JP5015570B2 - Biomaterial and method for producing biomaterial - Google Patents

Description

  The present invention relates to a biomaterial and a method for producing the biomaterial, and more particularly to a biomaterial and a method for producing the biomaterial that have excellent ability to bind to bone and can rapidly regenerate bone tissue.

  As a treatment method when the bone is largely lost, autologous bone transplantation in which a part of the patient's own normal bone is cut out and transplanted to the affected area, or an artificial bone transplantation in which an artificial bone made of an artificial material is transplanted is conventionally performed. ing. However, autologous bone transplantation limits the amount of bone that can be collected, and further damages normal tissue, which places a heavy physical burden on the patient.In addition, autologous bone transplantation bone used for autologous bone transplantation is normal for the patient. Since a new defect part is generated by cutting from a rough bone, it cannot be said to be an essential treatment method when the bone is largely lost. In addition, artificial bone grafting uses industrially produced artificial bone, so there is no problem like autologous bone grafting, but mechanical and biological properties of artificial bone are different from the original bone, Depending on the characteristics of the artificial bone, there is a problem that therapeutic uses are limited. For example, when a metal material such as a titanium alloy is selected as the material of the artificial bone, the metal material is usually high in strength, but has a high elastic modulus and lacks toughness. Occurs. In addition, when bioceramics such as hydroxyapatite is selected as the material of the artificial bone, the bioceramics usually have high biological activity and directly bond to the bone, but have the problem of low toughness like general ceramics. Furthermore, when a polymer such as ultra-high molecular weight polyethylene is selected as the material for the artificial bone, the polymer is usually excellent in flexibility, but lacks biological activity, and therefore has a problem that it does not directly bond to bone.

  As materials that can solve these problems, materials that are made by combining a flexible polymer and bioceramics having biological activity have been actively developed. As such a material, for example, “a biomaterial containing calcium phosphate and a lactic acid / glycolic acid / ε-caprolactone copolymer, and a preferable calcium phosphate used for this biomaterial is 650 ° C. to 1500 ° C. (Refer to Patent Document 1), “Inorganic powder particles are substantially uniformly dispersed in the organic polymer, have continuous pores inside, and on the surface and pore inner surface. An organic-inorganic composite porous body in which a part of the inorganic particles are exposed "(see Patent Document 2), and further" a biodegradable material containing a bioadsorbable polymer component and a bioactive filler. And a member characterized in that the particles of the filler are embedded in the surface of the component (see Patent Document 3). Since these materials are formed by combining a polymer and bioceramics, they have an advantage that they exhibit high strength and can be directly bonded to bone because they have bioactivity.

  Thus, although the materials described in Patent Documents 1 to 3 have already been proposed, a material for an artificial bone that can sufficiently regenerate bone tissue by sufficiently exerting bioactivity such as bioceramics is provided. It is desired.

JP 2001-54564 A (claim 1 and paragraph 0018 column) JP 2003-159321 A Special table 2005-508219 gazette

  An object of the present invention is to provide a biomaterial that has an excellent ability to bind to bone and can rapidly regenerate bone tissue, and to have an excellent ability to bind to bone and quickly regenerate bone tissue. An object of the present invention is to provide a method for producing a biomaterial.

As a first means for solving the above problems,
The first aspect of the present invention includes at least one polymer selected from the group consisting of polylactic acid, polyglycolic acid, and poly-ε-caprolactone, and 10 to 70% by mass with respect to the total mass of the polymer. A biomaterial comprising a dispersed ceramic powder made of calcium phosphate material powder, wherein the biomaterial has a maximum compressive strength of 1.5 MPa or more and a displacement in a compression direction when a compressive stress is applied. It is a porous body having a compressive strength at 30% of 50% or more of the maximum compressive strength and a porosity of 50 to 70%, and is present on the surface layer from the outermost surface of the biomaterial to a depth of 10 nm. The ceramic powder is 3% by mass based on the total mass of the polymer and the ceramic powder present in the surface layer measured by an X-ray photoelectron spectrometer. A biological material which is equal to or less than the upper 50%
2. The ceramic powder present in the surface layer is 5% by mass to 40% by mass with respect to a total mass of the polymer and the ceramic powder present in the surface layer. It is a biomaterial.

As a second means for solving the above problems,
Claim 3 is a method for producing a biomaterial according to claim 1 or 2 , wherein the polymer is molded together with the ceramic powder and immersed in an etching solution.
The method for producing a biomaterial according to claim 3 , wherein the etching agent is an alkaline aqueous solution.
5. The alkaline aqueous solution according to claim 5 is an aqueous solution having a pH of 12 or more, wherein at least one selected from the group consisting of hydroxides of alkali metal elements, hydroxides of alkaline earth metal elements and ammonia is dissolved. The method for producing a biomaterial according to claim 4 , wherein

  In the biomaterial according to the present invention, since the ceramic powder is 3% by mass or more with respect to the total mass of the polymer and the ceramic powder existing on the surface, the ceramic powder is present on the surface in a state of being exposed with a high degree of exposure. Yes. When such a biomaterial is compensated for, for example, in a bone-depleted portion (sometimes referred to as a bone-deleted portion) or a tooth-depleted portion (sometimes referred to as a tooth-deleted portion), the surface Since the biological activity of the ceramic powder exposed to the surface is sufficiently exerted, it is excellent in the ability to bind to the bone, and the bone tissue can be rapidly regenerated. Therefore, according to the present invention, it is possible to provide a biomaterial that is excellent in the ability to bind to teeth and bones and can quickly regenerate the teeth and bone tissues. And the biomaterial which concerns on this invention is utilized suitably for restoration or reproduction | regeneration, etc. of a bone defect part or a tooth defect part. Therefore, the biomaterial according to the present invention is suitable as a tooth / bone regeneration promoting filler.

  In addition, when a biomaterial in which ceramic powder is substantially uniformly dispersed is filled in, for example, a bone defect portion or a tooth defect portion, the polymer forming the biomaterial is gradually decomposed and / or absorbed. However, since the ceramic powder exposed on the new surface is substantially 3% by mass or more, such a biomaterial can maintain the initial bioactivity for a long period of time, and can rapidly accelerate the bone tissue. Regeneration can be maintained.

  When the ceramic powder contained in the biomaterial according to the present invention is a ceramic powder fired at a firing temperature of 1000 to 1600 ° C., the bioactivity and stability of the ceramic powder are enhanced. The material sufficiently exhibits the high bioactivity of the ceramic powder, is excellent in the ability to bind to bone, and can regenerate bone tissue even more rapidly.

  Furthermore, when a biological material that is a porous body having a porosity of 10 to 90% is filled in, for example, a bone defect portion or a tooth defect portion, a biological material such as osteoblasts enters, settles, and / or enters the pores. It is easy to grow, facilitates in vivo metabolism and bone formation, and the bioactivity of ceramic powder can be demonstrated not only on its surface but also on the pore surface. The bone tissue can be regenerated even more rapidly.

  A method for producing a biomaterial according to the present invention is a method in which a polymer is molded together with ceramic powder and then immersed in an etching solution without spraying a suspension containing the polymer and ceramic powder to produce a fiber assembly. Therefore, 3% by mass or more of ceramic powder can be exposed on the surface. Therefore, according to this invention, the manufacturing method of the biomaterial which can manufacture easily the biomaterial whose ceramic powder is 3 mass% or more with respect to the total mass of the polymer and ceramic powder which exist on the surface is provided. Can do.

  BEST MODE FOR CARRYING OUT THE INVENTION The best mode for carrying out the present invention will be described below, but the present invention should not be construed as being limited by the following description contents. The range easily conceivable or understandable based on this is also the scope of the present invention.

  The biomaterial according to the present invention includes a polymer and a ceramic powder.

  The ceramic powder may be a powder of an inorganic biomaterial having biocompatibility (also referred to as bioceramics), but has almost the same composition and / or structure as an inorganic substance found in hard tissues such as bones and teeth. It is preferably a powder of bioactive ceramics that has and significantly reacts with living tissue.

Examples of such bioactive ceramics include calcium phosphate materials, bioglass, crystallized glass (also referred to as glass ceramics), calcium carbonate, and the like. Examples of calcium phosphate materials include calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, α-type tricalcium phosphate, β-type tricalcium phosphate, Examples thereof include dolomite, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, fluorapatite, carbonate apatite, and chlorapatite. Examples of the bioglass include SiO ₂ —CaO—Na ₂ O—P ₂ O ₅ glass, SiO ₂ —CaO—Na ₂ O—P ₂ O ₅ —K ₂ O—MgO glass, and SiO ₂ —. Examples include CaO—Al ₂ O ₃ —P ₂ O ₅ glass. Examples of the crystallized glass include SiO ₂ —CaO—MgO—P ₂ O ₅ glass (also referred to as apatite wollastonite crystallized glass), CaO—Al ₂ O ₃ —P ₂ O ₅ glass, and the like. Is mentioned. These calcium phosphate materials, bioglass, and crystallized glass are, for example, “Chemical Handbook Applied Chemistry 6th Edition” (The Chemical Society of Japan, published on January 30, 2003, Maruzen Co., Ltd.), “Development of Bioceramics” And Clinic "(edited by Hideki Aoki et al., April 10, 1987, Quintessence Publishing Co., Ltd.). The bioactive ceramics may be produced as appropriate, or commercially available products may be used.For example, the calcium phosphate material may be a synthetic calcium phosphate material produced by a wet method, a dry method or a hydrothermal method, Alternatively, a natural calcium phosphate material separated from bone or teeth may be used.

  Among these, as the bioactive ceramic, a calcium phosphate-based material is preferable, and β-type tricalcium phosphate is particularly preferable in terms of excellent bioabsorbability and bioactivity.

  In addition, the bioactive ceramic is preferably fired at a firing temperature of 1000 to 1600 ° C, particularly preferably fired at 1000 to 1200 ° C. If the firing temperature of the bioactive ceramic is less than 1000 ° C. or the bioactive ceramic is not fired, the bioactivity of the bioactive ceramic cannot be sufficiently increased. On the other hand, if the firing temperature of the bioactive ceramic exceeds 1600 ° C. In some cases, the bioactive ceramic melts, and as a result, the structure of the bioactive ceramic is destroyed and the bioactivity is deactivated or cannot be prepared in a powder form. In particular, when the bioactive ceramic is a calcium phosphate material, a calcium phosphate material obtained by firing a calcium phosphate material having a Ca / P (molar ratio) of 1.40 to 1.45 at a firing temperature in the above range. Preferably there is. This calcium phosphate-based material can suppress the remaining of unreacted substances and the generation of hydroxyapatite during firing, and can exhibit high bioactivity.

  The ceramic powder is a powder formed by pulverizing or crushing the ceramic. The shape of the ceramic powder may be any shape that can be dispersed substantially uniformly in the polymer described later, and examples thereof include a spherical shape, an elliptical shape, a flat spherical shape, and a polyhedral shape.

  The ceramic powder may be a powder having an average particle diameter that can be dispersed substantially uniformly in the polymer described later, and the average particle diameter is 0.1 to 100 μm in terms of excellent dispersibility in the polymer. It is preferable that the thickness is 0.1 to 100 μm. In particular, when the ceramic is a calcium phosphate material, the average particle diameter of the calcium phosphate material is preferably 1 to 10 μm, and particularly preferably 1 to 5 μm. When the average particle size of the calcium phosphate material is in the above range, the dispersibility in the polymer is excellent and sufficient biological activity can be expressed. The average particle diameter of the ceramic powder can be measured by, for example, a laser diffraction particle size distribution measuring device (trade name “LA-750”, manufactured by Horiba, Ltd.).

  As the ceramic powder, one kind of ceramic powder can be used alone, or two or more kinds of ceramic powders can be used in combination.

  The ceramic powder contained in the biomaterial is 3% by mass with respect to the total mass of the ceramic powder present on the surface of the biomaterial and the later-described polymer present on the surface of the biomaterial and the ceramic powder present on the surface of the biomaterial. What is necessary is just content which becomes the above, for example, it is preferable that it is 10-70 mass% with respect to the total mass of the polymer and ceramic powder contained in a biomaterial, and it is especially preferable that it is 10-50 mass%. . When the content of the ceramic powder in the biomaterial is within the above range, the ceramic powder present on the surface of the biomaterial can be easily adjusted to 3% by mass or more, and the mechanical strength of the biomaterial is excellent.

  The polymer contained in the biomaterial is preferably a bioabsorbable polymer. When a biomaterial containing a bioabsorbable polymer and ceramic powder is supplemented to a bone defect or a tooth defect, etc., it is integrated with surrounding bone and / or teeth such as a bone defect or a tooth defect, and then the biomaterial is converted into a biomaterial. The contained bioabsorbable polymer is gradually decomposed and / or absorbed, and most of the biomaterial is replaced with a living tissue, so that a bone defect portion or a tooth defect portion can be quickly repaired.

  Such bioabsorbable polymers include at least one polymer selected from the group consisting of polylactic acid, polyglycolic acid, poly-ε-caprolactone and polybutyl succinate, and / or lactic acid, glycolic acid, ε -It is preferably a copolymer obtained by copolymerizing at least two monomers selected from the group consisting of caprolactone and succinic acid / butanediol. Since these polymers and copolymers have bioabsorbability and mechanical properties suitable as artificial bones and / or artificial teeth in vivo, they can rapidly regenerate bone tissue and It is possible to ensure the strength of the bone defect portion or tooth defect portion that has been compensated. In this invention, polylactic acid includes poly-L-lactic acid, poly-D-lactic acid, and poly-DL-lactic acid, and lactic acid includes L-lactic acid, D-lactic acid, and DL-lactic acid. .

  In the copolymer, the molar ratio of monomers to be copolymerized is adjusted according to the bone defect portion or tooth defect portion used, and even if it is a block copolymer, it is a random copolymer. The polymerization mode is not particularly limited. Examples of such copolymers include polylactic acid / polyglycolic acid copolymer, polylactic acid / poly-ε-caprolactone copolymer, polylactic acid / polybutyl succinate copolymer, polyglycolic acid / poly-ε. -Caprolactone copolymer, polylactic acid / polyglycolic acid / poly-ε-caprolactone copolymer, and the like.

  The bioabsorbable polymer is capable of achieving both rapid regeneration of bone tissue and strength of a bone defect portion or a tooth defect portion at a higher level. Polylactic acid, polyglycolic acid and poly-ε-caprolactone And at least one polymer is preferred, and poly-L-lactic acid is particularly preferred.

  The polymers can be selected according to the purpose of use because they have different biodegradation rates and strengths. Moreover, a sponge-like soft biomaterial can be produced from a hard biomaterial depending on the type of polymer used and the average molecular weight. Therefore, the average molecular weight of the polymer is not particularly limited, but for example, the viscosity average molecular weight is preferably 100,000 to 900,000.

  The polymer preferably has a crystallinity of 40% or more, more preferably 40 to 90%. When the degree of crystallinity of the polymer is 40% or more, there are many sites on the polymer surface that are the starting points for the formation of bone-like apatite. Therefore, a biomaterial containing such a polymer and ceramic powder is used as a bone defect or When the tooth defect part or the like is filled, bone-like apatite is rapidly formed. In particular, when the polymer is poly-L-lactic acid, the crystallinity thereof is preferably 40 to 90%, particularly preferably 50 to 90%. Therefore, when the biomaterial according to the present invention fills a missing tooth portion or a missing bone portion (sometimes referred to as a missing tooth bone portion), the regeneration of the teeth or bones is promoted and the tooth bones are promoted. It is suitable as a tooth / bone regeneration promoting filler capable of realizing rapid regeneration of a defect. The degree of crystallinity of the polymer can be calculated from the endothermic amount accompanying crystal melting measured by a differential scanning calorimeter and the exothermic amount accompanying crystal formation.

  A polymer can also be used individually by 1 type and can also use 2 or more types together. The polymer may be a mixture of the biodegradable polymer and other polymers. Moreover, a polymer may be manufactured by the polymerization method or copolymerization method employ | adopted normally, or a commercial item may be used.

  In the polymer contained in the biomaterial, the ceramic powder present on the surface of the biomaterial is 3% by mass or more based on the total mass of the polymer present on the surface of the biomaterial and the ceramic powder present on the surface of the biomaterial. What is necessary is just content, for example, it is preferable that it is 30-90 mass% with respect to the total mass of a polymer and the said ceramic powder, and it is especially preferable that it is 50-90 mass%. When the content of the polymer is within the above range, the ceramic powder present on the surface of the biomaterial can be easily adjusted to 3% by mass or more, and the mechanical strength of the biomaterial is excellent.

  The biomaterial contains the polymer and the ceramic powder, but may contain a component other than the polymer and the ceramic powder, such as a dispersant, if desired.

  The biomaterial includes the polymer and the ceramic powder, and is formed from the polymer and the ceramic powder. When the surface of the biomaterial is observed with an electron microscope or the like, both the polymer and the ceramic powder are exposed on the surface, and preferably the surface has a sea-island structure of the polymer and the ceramic powder (for example, , See FIG. And as for the biomaterial which concerns on this invention, the ceramic powder which exists on the surface is 3 mass% or more with respect to the total mass of the polymer which exists on the surface, and the ceramic powder which exists on the surface. When the ceramic powder on the surface of the biomaterial is less than 3% by mass with respect to the total mass, the ceramic material is hardly exposed on the surface of the biomaterial. Even if the tooth defect part is filled, the bioactivity of the ceramic powder is not sufficiently exhibited, and the bone tissue may not be regenerated quickly. The upper limit value of the mass ratio of the ceramic powder present on the surface of the biomaterial to the total mass (hereinafter, sometimes referred to as “mass ratio of the ceramic powder present on the surface”) is not particularly limited. The amount is preferably 50% by mass in terms of avoiding excessive use of the ceramic powder. The mass ratio of the ceramic powder present on the surface is preferably 5 to 40% by mass, and is preferably 5 to 30% by mass in that it has excellent ability to bind to bone and can rapidly regenerate bone tissue. Is particularly preferred.

  Here, the mass ratio of the ceramic powder present on the surface can be determined as follows. That is, the elemental analysis of the surface of the biomaterial is performed using an X-ray photoelectron spectrometer (for example, trade name “PHI QUANTERA SXM”, manufactured by ULVAC-PHI), X-ray beam diameter (diameter): 100 μm and path energy: The measurement is performed under a measurement condition of 280 eV, and the relative concentration ratio of elements existing on the surface of the biomaterial is measured. Based on the measured relative concentration ratio of the elements, the number of polymers and ceramics present on the surface of the biomaterial is calculated. Next, multiply the calculated number of existing polymers by the average molecular weight of the polymer, and multiply the calculated number of existing ceramics by the molecular weight of the ceramics to calculate the masses of the polymer and ceramics present on the surface of the biomaterial. To do. From the calculated polymer and ceramic mass, the mass ratio of the ceramic powder present on the surface is calculated. In the present invention, the mass ratio of the ceramic powder present on the surface is preferably calculated by the above method using an arbitrary plurality of positions on the surface of the biomaterial as a measurement region, and the average value thereof is preferably used.

  In this invention, the surface of the biomaterial refers to the surface layer from the outermost surface of the biomaterial to a depth of 10 nm. When the biomaterial is a porous body having a porous structure described later, the surface of the biomaterial is biomaterial. In addition, the surface of the pores, that is, the surface layer from the outermost surface of the pores to a depth of 10 nm is also included.

  As described above, the biomaterial is sufficient if the ceramic powder is present at the specific mass ratio of the ceramic powder present on the surface, and the ceramic powder present on the surface may be uniformly dispersed. , It may be dispersed non-uniformly.

  In addition, as described above, it is sufficient that the ceramic material is present at the specific mass ratio of the ceramic powder present on the surface as described above, but the ceramic powder is substantially uniform inside the biomaterial. It is preferable to be dispersed. When the ceramic powder is substantially uniformly dispersed inside the biomaterial, the biomaterial is supplemented in, for example, a tooth or bone defect, and the polymer forming the biomaterial is gradually decomposed and / or absorbed. Even so, the mass ratio of the ceramic powder exposed on the new surface is substantially 3 mass% or more. Therefore, such a biomaterial can maintain the initial biological activity for a long period of time, and can maintain the rapid regeneration ability of bone tissue.

  The biomaterial according to the present invention may be a dense body having substantially no pores on its surface and inside, or a porous body having a porous structure having pores on its surface and inside. Even if the biomaterial is a dense body, if such a biomaterial is supplemented in, for example, a bone defect portion or a tooth defect portion, the polymer contained in the biomaterial is gradually decomposed and / or absorbed. The ceramic powder is exposed on the surface of the biomaterial, and the bone tissue can be quickly regenerated. On the other hand, when the biomaterial is a porous body, when such a biomaterial is supplemented to, for example, a bone defect portion or a tooth defect portion, the polymer forming the biomaterial is gradually decomposed and / or absorbed. Thus, the ceramic powder is exposed on the surface of the remaining biomaterial, and the bone tissue can be rapidly regenerated, and the biological material such as osteoblasts invades, settles and / or grows in the pores, and the bone tissue Can be regenerated promptly, and thus the bone tissue can be regenerated more rapidly.

  The porous body has a porous structure having communication holes in which a plurality of pores communicate with each other. The communication between the pores may be regular or irregular. Further, some of the pores may be independent, that is, may not communicate with other pores, and some of the pores may communicate with several other pores. In the present invention, the porous structure having communication holes is a structure that can enter each pore through which a biological material such as a gas, liquid, or osteoblast is communicating from the outside of the biological material.

  When the biomaterial is a porous body, the porosity is preferably 10 to 90%, and particularly preferably 45 to 75%. When the porous body has a porosity in the above-mentioned range, when a biomaterial is supplemented to, for example, a bone defect portion or a tooth defect portion, a large amount of a biological material easily enters, settles and / or grows in the pores, Metabolism and bone formation in vivo become even faster, and the bioactivity of the ceramic powder can be fully exerted not only on the surface but also on the pore surface. It can be played back more quickly.

  Here, the porosity of the biomaterial can be calculated by a normal method. For example, the true density ρ of a biomaterial having the same composition as the measurement-target biomaterial and having no pores is measured in advance, and the true density ρ and the apparent density ρ ′ calculated from the volume and mass of the measurement-target biomaterial. From the above, it can be calculated by the equation [1- (ρ ′ / ρ)] × 100 (%). Or it can obtain | require as a calculated value from the ratio of the pore area in the electron micrograph of a biomaterial, and can also set it as a porosity as an approximate value.

  Such a porous body preferably has a pore diameter (sometimes referred to as a pore diameter) of 200 to 500 μm, particularly preferably 300 to 500 μm. If the pore diameter is within the above range, a large amount of biological material can easily enter, settle and / or grow in the pores while maintaining the strength of the porous body, and the bone tissue is regenerated even more rapidly. be able to. The pore diameter can be calculated by a usual method. For example, it can be calculated by observing the surface of the porous body with an electron microscope or the like, measuring the opening diameter of pores in the electron micrograph as an equivalent circle diameter, and arithmetically averaging them.

  Further, the porous body has a communicating portion where a plurality of pores communicate, that is, the pore diameter of the communicating hole is preferably 50 to 300 μm, and particularly preferably 50 to 150 μm. If the pore diameter of the communication hole is within the above range, a large amount of biological material can easily enter, settle and / or grow in the entire pores while maintaining the strength of the porous body, and bone tissue can be regenerated even more quickly. can do. This communication hole is usually not circular in cross section, and also has a distribution in the size (hole diameter) of the cross section, and it is considered that the communication part of open cells is usually the thinnest, but the communication hole If the pore diameter is within the above range, a larger amount of biological material can easily enter this portion quickly. Here, the hole diameter of the communication hole is a hole diameter as an average converted diameter measured with a mercury porosimeter.

  In the case where the biomaterial is a porous body, the surface of the pores in the biomaterial is similar to the surface of the biomaterial. It is 3 mass% or more with respect to the total mass of the ceramic powder which exists in the surface of material. Therefore, the biomaterial forming the porous body having a porous structure is excellent in the ability to bind to the bone, and can regenerate the bone tissue even more rapidly.

  Since the biomaterial according to the present invention contains the polymer and the ceramic powder as described above, it has both the bioabsorbability and mechanical properties of the polymer and the bioactivity of the ceramic. Since it is exposed on the surface of the biomaterial at a mass ratio, it has excellent mechanical properties and excellent ability to bind to bone, and can rapidly regenerate bone tissue.

  When the biomaterial is a porous body, the mechanical properties tend to be lower than that of the dense body. However, when the biomaterial according to the present invention is a porous body, in particular, the porous body has a firing temperature. When containing ceramic powder fired at 1000-1600 ° C., compressive stress is applied to a cylindrical biomaterial having a diameter of 10 mm × height of 10 mm at a speed of 1 mm / min using a load cell. In this case, the maximum compressive strength is 1.5 MPa or more, and the compressive strength when the amount of displacement in the compressive direction of the biomaterial is 30% is 50% or more of the maximum compressive strength. The maximum compressive strength is more preferably 1.5 to 30 MPa, particularly preferably 1.5 to 10 MPa, and the compressive strength when the displacement is 30% is 50 to 100% of the maximum compressive strength. Is particularly preferred. When the biomaterial has such a mechanical characteristic, the biomaterial is easily brittle even when a mechanical load is applied to the biomaterial when the biomaterial is supplemented to a bone defect portion or a tooth defect portion, for example. It is possible to avoid serious troubles such as breakage without destruction.

  The biomaterial of the present invention is used in a shape after production or in a desired shape after production of the biomaterial, for example, a powder shape, a fiber shape, a block shape or a film shape. Preferably, the shape similar to the shape of the bone defect portion or the tooth defect portion or the like, or the shape corresponding to the shape of the bone defect portion or the tooth defect portion, for example, a similar shape, etc. , Shaped, shaped and / or prepared and used. As described above, the biomaterial of the present invention is excellent in mechanical properties and bioactivity. In particular, the bioactivity of the ceramic powder exposed on the surface is sufficiently exerted, and is excellent in the ability to bind to bone. Since tissue can be quickly regenerated, as a tooth and / or bone replacement material, specifically, a bone defect or tooth defect in a living body is compensated for, such as a bone defect or tooth defect. It is suitably used as a regenerative medical material that repairs or regenerates the skin.

  The biomaterial production method according to the present invention (sometimes referred to as the production method of the present invention) is a method in which a polymer is molded together with ceramic powder and immersed in an etching solution.

  In carrying out the production method of the present invention, ceramics or ceramic powder obtained by crushing or crushing ceramics is fired at a firing temperature of 1000 to 1600 ° C., preferably 1000 to 1200 ° C., if desired. The firing time is not particularly limited, and can be adjusted to 1 to 12 hours, for example. The firing of ceramics or ceramic powder can be performed by a usual method.

  Next, the polymer is molded together with the ceramic powder, but it is preferable to mix the polymer and the ceramic powder before the molding because the ceramic powder can be uniformly dispersed in the polymer. The polymer and the ceramic powder may be mixed as long as the ceramic powder can be dispersed in the polymer so that the ceramic powder does not aggregate. For example, (1) the ceramic powder is added to the heat-melted polymer, and the mixture is stirred. The ceramic powder is uniformly dispersed in the polymer and then cooled and solidified, or (2) the ceramic powder is added to a polymer solution obtained by dissolving the polymer in a solvent or a polymer suspension obtained by suspending the polymer in the solvent. , A method of removing the solvent after stirring the mixture to uniformly disperse the ceramic powder, and (3) a method of mixing and stirring the polymer, the ceramic powder and the solvent, and then removing the solvent. it can. Examples of the solvent used in this method include solvents such as 1,4-dioxane, methylene chloride, chloroform, dichloroethane, dichloromethane, ethyl acetate, methanol, ethanol and water. In the methods (2) and (3), what is obtained after removing the solvent does not exhibit a fiber aggregate shape.

  By the way, in the case of using the copolymer as a polymer, in addition to the molding method, at least two kinds of the monomers constituting the copolymer and ceramic powder are mixed together in the presence of the ceramic powder. Alternatively, it is possible to employ a method in which at least two kinds of monomers are copolymerized, and the production of the polymer and the mixing of the ceramic powder are performed simultaneously or continuously.

  Thus, the mixture in which the ceramic powder is uniformly dispersed in the polymer or the mixture in which the polymer and the ceramic powder are simply mixed is heat-molded. In the thermoforming, the heating temperature and the heating time are appropriately determined according to the type or property of the polymer and ceramic powder. For example, poly-L-lactic acid is selected as the polymer, and tricalcium phosphate is selected as the ceramic. In this case, the heat molding is performed at a heating temperature of 100 to 300 ° C. for a heating time of 10 to 180 minutes. For the heat molding, a method capable of heat-molding the mixture may be employed, and examples thereof include heat molding by a hot press machine and injection molding.

  When the biomaterial according to the present invention is a porous material, it may be made porous by a known method. For example, an organic substance such as sucrose or an inorganic substance such as sodium chloride is dispersed in a polymer together with a ceramic powder and heat-molded. Then, the obtained molded product is dissolved in a solvent from which the organic substance or inorganic substance elutes, for example, water. Or a porous body can be manufactured by immersing in alcohol etc. for a predetermined time. In addition, a freeze-drying method, a method using a foaming agent, or the like can also be employed.

  In the production method of the present invention, an organic-inorganic mixture is produced by the thermoforming, or by the thermoforming and making porous. In the production method of the present invention, the organic-inorganic mixture is formed into a shape similar to the shape of a bone defect portion or a tooth defect portion by the thermoforming according to the use mode, or further crushed or Crushed into pulverized material. The pulverized product is usually granular or granular. Regardless of whether it is granular or granular, the average particle size of the particles is usually preferably in the range of 0.5 mm to 10 mm. And when the mass ratio of the ceramic powder which exists in the surface of each particle | grain in the said organic-inorganic mixture and the said ground material is 3 mass% or more, it does not need to implement a subsequent process. . That is, the biomaterial according to the present invention can be obtained by simply thermoforming the polymer with the ceramic powder or by thermoforming the polymer with the ceramic powder and the organic or inorganic substance, and then making it porous. Further, it can be produced by crushing or crushing.

  However, it is usually not easy to adjust the mass ratio of the ceramic powder existing on the surface of the biomaterial to a desired range. To adjust the mass ratio of the ceramic powder existing on the surface to 3% by mass or more, a polymer is used. It is effective to immerse the organic-inorganic mixture formed by heating together with ceramic powder and each particle in the pulverized product (sometimes referred to as an organic-inorganic mixture) in an etching solution.

  The etching solution for immersing the organic-inorganic mixture etc. decomposes and / or dissolves the polymer contained in the organic-inorganic mixture etc., for example, the polymer present on the surface of the organic-inorganic mixture etc. -What is necessary is just a liquid which does not decompose | dissolve and melt | dissolve the ceramic powder which exists on the surfaces, such as an inorganic mixture, For example, alkaline aqueous solution, an organic solvent, etc. are mentioned. By immersing the organic-inorganic mixture etc. with such an etchant, the surface of the organic-inorganic mixture etc. can be treated uniformly, especially when the organic-inorganic mixture etc. is a porous body, Not only the surface of the organic-inorganic mixture etc., but also the surface of the pores leading from the surface of the organic-inorganic mixture etc. to the inside can be treated uniformly. Further, the etching agent penetrates along the interface between the polymer and the ceramic powder present on the surface of the organic-inorganic mixture or the like, and the polymer can be efficiently eroded to expose the ceramic powder on the surface. In this way, a biomaterial having a desired shape formed from a polymer and ceramic powder can be produced. The etching solution is preferably an alkaline aqueous solution in that the polymer existing on the surface of the biomaterial can be rapidly eroded and the amount of erosion can be easily adjusted, and the alkaline aqueous solution having a pH of 12 or more. Is particularly preferred. Solutes used to adjust the alkaline aqueous solution include hydroxides of alkali metal elements (eg, Li, Na, K, etc.), hydroxides of alkaline earth metal elements (Mg, Ca, Sr, Ba, etc.) and It is preferably at least one selected from the group consisting of ammonia.

  The etching solution is adjusted to an arbitrary temperature according to the amount of polymer to be eroded, the mass ratio of the ceramic powder exposed on the surface, and specifically, for example, adjusted to a temperature of about 10 to 60 ° C. Further, when the etching solution is an alkaline aqueous solution, it is adjusted to an arbitrary concentration according to the pH of the aqueous solution, the amount of eroded polymer, the mass ratio of the ceramic powder exposed on the surface, and specifically, for example, The concentration is adjusted to about 0.5 to 5% by mass.

  The immersion treatment may be any treatment that simply immerses an organic-inorganic mixture or the like in an etching solution according to the amount of eroded polymer, the mass ratio of the ceramic powder exposed on the surface, and specifically, for example, organic- What is necessary is just to immerse an inorganic mixture etc. in etching liquid for 10 to 600 minutes.

  In the production method of the present invention, if desired, post-treatment such as washing treatment and drying treatment of the organic-inorganic mixture and / or biomaterial can be performed before and / or after the immersion treatment. These post-treatments can employ ordinary processing methods. In addition, in the production method of the present invention, the organic-inorganic mixture is formed into a shape similar to the shape of the bone defect portion or the tooth defect portion, or the shape corresponding to the shape of the bone defect portion or the tooth defect portion, if desired. For example, a process of shaping and / or preparing a similar shape or the like can be performed.

  In this way, 3% by mass or more of the ceramic powder can be quickly and easily exposed on the surface, and the biomaterial according to the present invention can be easily manufactured.

  The biomaterial obtained in this way has a shape similar to the shape of the bone defect or tooth defect to be compensated, or a shape corresponding to the shape of the bone defect or tooth defect, such as a similar shape, It is molded, shaped and / or prepared and, if desired, supplemented to a bone defect part or a tooth defect part together with a liquid harmless to the human body such as water and physiological saline. For example, the biomaterial according to the present invention includes a bone defect portion or a tooth defect, such as a bone defect portion or a tooth defect portion that has been lost by cutting an autologous bone graft bone used for autologous bone transplantation from a patient's own normal bone. It is prepared in a shape similar to the shape of the part and the like, and supplemented with the liquid that is harmless to the human body if desired. On the other hand, the biomaterial having the form as a pulverized product obtained as described above is mixed with a liquid harmless to the human body such as water and physiological saline, if desired, into a paste-like material, and a bone defect portion Or it is filled in a tooth defect portion or the like. In this way, in the pulverized material existing in the filled biomaterial and the filled paste, 3% by mass or more of the ceramic powder is exposed on the surface thereof, so that the bone defect portion or the tooth defect portion Regeneration of teeth or bones such as in this is achieved quickly.

  Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples. In addition, this invention is not limited to the content of the Example.

( Reference Example 1 )
0.9 g of poly-L-lactic acid (viscosity average molecular weight of about 300,000) having a crystallinity of 40% measured by the above method was dissolved in 20 g of 1,4-dioxane. To the obtained solution, 0.1 g of calcined tricalcium phosphate calcined at a calcining temperature of 1100 ° C. for 3 hours (the average particle diameter of calcined tricalcium phosphate measured by the above method is 2 μm) was added and sufficiently dispersed. A dispersion was obtained. Next, this dispersion was allowed to stand in a fume hood for 12 hours to volatilize 1,4-dioxane, and then heat-molded with a hot press, so that the content of the calcined tricalcium phosphate (β type) was poly. 10% by mass of a poly-L-lactic acid / calcined tricalcium phosphate mixture was obtained based on the total mass of -L-lactic acid and calcined tricalcium phosphate. This poly-L-lactic acid / calcined tricalcium phosphate mixture was immersed in 100 mL of a sodium hydroxide aqueous solution with a pH of 12.9 for 1 hour, and the surface was etched to obtain a biomaterial (dense body) of Reference Example 1 .

( Reference Examples 2-5)
Except having adjusted the content of baking tricalcium phosphate to the value of Table 1, it carried out similarly to the reference example 1, and obtained the biomaterial (dense body) of the reference examples 2-5 .

( Reference Examples 6-8)
Other than using 0.7 g of poly-L-lactic acid (viscosity average molecular weight 300,000) whose crystallinity measured by the above method was adjusted to the value shown in Table 1, and 0.3 g of the calcined tricalcium phosphate. In the same manner as in Reference Example 1 , biomaterials (dense bodies) of Reference Examples 6 to 8 were obtained.

( Reference Examples 9 and 10)
Except for using 0.3 g of calcined tricalcium phosphate having an average particle size of 5 μm or 10 μm , biomaterials (dense bodies) of Reference Examples 9 and 10 were obtained in the same manner as Reference Example 3 , respectively.

(Examples 1 to 4 )
0.5 g of poly-L-lactic acid (viscosity average molecular weight 300,000) having a crystallinity of 40% measured by the above method was dissolved in 20 g of 1,4-dioxane. In the obtained solution, 0.5 g of calcined tricalcium phosphate (β type, calcining temperature 1100 ° C., calcining time 3 hours) having an average particle diameter measured by the above method of 3 μm and 0.9 g of sucrose (Example 1) Alternatively, 2.1 g (Examples 2 to 4) was added and sufficiently dispersed to obtain a dispersion. Next, this dispersion is allowed to stand in a fume hood for 12 hours to volatilize 1,4-dioxane and then heat-molded with a hot press, and further immersed in pure water for 12 hours to elute sucrose. Each of the porous bodies of the poly-L-lactic acid / calcined tricalcium phosphate mixture in which the content of the calcined tricalcium phosphate is 50% by mass with respect to the total mass of the poly-L-lactic acid and the calcined tricalcium phosphate. Obtained. The porous bodies of these poly-L-lactic acid / calcined tricalcium phosphate mixtures were each immersed in 100 mL of an aqueous sodium hydroxide solution having a pH of 12.9 for 1 hour, etched on the surface, and the biomaterials of Examples 1 to 4 ( Porous body) was obtained.

(Comparative Examples 1-5)
Comparative Examples 1-5 biomaterials (dense bodies) were obtained in the same manner as Reference Examples 1-5 , respectively, except that the etching treatment with an aqueous sodium hydroxide solution of pH 12.9 was not performed.

When the surface of each of the biomaterials thus produced was observed with a scanning electron microscope (magnification rate 3000 times), all biomaterials had poly-L-lactic acid and calcined phosphorus on the surface, although there were differences in degree. Tricalcium acid was observed, and in particular, its surface had a sea-island structure of poly-L-lactic acid and calcined tricalcium phosphate. The scanning electron microscope (SEM) photograph which image | photographed the surface in the biomaterial of the reference example 3 and the comparative example 3 was shown in FIG.1 and FIG.2, respectively. 1 and 2, the white or gray portion is calcined tricalcium phosphate, and the black portion is poly-L-lactic acid. In FIG. 2 (the biomaterial of Comparative Example 3), most of the calcined tricalcium phosphate is buried inside the surface layer of poly-L-lactic acid, whereas in FIG. 1 (the biomaterial of Reference Example 3) It was confirmed that the calcined tricalcium phosphate was exposed on the surface due to the effect of the etching treatment.

Moreover, arbitrary three places on the surface of each manufactured biomaterial were measured by the above method using an X-ray photoelectron spectrometer (trade name “PHI QUANTERA SXM”, manufactured by ULVAC-PHI), and the arithmetic average value of the measured values Was calculated as the mass proportion of calcined tricalcium phosphate present on the surface. Moreover, the mass ratio of the calcined tricalcium phosphate in a pore surface is similarly used for the pore surface in the cut surface which cut | disconnected each biological material manufactured in Examples 1-4 by arbitrary surfaces using an X-ray photoelectron spectrometer. Was calculated. The results are shown in Table 1.

Furthermore, the porosity of each biomaterial manufactured in Examples 1 to 4 , the pore diameter of the pores, and the pore diameter of the communication holes were calculated by the above methods. The results are shown in Table 1.

Moreover, the “binding ability with bone” in each of the biomaterials produced in Reference Examples 1 to 10, Examples 1 to 4 and Comparative Examples 1 to 5 was evaluated by a simulated body fluid immersion test. Specifically, each biomaterial produced in Reference Examples 1 to 10 and Comparative Examples 1 to 5 was cut into a 10 mm × 10 mm × 2 mm plate and immersed in 100 mL of simulated body fluid adjusted to 36.5 ° C. for 1 day. Then, the plate-like body was taken out and the surface thereof was observed with a scanning electron microscope to confirm the presence or absence of precipitation of hydroxyapatite. In addition, each biomaterial produced in Examples 1 to 4 was cut into a cylindrical body having a diameter of 12 mm and a height of 5 mm, and similarly immersed in 100 mL of a simulated body fluid for 1 day, and then the cylindrical body was taken out, and its surface and pores The surface of each was observed in the same manner, and the presence or absence of precipitation of hydroxyapatite was confirmed. In this simulated body fluid immersion test, the test body is immersed in a simulated body fluid that has an inorganic ion concentration almost equal to that of human plasma and is supersaturated with respect to apatite, and the ability to form apatite on the surface of the specimen is evaluated. For details, see Otsuki et al., “Mechanizm of apatite formation on CaO—SiO ₂ —P ₂ O ₅ glasses in a simulated body fluid”, Journal of Non-Crysal Solid, 143, 84-92, 1992.

As is clear from Table 1, the biomaterials of Comparative Examples 1 to 5 in which the mass ratio of the ceramic powder on the surface of the biomaterial is less than 2% by mass have the ability to form hydroxyapatite in the simulated body fluid immersion test. In contrast, the biomaterials of Reference Examples 1 to 10 and Examples 1 to 4 had a mass ratio of the ceramic powder on the surface of the biomaterial of 3% by mass or more, so that both were immersed in simulated body fluid Hydroxyapatite was formed in the test, and it was confirmed that it had a rapid ability to form hydroxyapatite. In particular, according to Reference Example 1 and Reference Example 2 and the like, even if the ceramic powder content in the biomaterial is as low as 10% by mass or 20% by mass, the mass ratio of the ceramic powder on the surface is 3% by mass or more. It was found that the biomaterial exhibits a rapid ability to form hydroxyapatite. Moreover, according to Examples 1-4 , it turned out that the formation ability of the rapid hydroxyapatite is exhibited not only on the surface of the biomaterial but also on the pore surface.

( Reference Examples 11-17 )
The content of calcined tricalcium phosphate obtained by calcining at the calcining temperature shown in Table 2 (β type, the average particle diameter of calcined tricalcium phosphate measured by the above method is 2 μm) was adjusted to 30% by mass. Except having done, it carried out similarly to the reference example 1, and obtained the biomaterial (dense body) of the reference examples 11-17 .

( Reference Examples 18-24 )
Except having adjusted the content of the said calcined tricalcium phosphate to the value of Table 2, it carried out similarly to the reference example 12, and obtained the biomaterial (compact body) of the reference examples 18-24 .

(Examples 6 to 12 )
0.7 g of poly-L-lactic acid (viscosity average molecular weight of about 300,000) having a crystallinity of 40% measured by the above method was dissolved in 20 g of 1,4-dioxane. To the obtained solution, calcined tricalcium phosphate obtained by calcining at the calcining temperature shown in Table 2 for 3 hours (β type, average particle diameter of calcined tricalcium phosphate measured by the above method is 2 μm) 0.3 g And 2.4 g of sucrose was added and sufficiently dispersed to obtain a dispersion. Next, this dispersion is allowed to stand in a fume hood for 12 hours to volatilize 1,4-dioxane and then heat-molded with a hot press, and further immersed in pure water for 12 hours to elute sucrose. is allowed, sintered porous body of tricalcium phosphate 30% by weight of poly -L- acid / fired tricalcium phosphate mixture content of the total mass of the sintered tricalcium phosphate and polylactic -L- lactic acid, respectively Obtained. The porous bodies of these poly-L-lactic acid / calcined tricalcium phosphate mixtures were each immersed in 100 mL of a sodium hydroxide aqueous solution having a pH of 12.9 for 1 hour, and the surface was etched to obtain the biomaterials of Examples 6 to 12 ( Porous body) was obtained.

(Examples 13 to 18 )
Biological materials (porous bodies) of Examples 13 to 18 were obtained in the same manner as Example 6 except that the contents of the calcined tricalcium phosphate and sucrose were adjusted to the values shown in Table 2.

(Example 19 )
A biomaterial (porous body) of Example 19 was obtained in the same manner as Example 7 except that the sucrose content was adjusted to the values shown in Table 2.

(Examples 20 and 21 )
The biomaterials (porous bodies) of Examples 20 and 21 were obtained in the same manner as in Example 7 , except that the sucrose particle size was adjusted and the pore diameter was adjusted to the values shown in Table 2.

  When the surface of each of the biomaterials thus produced was observed with a scanning electron microscope (magnification rate 3000 times), all biomaterials had poly-L-lactic acid and calcined phosphorus on the surface, although there were differences in degree. Tricalcium acid was observed, and in particular, its surface had a sea-island structure of poly-L-lactic acid and calcined tricalcium phosphate.

Moreover, arbitrary three places on the surface of each biomaterial manufactured in Reference Examples 11 to 24 were measured in the same manner as in Reference Example 1, and the mass ratio of calcined tricalcium phosphate present on the surface was calculated. Moreover, the pore surface in the cut surface which cut | disconnected each biological material manufactured in Examples 6-21 in arbitrary surfaces was measured similarly using an X-ray photoelectron spectrometer, and the mass of the calcined tricalcium phosphate in a pore surface The percentage was calculated. Furthermore, the porosity of each biomaterial manufactured in Examples 6 to 21 , the pore diameter of the pores, and the pore diameter of the communication holes were calculated by the above methods. The results are shown in Table 2.

Moreover, the “binding ability with bone” in each of the biomaterials produced in Reference Examples 11 to 24, Examples 6 to 21 and Reference Example 3 was evaluated by the simulated body fluid immersion test. Specifically, each biomaterial produced in Reference Example 3 and Reference Examples 11 to 24 was cut into a plate of 10 mm × 10 mm × 2 mm, and 0.5 mL and 100 mL of simulated body fluid adjusted to 36.5 ° C. After being immersed for 1 day, the plate-like body was taken out and the surface thereof was observed with a scanning electron microscope to confirm the presence or absence of precipitation of hydroxyapatite. In addition, each biomaterial produced in Examples 6 to 21 was cut into a cylindrical body having a diameter of 12 mm and a height of 5 mm, and similarly immersed in 100 mL of simulated body fluid for 0.5 days and 1 day, and then the cylindrical body was taken out. The surface and the surface of the pores were observed in the same manner to confirm the presence or absence of precipitation of hydroxyapatite.

The compressive strength when the maximum compressive strength and the amount of displacement in the compression direction in the biomaterials of Examples 6 to 21 are 30% is measured by the above method, and the compressive strength when the amount of displacement in the compression direction relative to the maximum compressive strength is 30%. (Referred to as “intensity ratio” in Table 2). The results are shown in Table 2.

As is clear from Table 2, the biomaterials produced in Reference Examples 3, 11-24 and Examples 6-21 have a mass ratio of ceramic powder on the surface of the biomaterial of 3% by mass or more. In the simulated body fluid immersion test (1 day immersion), it was confirmed that hydroxyapatite was formed and it had a rapid ability to form hydroxyapatite. In particular, the biomaterials produced in Reference Examples 12 to 24 and Examples 6 to 21 containing ceramic powders fired at a firing temperature of 1000 to 1600 ° C. are simulated body fluid immersion tests ( 0.5 day immersion). It was confirmed that hydroxyapatite was formed even in, and that it had a more rapid ability to form hydroxyapatite than Reference Example 11 . Moreover, although the biomaterial manufactured in Examples 6-21 is a porous body, the maximum compressive strength is 1.5 MPa or more, and the compressive strength when the amount of displacement in the compression direction is 30%. It was 50% or more of the maximum compressive strength. That is, these biomaterials have excellent mechanical properties, for example, when they are compensated for in a bone defect portion or a tooth defect portion, the biomaterial is easily brittle even if a mechanical load is applied to these biomaterials. It was found that it was possible to avoid serious malfunctions such as damage without breaking.

FIG. 1 is a scanning electron microscope (SEM) photograph obtained by photographing the surface of the biomaterial of Reference Example 3. FIG. 2 is a scanning electron microscope (SEM) photograph obtained by photographing the surface of the biomaterial of Comparative Example 3.

Claims (5)

Calcium phosphate dispersed within the polymer in an amount of 10 to 70% by mass based on the total mass of at least one polymer selected from the group consisting of polylactic acid, polyglycolic acid and poly-ε-caprolactone and the polymer A biomaterial containing ceramic powder composed of a powder of a system material,
When the compressive stress is applied, the biomaterial has a maximum compressive strength of 1.5 MPa or more, a compressive strength when the amount of displacement in the compression direction is 30%, and 50 % or more of the maximum compressive strength, and 50 to A porous body having a porosity of 70%,
The ceramic powder existing in the surface layer from the outermost surface of the biomaterial to a depth of 10 nm is 3% by mass with respect to the total mass of the polymer and the ceramic powder existing in the surface layer measured by an X-ray photoelectron spectrometer. A biomaterial characterized by being 50% by mass or less.   The biomaterial according to claim 1, wherein the ceramic powder existing in the surface layer is 5% by mass to 40% by mass with respect to a total mass of the polymer and the ceramic powder existing in the surface layer.   The method for producing a biomaterial according to claim 1 or 2, wherein the polymer is molded together with the ceramic powder and immersed in an etching solution.   The method for producing a biomaterial according to claim 3, wherein the etching agent is an alkaline aqueous solution.   The alkaline aqueous solution is an aqueous solution having a pH of 12 or more, wherein at least one selected from the group consisting of hydroxides of alkali metal elements, hydroxides of alkaline earth metal elements and ammonia is dissolved. The manufacturing method of the biomaterial of Claim 4.

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