JPH0325181B2 - - Google Patents

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention is directed to artificial bone materials suitable for use in dentistry, oral surgery, orthopedic surgery, etc. Made from granular porous sintered hydroxyapatite, which has excellent biocompatibility and can be filled into bone defects and voids to promote the formation of new bone in the area, and can be integrated with the bone structure of the living body. The present invention relates to a method of manufacturing an artificial bone material comprising:

Conventional technology Conventionally, in dental treatment, there has been a problem in which the alveolar bone is resorbed after tooth extraction, making it impossible to secure dentures etc. In addition, in oral surgery and orthopedic treatment, there has been a problem in cases such as traffic accidents, bone tumors, etc. In order to replace the bone lost due to this disease, attempts have been made to transplant bone from other parts of the patient, i.e., autologous bone, but since bone tissue other than the damaged area is removed, the patient's There were problems such as the extremely heavy physical and psychological burden and the inability to collect enough autologous bone to fill in extensive bone defects.

Under these circumstances, research on artificial tooth roots and artificial aggregates has been actively conducted in recent years. When implanting these artificial bones into a living body, it is necessary to select materials that are non-toxic, safe, have considerable mechanical strength, and are easily bonded to living tissue. Furthermore, it is preferable to use a material that naturally disappears in the living body and is replaced by new bone.

In recent years, sintered bodies of tricalcium phosphate, hydroxyapatite, or calcium phosphate compounds with a special apatite-type crystal structure have attracted attention as materials that meet these requirements, and artificial bones using these materials,
Research into artificial joints, artificial tooth roots, etc. is actively being conducted.

By the way, when an artificial bone or tooth root is implanted in the body, in order to make it easier to bond with the living tissue, it is necessary to make it porous so that the living tissue can enter the pores and fix it. and to achieve this purpose, e.g. pore size 0.03
It has been proposed to use a porous calcium phosphate sintered body having pores of about 1.2 mm (Japanese Patent Application Laid-open Nos. 149389-1989 and 7856-1987).

However, this artificial aggregate made of porous calcium phosphate sintered material is hard and brittle.
It has the drawback of not having sufficient mechanical strength, and since the material is dense, it is not necessarily satisfactory in terms of in-vivo absorption and replacement of new bone.

Furthermore, a bone defect filling material has been proposed in which a powder of an apatite-type crystal structure calcium phosphate compound with a crystal grain size of 50 Å to 10 μm is made into a fluid or plastic state by adding physiological saline etc.
−54841). However, since the calcium phosphate compound used in this filling material is in the form of a fine powder, when this material is filled into a bone defect and sutured, the fine powder adheres to the surface of the skin wound, making suturing difficult. It has the disadvantage of being.

Problems to be Solved by the Invention The purpose of the present invention is to improve the above-mentioned drawbacks, to fill bone defects and voids, to promote the formation of new bone in the areas concerned, and to provide bone tissue itself. It is an object of the present invention to provide a manufacturing method for obtaining an artificial bone material that can be integrated into one body, has excellent biocompatibility, and does not cause any adverse effects during surgery.

Means for Solving the Problems The present inventors have developed a method using hydroxyapatite as a raw material.
As a result of intensive research to obtain an artificial bone material that can be smoothly integrated into bone tissue without causing any side effects when used to fill bone defects or voids,
The inventors have discovered that the objective can be achieved by granulating a mixture of hydroxyapatite and crystalline cellulose and firing it under predetermined conditions, and based on this knowledge, the present invention has been accomplished.

That is, the present invention provides 100 parts by weight of hydroxyapatite powder with an average particle size of 0.1 to 10 μm and 100 parts by weight of hydroxyapatite powder with an average particle size of 10 to 10 μm.
After granulating a mixture with 2 to 100 parts by weight of 100 μm crystalline cellulose into granules with a particle size of 0.1 to 3.0 mm,
The present invention provides a method for producing an artificial bone material characterized by firing at a temperature of ~1400°C.

The hydroxyapatite used in the present invention may be apatite synthesized by a dry method or a wet method, or may be a living body apatite recovered from bones and teeth of various vertebrates. It is desirable to use this raw material, hydroxyapatite, that has been ground into as fine a powder as possible.
Due to equipment limitations such as crushers and classifiers and handling problems, the average particle size is 0.1 to 10 μm, preferably
A thickness in the range of 0.5 to 7 μm is used.

Next, the crystalline cellulose used in the present invention is a fine powder obtained by hydrolyzing cellulose with mineral acid, washing and removing the amorphous portion, then grinding, refining, and drying, and sintering hydroxyapatite. It is blended in order to form continuous pores with a desired pore size during the process. In the present invention, the pore size is 10~
In order to obtain porous granules with continuous pores of 100 μm and a porosity of 20 to 50%, the average particle size is 10 to 100 μm.
25 per 100 parts by weight of hydroxyapatite powder
It is necessary to mix it in a proportion of ~100 parts by weight.
When using particles with an average particle size of less than 10 μm, the pore size of the continuous pores of the resulting porous granules becomes too small, making it difficult for osteoclasts to invade when used as a filler in a living body, resulting in new growth. Replacement with bone becomes slow, and if particles with an average particle size larger than 100 μm are used, the resulting porous granules
It has continuous pores with a pore size larger than 100 μm, but fibrous cells grow preferentially in the continuous pores with such a large pore size, which causes inhibition of the growth of bone lining cells.

Until now, plastics such as methyl methacrylate, polypropylene, and polystyrene have been used as sublimable substances to form pores in the production of calcium phosphate-based porous granules, but these substances are not completely removed during sintering. If used as is, it will have a negative effect on the human body,
The crystalline cellulose used in the present invention is harmless to the human body, is not contaminated by microorganisms such as mold or bacteria, and is chemically inert, so it is completely harmless even if taken into the body.

In addition, as mentioned above, this crystalline cellulose is
It is necessary to use it in a proportion of 25 to 100 parts by weight per 100 parts by weight of hydroxyapatite. If the amount is less than this, the porosity of the artificial bone material obtained will be less than 20%, and sufficient continuous pores will not be formed.If the amount is too large, the porosity will exceed 50%, and the apparent density and mechanical strength will be Significantly decreased. In terms of mechanical strength, 30 to 70 parts per 100 parts by weight of hydroxyapatite
The preferred range is 40 to 60 parts by weight.

Any means may be used to mix the hydroxyapatite powder and crystalline cellulose as long as they can be mixed together. For example, hydroxyapatite powder and crystalline cellulose may be mixed as is using an appropriate mixer, or hydroxyapatite powder may be formed into granules with a particle size of 20 to 200 μm in advance and mixed with crystalline cellulose. You may. Furthermore, it is also possible to wet the surface of crystalline cellulose with water or other solvent, and then uniformly adhere hydroxyapatite thereto.

In the present invention, it is necessary to granulate the thus prepared mixture of hydroxyapatite powder and crystalline cellulose into granules with a particle size of 0.1 to 3.0 mm. During this granulation, a binder such as polyvinyl alcohol can be added if necessary.

If the particle size is less than 0.1 mm, it will adhere to the surface of the skin wound and suturing will be difficult when filling bone defects etc., and if it exceeds 2 mm, it will be difficult to suture with saline. If this is added, a uniform slurry will not be formed, making handling during surgery difficult.

The granules thus granulated are then gradually heated to a temperature of 900-1400°C and calcined at this temperature. Firing time is usually 0.5 to 3 hours.
Although the firing can be carried out without applying pressure, it is preferable to carry out the firing by applying a pressure of 300 to 1000 kg/cm ² using a hot press, for example.

The granular porous hydroxyapatite sintered body thus obtained can be used as a uniform slurry by adding physiological saline, for example. At this time, the ratio of the sintered hydroxyapatite and physiological saline is usually 2:1 to 1:2 on a weight basis.
selected within the range.

Effects of the Invention Since the artificial bone material obtained by the present invention uses hydroxyapatite and crystalline cellulose, which is harmless to the human body, it will not cause any adverse effects even if it is filled into the human body for a long period of time. I'm not there.
In addition, since it uses a granular porous apatite sintered body with a grain size of 0.1 to 2.0 mm, which has continuous pores with a pore diameter of 10 to 100 μm and a porosity of 20 to 50%, it can be used to remove bone defects and voids. When filled with Osteoclast cells (50~
100 μm) and bone mole cells (20 to 30 μm) enter the pores, and under their influence, the growth and absorption of new bone occurs normally, and a strong bond between hydroxyapatite and new bone is realized. shows. Furthermore, since it does not adhere to the skin wound surface during suturing, surgery can be performed easily. Therefore, this artificial bone material is suitable for treatments such as dentistry, oral surgery, and orthopedics.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples.

Example Hydroxyapatite synthesized by a wet method was calcined at 900° C. for 1 hour, and then ground to an average particle size of 0.5 μm using a ball mill. Next, 2 parts by weight of polyvinyl alcohol and 50 parts by weight of crystalline cellulose powder with an average particle size of 50 μm were added to 100 parts by weight of this material.
After mixing, this was granulated into granules with a particle size of 0.5 to 3.0 mm, and heated to 1350°C at a heating rate of 100°C per hour.
After sintering at this temperature for 1 hour, the average pore size was 50μ.
A granular sintered body of hydroxyapatite with a porosity of 26% and having continuous pores of m was obtained.

100 parts by weight of physiological saline was added to 100 parts by weight of the granular porous hydroxyapatite sintered body thus obtained to form a slurry, thereby obtaining the artificial bone material of the present invention.

Comparative Example A porous hydroxyapatite sintered powder with a particle size of 5 to 10 μm (before granulation in the example) was prepared in the same manner as in the example.
An artificial bone material was obtained by adding 100 parts by weight of physiological saline to 100 parts by weight to form a slurry.

Application example When a surgery was performed to fill the bone defect in the mandible of a rabbit with the artificial bone material obtained in the example, no adhesion to the skin wound surface was observed, suturing was extremely easy, and the wound The tumor was cured without surface incision or reactive inflammation.

When the bone structure after this surgery was observed under a microscope 12 and 24 weeks later, the following findings were obtained.

After 12 weeks, the new bone structure formed between the hydroxyapatite granules increases in thickness and density, and a lamellar structure is clearly observed. In addition, osteoclasts appeared in some areas and were observed to be resorbing new bone with a lamellar structure formed in contact with hydroxyapatite granules, indicating the active progress of bone remodeling. . In the pores inside the hydroxyapatite granules,
Bone algae cells invade and new bone formation is observed along the pore walls. No reaction inflammation was observed in the surrounding area of the transplant site, indicating a good healing process.

After 24 weeks, the new bone formed between the hydroxyapatite granules becomes thicker and denser.
Hydroxyapatite granules are scattered between the new bones. The pores inside the hydroxyapatite granules are filled with new bone, and some are also resorbed by osteoclast-like multinucleated giant cells. It can also be seen that the lacunae of the new bone are arranged in a regular manner, and the lamellae are arranged in the longitudinal direction of the jawbone. Furthermore, enlarged Haversian canals and bone marrow formation were observed, forming a strong matrix with hydroxyapatite granules and bone tissue, resulting in complete bone regeneration.

Comparative application example When a surgery was performed in which the artificial bone material obtained in the comparative example was used to fill a bone defect in the mandible of a rabbit in the same manner as in the application example, the material adhered to the skin wound surface and suture closure was difficult. It was hot. In addition, even after suturing, dehiscence of the wound surface and reactive inflammation of the tissue were observed, and healing was delayed.

In addition, changes in bone structure after 12 and 24 weeks were observed using a microscope, and the following findings were obtained.

In other words, even after 12 weeks, reactive inflammation in the tissue around the implantation site continues, and particles around the host bone are still connected to the new bone, but most of them are surrounded by fibrous connective tissue. was.

Furthermore, after 24 weeks, the reactive inflammation in the tissue around the implantation site had disappeared, but the generation of new bone was limited to the surroundings of the host bone, and most of the particles were transferred to the fibrous connective tissue. The bone was surrounded and complete bone healing could not be achieved.

Claims (1)

[Claims] 1 Hydroxyapatite powder with an average particle size of 0.1 to 10 μm
A mixture of 100 parts by weight and 25 to 100 parts by weight of crystalline cellulose with an average particle size of 10 to 100 μm is mixed with a particle size of 0.1 to 3.0 mm.
A method for producing an artificial bone material, which comprises granulating the material into granules and then firing at 900 to 1400°C.