Bioactive implant material

Description: TECHNICAL FIELD [Detailed description of the invention]

Industrial application field The present invention relates to novel bioactive implant materials. More specifically, the present invention is a non-calcium phosphate implant that has high strength, good acid resistance, and excellent bioactivity, and is suitable as a substitute material for biohard tissues such as artificial bones, artificial tooth roots, and artificial joints. It is about materials. Conventional technology So far, metals such as stainless steel, metallic titanium, and nickel-cobalt alloys and ceramics such as alumina and zirconia have been used as substitute materials for biohard tissues such as artificial bones, artificial tooth roots, and artificial joints. However, since they do not have the property of assimilating with living tissue, they remain in the body as unnecessary foreign substances after the role is completed, and there is an inconvenience that surgery for removal must be performed to remove them. there were. On the other hand, calcium phosphate-based materials similar in composition to bones and teeth assimilate over time in the living body and gradually bind directly to living tissues, so it is necessary to perform excision surgery even if they remain in the body. Recently, calcium phosphate-based ceramics mainly composed of apatite, tricalcium phosphate, bioglass, etc. have been attracting attention as bioactive implant materials. However, these calcium phosphate-based ceramics have a drawback that their applicable range is significantly limited because their mechanical strength is lower than that of stainless steel, metals such as titanium metal, and metal oxide-based ceramics such as alumina and zirconia. there were. In order to improve such defects, a sintered body in which alumina, silica, and other metal oxides are mixed with a calcium phosphate compound (Japanese Patent Publication No. 57-40803), β-tricalcium phosphate crystals and apatite crystals are used. High-strength crystallized glass composed of diopside crystals (Japanese Patent Laid-Open No. 61-197446), a material in which hydroxyapatite is fused to the surface of a core material having biocompatibility and strength (Japanese Patent Laid-Open No. 63-300754), Crystallized glass (Japanese Patent Laid-Open No. 63-303830) in which a strengthening component such as magnesium and silica is contained in a calcium phosphate-producing component has been proposed. However, all of these materials are based on the premise that in order to be assimilated with living tissue in the living body, the composition must be based on a calcium phosphate-based compound having the same quality as bone and teeth, and the selection of the composition is based on the premise. Due to the limited range, it was not always possible to sufficiently improve the physical properties. In addition, β-tricalcium phosphate has solubility in the living body and may be disintegrated before sufficient assimilation is performed. In addition, a calcium phosphate compound contains strengthening components such as alumina, silica, and diopside. The fired product may also be transformed into β-tricalcium phosphate, which may cause the same problem. Problems to be solved by the invention The present invention overcomes the drawbacks of such conventional implant materials, can be produced at a relatively low firing temperature, exhibits high mechanical strength, and has excellent biocompatibility. It was made for the purpose of providing. Means to solve problems As a result of various studies on bioactive implant materials, the present inventors have conducted CaO and SiO.₂And among ceramics containing MgO as an essential component, when they come into contact with body fluids, calcium phosphate compounds are generated at the contact parts, and despite being non-calcium phosphate ceramics, they exhibit good biocompatibility, especially bioactivity. We found this and came up with the present invention based on this finding. That is, the present invention describes CaO and SiO.₂And a bioactive implant material made of ceramics having a diopside composition containing MgO as an essential component. The bioactive implant material of the present invention is CaO, SiO₂It is composed of ceramics having a diopside composition containing MgO as an essential component, and CaO and SiO in this composition.₂The ratio with and is in the range of 1: 2 to 1: 3 by weight. If it deviates from this range, the sintering temperature at the time of manufacturing must be raised, and the strength and biocompatibility decrease. In addition, the content of MgO in the ceramics is in the range of 35% by weight or less based on the total weight, and by containing such MgO, the adhesion to bone is generally improved even if the firing temperature is lowered. be able to. The ceramics used in the present invention are characterized in that when they come into contact with a phosphorus-containing aqueous solution, for example, a simulated body fluid or a body fluid, a calcium phosphate-based compound such as hydroxyapatite is produced on the contact surface. Due to these characteristics, when this is implanted in a living body, an amorphous calcium phosphate-based compound having good biocompatibility is uniformly and rapidly precipitated on the contact surface with the living bone, and new bone is generated. To promote. Moreover, the joint portion with the living bone thus formed is extremely continuous because the components in the composition form an inclined structure and are crystallinely continuous between the implant and the living bone. Produces a strong bond. On the other hand, conventional implants made of hydroxyapatite do not deposit calcium phosphate compounds on the surface, so the formation of new bone is uneven and slow, and there are few new bones that come into contact with the implant at the initial stage, so the joint is weak. It becomes. The ceramic used in the present invention needs to have a diopside composition. By having such a composition, it can be fired at a relatively low temperature of 1200 to 1350 ° C, and has a high bending strength. The ceramics used in the present invention can be obtained by mixing calcium oxide, silicon oxide and, in some cases, magnesium oxide in a required ratio, calcining the calcined product, crushing the calcined product, and firing the calcined product again according to a conventional method. .. In this case, instead of these oxides, substances capable of producing these oxides under firing conditions, such as calcium and magnesium carbonates, bicarbonates, hydroxides and silicic acids, may be used. These raw materials can be used as powders or granules, as well as slurries or solutions. Instead of using raw materials corresponding to these individual components, preformed diopside CaO · 2SiO₂-MgO can also be crushed and used. In addition to the above-mentioned essential components, the ceramics used in the present invention usually have an optional component in an amount of 5% by weight or less, for example, Al, in order not to impair the desired physical properties as needed.₂O₃, TiO₂, Na₂OK₂O, ZnO, B₂O₃Etc. can be blended. In order to produce the implant material of the present invention, for example, the above-mentioned raw materials for ceramics are powdered and mixed well with a mixer such as a ball mill, a vibration mill, an automatic mortar, a mixer, a juicer, a sand mill, a whisk, etc., and then mixed well. Dry at 50-300 ° C for 10 minutes to 100 hours, then bake at 500-1600 ° C, preferably 800-1600 ° C for 10 minutes to 200 hours. The calcined product thus obtained is crushed, and if necessary, a binder such as polyvinyl alcohol is added to form a desired shape by a pressing method, a slip casting method, etc., and then dried, and this is dried at 800 to 1600 ° C. , Preferably fire at a temperature in the range of 1100 to 1550 ° C. The particle size of the raw material powder at this time is BET, which is usually 0.5 m.²/ g or more, preferably 1 m²/ g or more, more preferably 3m²Set to / g or more. In addition, the molding pressure is 1 to 3000 kg / cm.²Is used. The firing time is usually 10 to 20 hours. Further, although firing is performed at normal pressure, it can also be performed under pressure if necessary. The pressure at this time is usually 10 to 3000 kg / cm.²It is selected in the range of. The implant material of the present invention can also be formed as a porous body having independent pores and continuous pores. When a porous body is formed using the bioactive implant material of the present invention, the strength is higher than that of the conventional calcium phosphate-based material, so that the pore diameter and porosity range can be selected relatively freely, and high biocompatibility. You can get sex. This porous body is usually formed to have a pore diameter of 5 to 2000 μm, preferably 10 to 1000 μm, a porosity of 10 to 80%, preferably 20 to 70%, and more preferably 25 to 60%. This product is produced by mixing a pyrolytic substance, an organic fiber, or the like into a raw material and firing it in accordance with a conventional method for producing porous ceramics. The porous implant material thus obtained usually has a compressive strength of 10 MPa or more, often 15 MPa or more. The implant material of the present invention may be used as a block having a required shape, or may be used as granules for filling a bone defect. In this case, the granule diameter is usually selected in the range of 0.05 to 5 mm, preferably 0.1 to 3 mm, and more preferably 0.1 to 2 mm from the viewpoint of newborn bone formation and strength. Effect of the invention The bioactive implant material of the present invention has strength and acid resistance comparable to that of bioalumina, and adhesion to new bone progresses much faster than calcium phosphate implant materials such as β-tricalcium phosphate and hydroxyapatite. And form a uniform bond. In addition, the joint with the living bone is low-crystal or amorphous, and its components have a continuous concentration gradient, and the closer to the living bone, the more similar the component composition to the living bone. Therefore, there are various advantages such as strong bondability and less fatigue. 4 Therefore, the implant material of the present invention is suitably used as a substitute material for living hard tissues such as artificial bones, artificial tooth roots, and artificial joints. Example Next, the present invention will be described in more detail by way of examples. The method for measuring the bending strength and acid resistance of the sample is as follows. (1) Relative density; Powder (5m) obtained by measuring the sintering density of the sample by the Archimedes method and crushing the sintered body.²The true density of / g) was measured and calculated as the ratio of the two. (2) Bending strength; The sample was cut into 3 × 4 × 40 mm, mirror-polished, and measured by a 3-point bending test under the conditions of a span distance of 36 mm and a crosshead speed of 0.5 mm / min (n = 10). (3) Compression strength; The sample was cut into 10 × 10 × 10 mm and measured by a compression test under the condition of a crosshead speed of 0.5 mm / min (n = 10). (4) Fracture toughness value (Kic); Measured based on ASTM E399-83. (5) Crystal grain size; From the crystal grain area measured by a scanning electron microscope, the average diameter was calculated assuming this as a circle. (6) Hydroxyapatite formation; Na⁺142.0 mmol, K⁺5.0 mmol, Mg²⁺1.5 mmol, Ca²⁺2.5 mmol, Cl^-148.8 mmol, HCO₃^-4.2 mmol, and HPO₄^2-Keep 150 ml of a pseudo-body fluid consisting of an aqueous solution containing 1.0 mmol at 37 ° C, immerse the sample (3 mm × 4 mm × 2 mm, 6 pieces) in this, observe the precipitated phase with SEM 7 days later, and perform the following evaluation. Judgment was made by the standard. The components of the precipitated phase were measured by electron beam diffraction. 5 ... Precipitated throughout 4 ... Precipitated almost entirely but not partially 3 ... about half precipitation 2 ... Slightly precipitated 1 ... Almost no precipitation 0 ... No precipitation at all (7) Acid resistance; surface area 200 mm in 200 cc of pH 4 lactic acid aqueous solution²The sample was charged and left for 48 hours while keeping the solution temperature at 37 ° C in a constant temperature bath and shaking the solution slightly. The test sample was immediately washed with water, dried, and then evaluated by measuring the weight loss rate. Examples 1 to 4, Comparative Example 1 CaO, MgO and SiO with an average particle size of 5 μm₂The powder was mixed at a predetermined ratio, dried at 80 ° C for 5 hours, and then baked at 950 ° C for 5 hours. Next, this calcined product was crushed, 2% by weight of polyvinyl alcohol was added as a binder, and the molding pressure was 50 kg / cm.²The implant material having the composition shown in Table 1 was obtained by press molding at 80 ° C, drying at 80 ° C for 5 hours, and firing at 1350 ° C for 2 hours. The results of the bending strength and acid resistance tests of this product are shown in Table 1 together with the test results of hydroxyapatite.<img file="JP2898331B2_D0001.tif" /> From these results, it can be seen that the product of the present invention is less likely to break than hydroxyapatite, can withstand long-term use, and has excellent durability. Moreover, when the formation state of hydroxyapatite in the simulated body fluid was observed, the formation of hydroxyapatite was observed on the surface of each of the products of the present invention after 3 days. For comparison, the same test was performed on alumina and titanium, but no hydroxyapatite formation was observed even after 10 days. Examples 5 to 7, Comparative Examples 2 to 13 Implant materials having the compositions shown in Table 2 were produced in the same manner as in Examples 1 to 4 except that the raw material ratio and the firing temperature were changed. Table 2 shows the physical characteristics of the ceramics obtained in this way.<img file="JP2898331B2_D0002.tif" /> As is clear from this table, although the conventional implant materials do not have the ability to produce hydroxyapatite, all the implant materials of the present invention show good ability to produce hydroxyapatite. Examples 8 to 24, Comparative Examples 14 to 20 Predetermined amount of CaO, SiO₂To the powder mixture consisting of and MgO, the amount of crystalline cellulose shown in Table 3 was added as a pyrolyzable substance, dried at 70 ° C. for 5 hours, and then calcined and calcined at the temperature shown in Table 3 to obtain granules. Manufactured body and block porous implant materials. The physical characteristics of the obtained implant material are shown in Table 3 (granule) and Table 4 (block). The biocompatibility test was performed as follows. A 3 × 4 × 6 mm filling hole was formed in the mandible of a mature male rabbit weighing 2.5 to 2.8 kg, and a porous implant material was filled in the mandible. Six weeks after the operation, a non-decalcified polished specimen was prepared, and the SEM image of the interface between the implant material and the new bone was observed and judged according to the following evaluation criteria. a ... The newborn bone was completely adhered to the implant material and completely penetrated into the implant hole. b ... More than half of the new bone adhered to the implant material and more than half of it had penetrated into the implant hole. c ... More than half of the new bone adhered to the implant material and partly penetrated into the implant hole. d ... The newborn bone was partially adhered to the implant material and partially penetrated into the implant hole.<img file="JP2898331B2_D0003.tif" /><img file="JP2898331B2_D0004.tif" /> As is clear from this table, the implant material of the present invention exhibits higher strength than calcium phosphate-based implant materials such as hydroxyapatite and tricalcium phosphate even when made into a porous body, and has biocompatibility. It is high and has a strong adhesion with new bones. Application example The diopside (Sample A) obtained in Example 5, the hydroxyapatite (Sample B) containing 20% by weight of the diopsite composition, and the hydroxyapatite (Sample C) were each formed into blocks having a size of 3 × 4 × 6 mm, and these were formed into blocks having a size of 3 × 4 × 6 mm. A 2.5-2.8 kg male mature rabbit was implanted in the mandible and the course was observed. Two weeks after the treatment, the formation of new bone was observed in all the samples, but in sample A, the contact between the sample block and the new bone was close as a whole, whereas in sample B and sample C, one Most of them had gaps, only the parts were in direct contact. Four weeks after the procedure, it was observed that the thickness of the layer structure of the contact portion with the newborn bone increased for sample A, but for sample B and sample C, the thickness of the layer structure of the contact portion increased. No change was observed. Twenty-four weeks later, the new bone and the periosteal bone were integrated in each sample, and the boundary between them became unclear, but the arrangement of bone cells in sample B and sample C was parallel to the sample block and was parallel to the periosteal bone. In the case of sample A, the arrangement of bone cells is completely uniform with that of the mother bed bone, and the joint with the mother bed bone and the periosteal side of the outer surface of the block are completely different from each other. Was not recognized. FIG. 1 is a spectral diagram of EPMA showing the compositional change of the junction between diopside and new bone after 12 weeks for sample A, and a concentration gradient of the components is formed in the intermediate layer between new bone and diopside. You can see that. In addition, Fig. 2 shows a high-resolution image of the junction between sample A and the mother bed bone after 24 weeks by a transmission electron microscope, and as is clear from this, the arrangement of bone cells is on the diopside side. It is exactly the same as the mother's floor bone side, and the boundary is hardly identified.

[Simple explanation of drawings]

Fig. 1 is an analysis graph by EPMA showing the concentration gradient of the component at the joint with the mother bed bone when the implant material of the present invention is implanted in the animal body, and Fig. 2 is the arrangement of the crystal structure of the same joint. It is a transmission electron micrograph which shows.