of carbon dioxide content of the composite block obtained in Example 2 by CHN analysis. It was found that the carbonate content of the blocks increased as the concentration of ammonium carbonate solution increased.

FIG. 12 shows a SEM photograph of the composite block obtained in Example 2. Similar to Example 1, it had a structure in which fine plate-like crystals were accumulated. No finding was observed inside the composite block that a specific component of the composite block (silica-OCP composite block) before being immersed in the solution was eluted. Moreover, it did not disintegrate even after being immersed in water for 1 hour. That is, it was found that the obtained composite block was hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components.

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

FIG. 13 shows a photograph of the composite block obtained in Example 3. The composite blocks maintained the shape of the mold, and each had a volume of 80 mm ³ or more. Note that the DTS strength of the composite blocks obtained in Example 3 was all 0.2 MPa or more, and did not disintegrate even when pinched with tweezers, and did not disintegrate even after being immersed in water for 1 hour. That is, it was found that the obtained composite block was hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components.

FIG. 14 shows the results of XRD analysis of the composite block obtained in Example 3. It was found that OCP was formed at any Ag concentration.

FIG. 15 shows the results of the antibacterial test of the composite block obtained in Example 3. In the Ag-containing composite block, areas around which no bacteria were present were clearly observed. On the other hand, in the case of the Ag-free composite block, clear contact between the sample and bacteria was observed.

[Example 4] Preparation of silica-OCP composite block containing quaternary ammonium salt As the aqueous solution (B), 2.16 mL of a sodium silicate solution with a concentration of 38% by mass and cetylpyridinium chloride (CPC) with a concentration of 0 to 200 mmol/L were added. ) A composite block was obtained in the same manner as in Example 1, except that a mixture of 2.16 mL of an aqueous solution was dropped and kneaded to obtain a mixed mud. That is, the water mixing ratio is 2.16, and the silicate concentration in the aqueous solution (B) is 19% by mass.

FIG. 16 shows a photograph of the composite block obtained in Example 4. The composite blocks maintained the shape of the mold, and each had a volume of 80 mm ³ or more. In addition, the DTS strength of the composite blocks obtained in Example 4 was all 0.36 ± 0.12 MPa or more, and did not disintegrate even when pinched with tweezers, and did not disintegrate even when immersed in water for 1 hour. Ta. That is, it was found that the obtained composite block was hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components.

FIG. 17 shows the results of XRD analysis of the composite block obtained in Example 4. It was found that OCP was formed at any CPC concentration.

FIG. 18 shows the results of FT-IR analysis of the composite block obtained in Example 4. From FIG. 18, in addition to the phosphoric acid group absorption band, a silanol group band was observed. That is, it was found that the composite block had a structure in which silica hydrogel and OCP were combined.

FIG. 19 shows the results of the antibacterial test of the composite block obtained in Example 4. In the composite blocks containing CPC, areas where bacteria were not present were clearly observed. On the other hand, in the composite block containing no CPC, clear contact between the sample and bacteria was observed.

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

FIG. 20 shows a photograph of the composite block obtained in Example 5. The composite blocks maintained the shape of the mold, and each had a volume of 80 mm ³ or more. Note that the DTS strength of the composite blocks obtained in Example 5 was all 0.1 MPa or more, and did not disintegrate even when pinched with tweezers, and did not disintegrate even after being immersed in water for 1 hour. That is, it was found that the obtained composite block was hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components.

FIG. 21 shows the results of XRD analysis of the composite block obtained in Example 5. It was found that OCP was formed at any CPC concentration.

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

FIG. 22 shows a photograph of the composite block obtained in Example 6. The composite blocks maintained the shape of the mold, and each had a volume of 80 mm ³ or more. The 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). Moreover, it did not disintegrate even when picked with tweezers.

FIG. 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).

FIG. 24 shows the results of FT-IR analysis of the composite block obtained in Example 6. From FIG. 24, in addition to the phosphoric acid group absorption band, a silanol group band was observed. That is, it was found that the composite block had a structure in which silica hydrogel and OCP were combined.

FIG. 25 shows a 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-shaped crystals were densely aggregated, and some of them were fused. Further, it did not disintegrate even after being immersed in water for 1 hour. That is, it was found that the obtained composite block was hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components.

[Example 7] Preparation of dicarboxylic acid-containing silica-OCP composite block Example 1 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. A composite block body was obtained in the same manner as in 6. That is, the water mixing ratio is 2.57, and the silicate concentration in the aqueous solution (B) is 13% by mass.

FIG. 26 shows a photograph of the composite block obtained in Example 7. The composite blocks maintained the shape of the mold, and each had a volume of 80 mm ³ or more. The DTS strength of the composite blocks obtained in Example 7 was all 0.1 MPa or more, and the DTS strength of the composite blocks obtained by further adding 0.6 g of thiomalic acid was 1.23 ± 0. .31 MPa, which was slightly higher than when thiomalic acid was not added (Example 6). Moreover, it did not disintegrate even when picked with tweezers.

FIG. 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 had a single OCP phase. Furthermore, it was observed that the d(100) peak of OCP was shifted from 4.7° to 4.2° to the lower angle side. This revealed that thiomalic acid was contained between the OCP layers.

FIG. 28 shows the results of FT-IR analysis of the composite block obtained in Example 7 (added with 0.6 g of thiomalic acid). From FIG. 28, in addition to the absorption band of phosphoric acid groups, bands of silanol groups and carboxyl groups were observed. That is, it was found that the composite block had a structure in which silica hydrogel, OCP, and carboxylic acid were combined.

FIG. 29 shows a 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-shaped crystals were densely aggregated, and some of them were fused. Further, it did not disintegrate even after being immersed in water for 1 hour. That is, it was found that the obtained composite block was hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components.

[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 was placed on an alumina baking dish, heated to 1000°C at a temperature increase rate of 5°C/min in an electric furnace, and baked at 1000°C for 12 hours.

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

FIG. 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 had a mixed phase of tricalcium phosphate β phase and cristobalite.

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

FIG. 32 shows a photograph of the composite block obtained in Example 9. The composite blocks maintained the shape of the mold, and each had a volume of 80 mm ³ or more.

FIG. 33 shows the measurement results of the DTS strength of the composite block obtained in Example 9. All of the composite blocks had a pressure of 0.1 MPa or more, and did not disintegrate even when pinched with tweezers. Further, the composite block obtained in Example 9 did not disintegrate even after being immersed in water for 1 hour. That is, it was found that the obtained composite block was hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components.

FIG. 34 shows the results of XRD analysis of the composite block obtained in Example 9. In each of the obtained composite blocks, a clear peak was observed around 4.7°, indicating that the composite blocks contained OCP.

[Comparative Example 1] Preparation of silica-supported OCP powder Following Example 1 of Patent Document 1, silica-supported OCP powder was obtained as follows.
2.39 g of calcium hydrogen phosphate dihydrate (DCPD) powder was used as the ceramic (A), and 20 mL of a 1 mol/L sodium silicate solution was used as the aqueous solution (B). The ceramic (A) and the 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 form the silica-supported OCP powder. Obtained. That is, the water mixing ratio is 8.37.
0.1 g of the obtained powder was placed in a stainless steel uniaxial pressure mold with a diameter of 8 mm, and a block was formed by applying a load of 100 MPa using a hydraulic press.The block was then placed in distilled water and allowed to stand still for 30 minutes at room temperature. I placed it.

FIG. 35 shows photographs of the silica-supported OCP powder obtained in Comparative Example 1, the block body, and the block body 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 by pressurization, but due to the water mixing ratio exceeding 6.00 in the production conditions, distillation was not possible. Disintegrated by immersion in water.

Claims (18)

A composite block body that is hardened by chemical bonding of inorganic components or entanglement or fusion of crystals of inorganic components,
A silica-calcium phosphate composite block comprising calcium phosphate containing silicic acid in its crystal structure, having a volume of 2.0 mm ³ or more, and a DTS strength of 0.1 MPa or more. The composite block according to claim 1, wherein the calcium phosphate contains octacalcium phosphate. 3. The composite block according to claim 2, wherein the water-containing layer of the octacalcium phosphate is replaced by silicic acid. The composite block according to claim 1, wherein the calcium phosphate contains carbonate apatite or hydroxyapatite. The composite block according to claim 1, wherein the calcium phosphate includes a tricalcium phosphate α phase or a tricalcium phosphate β phase. 6. The calcium phosphate according to claim 1, further comprising at least one selected from the group consisting of silver, copper, gallium, strontium, magnesium, zinc, and lanthanoids. Composite block. 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. The composite block body according to any one of 1-5. The composite block body according to any one of claims 1 to 5, which is a porous body. The composite block body according to claim 6, which is a porous body. The composite block body according to claim 7, which is a porous body. A ceramic (A) containing calcium and/or phosphoric acid, and an aqueous solution (B) having a silicate concentration of 10% by mass or more and containing no ceramic (A) among calcium and phosphoric acid. A mixed mud is obtained by mixing the aqueous solution (B) to the ceramic (A) so that the weight ratio (water mixing ratio) is 0.30 or more and 6.00 or less to obtain a mixed mud containing silicate-containing calcium phosphate. Preparation process;
a composite block body 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, the method comprising: The manufacturing method according to claim 11, characterized in that the ceramic (A) is calcium phosphate. The manufacturing method according to claim 11, wherein the silicic acid-containing calcium phosphate obtained in the mixed mud preparation step contains silicic acid-containing octacalcium phosphate. The method further includes the step of immersing the composite block obtained by the manufacturing method according to claim 13 in a solution containing carbonic acid, and phase-transforming the silicate-containing octacalcium phosphate to a silicate-containing carbonate apatite phase. A method for producing a silica-calcium phosphate composite block, characterized by: Further comprising the step of immersing the composite block obtained by the manufacturing method according to claim 13 in a solution containing no carbonic acid, the phase transition of the silicic acid-containing octacalcium phosphate to a silicic acid-containing hydroxyapatite phase is carried out. A method for producing a silica-calcium phosphate composite block, the method comprising: In the mixed mud preparation step, further 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. The manufacturing method according to any one of claims 11 to 15, characterized in that a compound containing at least one selected compound is mixed to prepare a mixed mud containing the compound. The manufacturing method according to any one of claims 11 to 15, wherein the composite block body is a porous body. 17. The manufacturing method according to claim 16, wherein the composite block body is a porous body.