JPH0747042B2 - Artificial bone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention relates to an artificial bone as a bioceramic, and more particularly to an artificial bone containing hydroxyapatite and tricalcium phosphate.

[Conventional technology]

Conventionally, it is known to use various metal alloys, organic substances, etc. as a substitute for hard tissues of a living body. However, in general, it has a drawback that it shows deterioration due to dissolution or toxicity to the living body in the environment of the living body and is accompanied by a foreign body reaction. Therefore, at present, ceramic-based materials that are excellent in affinity with living organisms and do not have the above-mentioned drawbacks are being used.
Among these ceramic materials, alumina, carbon, tricalcium phosphate or hydroxyapatite, which has excellent biocompatibility, is being developed, and artificial bones or the like made of a single crystal are being developed and are attracting attention. In particular, hydroxyapatite is preferable because it can be expected to generate new bone soon after the implantation. Furthermore, hydroxyapatite does not contact new bone through connective tissue like alumina,
Has excellent affinity.

On the other hand, there is also a method of using these materials in the form of a porous body as a filling material for bone defects and voids, but it is insufficient in strength.

For example, JP-A-60-21763 discloses a hydroxyapatite sintered body as a porous material having continuous pores with a pore size of 10 to 100 μm as an artificial bone material, which is rapidly dissolved and absorbed to replace new bone. A method for producing the sintered body, which is produced by adding a thermally decomposable substance such as crystalline cellulose to hydroxyapatite powder, is disclosed.

As described above, hydroxyapatite is extremely excellent as an artificial bone material and has a remarkable biocompatibility. However, since its solubility product in water is as small as 10 ^-59 , it is practically hardly absorbed in the living body. That is, histologically, it exists as a foreign substance that is an inorganic substance to the living body for a long time.

Further, the above-mentioned tricalcium phosphate is a material that is easily absorbed in the living body, but the foreign body reaction is strong when it is implanted in the living body,
It has the disadvantage of inferior bone formation.

[Problems to be Solved by the Invention]

Therefore, an object of the present invention is to provide an ideal artificial bone which has excellent affinity and is remarkable in bone forming ability, and at the same time is practically uniformly dispersed in a living body.

Another object of the present invention is to provide an artificial bone that is free of foreign body reaction and integrates with surrounding bone tissue in a particularly short period of time without the need for connective tissue.

Still another object of the present invention is to provide an artificial bone capable of repairing and restoring the structure and function of a bone tissue defect portion particularly quickly.

[Means for Solving the Problems]

According to the present invention, an artificial bone having a weight ratio of hydroxyapatite to tricalcium phosphate in the range of 5:95 to 95: 5, wherein the hydroxyapatite primary particles having a particle diameter of 10 μm or less and the tricalcium phosphate primary particles are used. There is provided an artificial bone obtained by sintering particles, wherein hydroxyapatite and tricalcium phosphate are uniformly dispersed.

The present invention will be described in more detail below.

In the present invention, when attention is paid to the osteogenesis promoting ability of hydroxyapatite that new bone is generated at an early stage at the site when the hydroxyapatite is filled in the bone defect portion and the bone void portion, phosphoric acid which is easily absorbed in the living body. By using tricalcium in combination, we succeeded in producing a new artificial bone that compensates for the drawbacks of both hydroxyapatite and tricalcium phosphate.

In the present invention, the weight ratio of hydroxyapatite to tricalcium phosphate should be in the range of 5:95 to 95: 5. By arbitrarily selecting the weight ratio of hydroxyapatite and tricalcium phosphate within the above range, it is possible to control the degree of bone formation and resorption of artificial bone during implantation in a living body. An ideal artificial bone, when embedded in a bone defect or void, prompts repair of the bone defect and void as soon as possible, and an artificial bone that is not the original tissue for the living body is a biological body after repair. Those that are absorbed by are preferred. If the amount is less than 5% by weight of hydroxyapatite, the desired bone forming ability cannot be obtained, which is not preferable. vice versa,
If the amount of hydroxyapatite is more than 95% by weight, it will be poorly absorbed into the living body.

In the present invention, it is an essential requirement that hydroxyapatite and tricalcium phosphate are uniformly dispersed. If the uniform dispersion is not achieved, the ability of hydroxyapatite to promote osteogenesis and the absorbability of tricalcium phosphate into the living body cannot be fully exhibited. However, uniform dispersion cannot be achieved simply by mixing hydroxyapatite and tricalcium phosphate.

In the present invention, when the mechanism of bone metabolism during implantation of artificial bone was grasped and developed, hydroxyapatite and phosphorus per area of 0.5-1.0 mm ^{2 of} trabecular bone unit, which is one of the bone forming units of bone metabolism. The presence of both materials of tricalcium acid made it possible to obtain practically sufficient bone formation promoting ability and absorbability. For trabecular bone units, for example,
Published by Nishimura Shoten, edited by Eiaki Takahashi, “Handbook of bone morphology measurement”, pages 3 to 17: Outline of histological dynamics of bones, and published by Ikuyaku Shuppan, Tatsuo Suda, “Bone Science”, page 65 It is described in “Tissue development and growth of bone” on page 75.

In the present invention, the presence of materials of both hydroxyapatite and tricalcium phosphate per area of trabecular bone unit 0.5 to 1.0 mm ² is the reason why practically sufficient bone formation promoting ability and absorbability are obtained. The bone remodeling changes depending on the values of the bone unit (cortical bone portion) and trabecular bone unit, but the trabecular portion (cancellous bone portion) is particularly easily absorbed and the area can be easily measured. That is, since the formation of new bone is promoted by the presence of hydroxyapatite in the process of new bone formation during implantation of artificial bone, and the process of resorption of artificial bone promotes the resorption with tricalcium phosphate present as a nucleus, It is highly preferred that both hydroxyapatite and tricalcium phosphate materials be present per unit area of the beam.
In the present invention, the size of the trabecular bone unit may include voids such as micropores.

In the present invention, the primary particles forming the artificial bone are uniformly dispersed from the molding stage to 10 μm or less, preferably 5 μm or less.
The particle size is not more than μm. This is because it is necessary to prevent abnormal particle growth due to agglomerated particles during sintering.

In order to further promote the absorption of the artificial bone of the present invention into a living body, a micro clutch or a micropore may be added to the artificial bone.

In the present invention, in order to achieve the above-mentioned uniform dispersion, it is preferable to synthesize and mold as fine primary particles as possible by a wet synthesis method. In the wet synthesis, the synthesis temperature greatly affects the particle size of the primary particles, and the lower the temperature, the finer the primary particles can be synthesized. The temperature range that can be preferably used in the wet synthesis in the present invention is about 0 ° C to 80 ° C.
It is in the range of 0 ° C, and more preferably in the range of 0 ° C to 50 ° C. When the synthesis temperature exceeds 80 ° C, the particle size of the primary particles produced becomes large, and when it is lower than 0 ° C, the stirring operation becomes impossible due to freezing, which is not desirable. Although the particle size of the dried primary particles synthesized by the wet synthesis method is extremely fine, it is preferably pulverized after calcination because it agglomerates in the drying and calcination stages. However, in the artificial bone of the present invention, as long as the particle size of the primary particles is 10 μm or less, particularly 5 μm or less, the presence of aggregated particles is acceptable. This is a non-stoichiometric hydroxyapatite whose primary particle dried product has a structure of hydroxyapatite, but the ratio of calcium to phosphorus is different from the theoretical value of 1.67, and when it is calcined, it is uniformly dispersed. This is because a mixed system of hydroxyapatite and tricalcium phosphate can be obtained, and the dispersed state can be maintained well even if the mixed system is fired after molding.

In the present invention, in addition to the above-mentioned wet synthesis method, hydroxyapatite and tricalcium phosphate which are separately synthesized in advance by a known wet synthesis method, dry synthesis method or hydrothermal synthesis method are mixed and dispersed and used. You can also

As the artificial bone material of the present invention, both granules and porous bodies can be preferably used.

〔Example〕

 Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 While maintaining the temperature at 5 ° C., while stirring the calcium hydroxide suspension 2 having a concentration of 0.5 mol / mol, a phosphoric acid aqueous solution having a concentration of 30 wt% was added to change the Ca / P mole ratio. Hydroxyapatite was synthesized so that the ratio was 1.66, 1.64, 1.60, 1.57, 1.54 and 1.51, respectively, to obtain a suspension. After this suspension was centrifuged, it was dried overnight at 105 ° C. The obtained dried product was calcined at 800 ° C. for 3 hours and finely pulverized, and then 60 g of a 5% aqueous solution of polyvinyl alcohol having a degree of polymerization of 1700 was added, mixed and dried, and molded to remove the binder. When the dried product was observed with a transmission electron microscope, it was found to be extremely fine particles. When the particle size of the primary particles was measured, it was about 0.03 μm for dried products and about 0.1 μ for calcined products.
m, the average particle size (aggregated particle size) of the pulverized product after fine pulverization is about
It was 1.5 μm. Then, a sintered body was manufactured by firing at a temperature of 1100 ° C. As a result of identifying and quantifying the sintered body by the X-ray diffraction method, all were hydroxyapatite and tricalcium phosphate. The amount of tricalcium phosphate corresponding to the above Ca / P molar ratio is 7, 18, 40, 5 respectively.
The polymerization rates were 8, 76 and 94%. As a result of observing the dispersion state with a polarization microscope using a sintered body as a thin piece, the presence of hydroxyapatite and tricalcium phosphate in all the above compositions in the area (0.5 to 1.0 mm ² ) corresponding to the trabecular bone unit. Was confirmed. Further, when these thin pieces were etched with a hydrochloric acid aqueous solution and the particle size was measured using a scanning electron microscope, no particles of 2 μm or more were observed.

Example 2 The dried product of each Ca / P molar ratio produced in Example 1 was used to form a polyurethane foam by a method of replicating the shape of the polyurethane foam, and the mixture was baked at a temperature of 1100 ° C. to obtain 7 × 7 × 9 m.
A m-sized porous body was produced. The average pore diameter of the porous body is 2
It was 80 μm and the porosity was 85%.

A hole was made in the condyle of the tibia of the beagle dog, and eight types of manufactured porous bodies were embedded therein. June, 1 year and 2 years after the operation, the implant is taken out, cut in the longitudinal direction of the tibia, and then polished to about 100 μm.
A thin section of was prepared. Contact microradiographs of these thin sections were taken with a soft X-ray machine, and further,
The area ratio of the porous body and the new bone was measured with an image analyzer.
The results are shown in Tables 1 and 2 below. The same procedure was performed for tricalcium phosphate 100% by weight and hydroxyapatite 100% by weight. The results are also shown in Tables 1 and 2.

As is clear from the results shown in Tables 1 and 2, the area ratio of the embedded porous body tends to decrease with the passage of the embedding period and as the tricalcium phosphate content increases. It can be judged that it is easily absorbed by the living body. In particular, when tricalcium phosphate was 100% by weight, the amount of tricalcium phosphate was very small and easily absorbed after 2 years, but new bone formation was small over the entire period.

Further, when hydroxyapatite was 100% by weight, bone formation was good, but the residual amount of the porous body after 2 years was almost unchanged from that before implantation, and it was found that it was not absorbed. .

Also, after the above measurement, these thin sections were polished to 20 μm,
Histological observation was performed. As a result, the appearance of foreign body giant cells was particularly high when tricalcium phosphate was 100% by weight,
Observed over a long period of time. In the resorption pit, an image was observed in which particles around 1 μm, which are considered to be primary particles of the porous body, were phagocytosed by osteoclasts, and the shorter the embedding period, the more marked the phagocytosis.

Example 3 Commercially available hydroxyapatite powder (average particle size 5 μm)
60 parts by weight and 40 parts by weight of tricalcium phosphate powder were mixed in a pot mill, calcined at 800 ° C. for 3 hours and then finely pulverized to give a polyvinyl alcohol 5% aqueous solution having a degree of polymerization of 1700 60
g was added, mixed and dried, and then molded. After debinding
A sintered body was obtained by firing at a temperature of 1100 ° C. When the dispersed state was observed with a polarizing microscope using a sintered body as a thin piece, in the area corresponding to the trabecular bone unit (0.5 to 1.0 mm ² ), the proportion not containing particles of hydroxyapatite and tricalcium phosphate was about 30. %Met. Further, when the particle size was measured by the same method as in Example 1, many particles exceeded about 5 μm, and many particles with a maximum size of 10 μm were also observed.

Example 4 A test was conducted in the same manner as in Example 2 using the same formulation as in Example 3. The results are shown in Tables 1 and 2 below.

[Effect of the Invention] According to the present invention, hydroxyapatite and tricalcium phosphate are extremely uniformly dispersed, and when they are embedded in a bone defect portion and voids in a living body, formation of new bone and artificial bone in a short time. Absorption of the is observed, and early healing of the affected area can be achieved.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Yoshitaka Okubo Yoshitaka Okubo 2270, Yokoze, Chichibu-gun, Saitama Sanryo Mining & Cement Co., Ltd. Ceramics Research Laboratory (72) Toshiyuki Kurosawa 2270 Yokose, Yokose, Chichibu-gun, Saitama Sanryo Mining Cement Co., Ltd. Ceramics Research Laboratory (72) Inventor Takeshi Hyakutomi 2270 Yokose, Yokose-cho, Chichibu-gun, Saitama Prefecture Sanryo Mining Cement Co., Ltd. Ceramics Research Laboratory (56) Reference JP 62-69823 (JP, JP, 69-823) A) JP-A-63-89164 (JP, A) JP-A-63-111875 (JP, A) JP-A-1-293877 (JP, A)

Claims (1)

[Claims] 1. An artificial bone having a weight ratio of hydroxyapatite to tricalcium phosphate in the range of 5:95 to 95: 5, wherein the hydroxyapatite primary particles and the tricalcium phosphate primary particles having a particle size of 10 μm or less. Obtained by sintering and
An artificial bone characterized in that hydroxyapatite and tricalcium phosphate are uniformly dispersed.