JPH05305134A - Porous calcium phosphate material for bone formation - Google Patents

Abstract

PURPOSE:To achieve a growth of a bone in a short time by arranging a molded product which is composed of calcium phosphate to be used for filling a lost part or the like of the bone in such a manner as to let pores truly spherical with a specified diameter having the surface thereof formed rugged finely disperse with a specified porosity. CONSTITUTION:Calcium phosphate employs a signal phase of hydroxyapatite [Ca10 (PO4)6 (OH)2] which is the same in composition as the inorganic component of a natural bone and allows the forming of a bone quickly in vivo. A powder of hydroxyapatite is mixed with material for forming truly spherical pores comprising an organic compound or carbon that allows thermal decomposition at a specified ratio and made closer properly by a pressing and then, the more forming material is burnt away by heating in an atmosphere of an inert gas to be baked in the atmospheric air. This enables the obtaining of a porous calcium phosphate material in which truly spherical pores with a uniform size of 100-300mum having the surface thereof formed rugged finely are dispersed three dimensionally with a porosity of 50-80%.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a bone-forming porous calcium phosphate for filling a bone defect or void caused by a disease, an accident or a surgical operation to generate new bone in this portion. The present invention relates to a material, and in particular, it is a material suitable for a support when an osteogenic factor is added to accelerate bone formation.

[0002]

2. Description of the Related Art In surgery, orthopedics and oral surgery, autologous bones are collected from other parts of a person's body and filled in the bone defects and voids caused by illness, accident or surgery. By doing so, reconstruction of the bone tissue of the relevant portion is performed. However, the patient suffers from the increased number of operations for bone harvesting. Although alternative materials have been conventionally used for the purpose of reducing this pain, in the case of metal-based materials, toxic metal ions may elute due to dissolution in the living body. Further, even in the case of a ceramic material, although alumina and zirconia exist stably in the living body, mechanical bonding is inevitably used for bonding with the bone tissue itself. In contrast,
Among ceramic materials, calcium phosphate-based tricalcium phosphate [Ca ₃ (PO ₄ ) ₂ ], hydroxyapatite, tetracalcium phosphate [Ca ₄ O (PO ₄ ) ₃ ].
Is chemically bonded to bone tissue in vivo, and is being applied to artificial bones and teeth. In particular, hydroxyapatite is used as a material for coating the surface of a metal material such as titanium by a method such as thermal spraying, and the metal material on which this hydroxyapatite coating is formed is used for artificial tooth roots and hip joints. Further, as a filler for the bone defect portion, a sintered body of natural hydroxyapatite or synthetic hydroxyapatite obtained by burning cow bone or fish bone as a raw material is used.

[0003]

However, the above-mentioned materials have a problem that bone formation in vivo is not carried out promptly and a long period of time is required for healing. In order to improve this, a sintered body has been proposed which has a porous structure to circulate body fluid in a living body and to invade various cells inside to promote bone formation. The formation speed is not sufficient. In addition, as another method for accelerating bone formation, F
GF (fibroblast growth factor), BMP (bone mor
There is an example of implanting bone morphogenetic proteins such as phogenetic protein) with bone demineralization residue and glass fiber as a support. However, although bone formation is promoted, cartilage formation is observed in the early stage. There is. We have
As a result of diligent research, the use of a calcium material having a specific structure improves the rate of bone formation, and when used as a support for the osteogenic factor, cartilage formation was not observed, and it was extremely short-term. The present invention has been completed by finding that bones are cultivated satisfactorily.

[0004]

In order to solve the above-mentioned problems, the present invention is a molded product made of calcium phosphate, having 50 to 80 true spherical pores having a uniform size of 100 to 300 μm. It is characterized in that it is formed three-dimensionally continuously with a porosity of%, and that the surface of the pores is constituted by fine irregularities. The second invention has a particle size of 3
A granular body composed of calcium phosphate particles having a diameter of 0 to 1000 μm, in which the spherical pores having a uniform size of 100 to 300 μm are three-dimensionally continuous with a porosity of 50 to 80%. It is characterized in that the surface of the pores is constituted by a fine uneven surface.

Hydroxyapatite [Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ] single phase is suitable as the above-mentioned calcium phosphate, and it is synthesized by a dry method, a wet method or the like. Hydroxyapatite has the same composition as the mineral component of natural bone, and bone formation in vivo is fast. However, Ca and P
When the hydroxyapatite having a non-stoichiometric composition with a ratio of Ca / P = 1.67 deviates from 1300
When heat-treated at a high temperature of ℃ or higher, tricalcium phosphate or tetracalcium phosphate appears due to decomposition. When they are implanted in a living body, these decomposition products are easily dissolved, so that the pH of the body fluid around the support is increased and the bone formation is delayed. Therefore, it is preferable that the hydroxyapatite has a single phase without decomposition products even after sintering. Further, the above-mentioned calcium phosphate material can retain an osteogenic factor.

The method for producing the calcium phosphate material of the present invention is not particularly limited. For example, hydroxyapatite powder synthesized by a wet method is mixed with a pyrolyzable organic substance or a spherical pore forming material made of carbon in a predetermined ratio. After mixing with a mold and densifying with a die and isostatic pressing, the mixture is heated in an atmosphere of an inert gas such as nitrogen or in the atmosphere to burn off the pore-forming material, and then in the atmosphere. It can be created by sintering. In the case of a granular powder, it is possible to obtain a porous granule having a predetermined particle size by crushing after isostatic pressing, or after sintering, and pulverizing. When the hydroxyapatite powder used at this time has a size of several to several tens of μm, the surface of the hydroxyapatite powder is likely to have irregularities when it is brought into close contact with the spherical pore-forming material by a press, and the irregularity shape is maintained even after sintering. Is maintained.

[0007]

EFFECTS OF THE INVENTION According to the present invention, the pores have good penetrability and have a structure in which blood flow is not obstructed even when implanted in the body, and oxygen in blood is well supplied and does not pass through cartilage. The bone is well formed by the method, and after the bone is formed, continuous pores that maintain blood flow remain inside. Further, when the calcium material of the present invention was implanted in a living body together with a bone morphogenetic factor such as BMP, good bone formation was shown even in a region without bone (subcutaneous), and the bone periphery such as a bone defect portion or a void portion was shown. The present invention is effective not only in bone formation but also in the treatment of forming bone in a bone-free portion such as alveolar bone degenerated by alveolar pyorrhea.

A detailed reason for limiting the structure will be described below together with the detailed operation. The calcium material of the present invention is composed of a porous body, which effectively introduces osteoblasts existing in the living body into the inside of the support, and maintains the blood flow to the inside of the support, thereby promoting bone formation. This is for speed. Therefore, in order to stably retain osteoblasts of about 10 μm and efficiently perform osteogenesis, the pore diameter must be 100 to 300 μm. When the pore diameter is less than 100 μm, bone-forming cells cannot enter the pores, and when it exceeds 300 μm,
With the circulation of body fluid, cells easily flow out,
It is limited to the above range.

[0009] Also, the cells penetrate into the calcium material,
To maintain sufficient blood flow, all pores must be continuous, and in order to have non-anisotropic three-dimensional pore continuity, a perfect spherical pore shape is optimal. ..
Furthermore, in order to allow cells to uniformly penetrate into the entire porous body, it is desirable that the pore diameter be as uniform as possible.
If the porosity is less than 50%, the continuity of the formed pores is reduced and independent closed pores are generated, so that cell invasion and blood circulation cannot be performed. Also, in the case of the closest packing of spheres of uniform diameter, the volume occupied by spheres is 74%. Considering the fine pores of calcium phosphate, if it exceeds 80%, calcium phosphate powder will be sufficient between the pore-forming materials. It is not filled up to a certain amount, and densification cannot be achieved even by an isotropic hydrostatic press, so the above range is set.

The surface of the calcium phosphate in the pores is not in a smooth state, but has fine irregularities so that cells can be smoothly attached to the surface, which is a factor for accelerating bone formation. Moreover, even if a hydroxyapatite single phase is used as calcium phosphate, its surface is likely to be eluted in vivo and a local increase in pH tends to occur in vivo to slow down invasion of osteoblasts. Before filling the material into the living body, it is desirable to remove components that are likely to be eluted by immersing it in a neutral phosphate buffer solution and then washing it. Formation can be accelerated. In addition, calcium phosphate material 30
When it is used in a granular state of 0 to 1000 μm, invasion of osteoblasts is rapidly completed throughout the filled hydroxyapatite, and the entire bone formation is performed. Granule diameter is 300μm to ensure pore diameter of 100μm or more
The above is required, and if it exceeds 1000 μm, the same behavior as bulk occurs and the characteristics as a granule are lost, so the above range is set.

[0011]

【Example】

(Example 1) Calcium hydrogen phosphate dihydrate [CaHP
O ₄ .2H ₂ O] was hydrolyzed in an alkaline aqueous solution to obtain a hydroxyapatite powder (calcium phosphate powder) having a calcium to phosphorus ratio (Ca / P) of 1.67. This powder was flaky crystals having a particle size in the range of 1 to 120 μm and an average particle size of 15 μm. This powder was calcined in the air at 800 ° C. for 3 hours and then 100 to 2
Acrylic spherical resin having a diameter of 00 μm was mixed at a weight ratio of 5: 4.

This mixed powder is pressed with a die press to 200
at a pressure of kg / cm ^2, after forming a 20mm diameter × 4 mm thick, and rubber-pressed at a pressure of 3000 kg / cm ^2.
This is heated to 600 ° C. in a nitrogen atmosphere to decompose and evaporate the acrylic resin, then 1200 ° C. in the atmosphere,
Sintered for hours. The porosity of the porous hydroxyapatite prepared in this way is about 70%, and the inner surface of the pores is fine when flaky hydroxyapatite adheres to the spherical resin as shown in the SEM observation image of FIG. The irregularities (roughness of about 1 μm) were retained. This porous body was molded into a size of 5 × 5 × 3 mm, and in the case of only the porous body, the case of adding bone marrow cells, or the case of adding bone morphogenetic protein, each test piece was implanted subcutaneously on the back of a mouse. Was observed.

As a result, in the case of only hydroxyapatite, cells invaded only the surface layer of the porous body after 3 weeks, but penetrated into the interior with the passage of time, and completely invaded after 9 weeks. .. In addition, partial bone formation was observed after 9 weeks. Even when bone marrow cells were added, bone formation was similar to that of hydroxyapatite alone. On the other hand, when the bone morphogenetic protein was added, the cells invaded rapidly, and 6 weeks later, the cells invaded the inside. In addition, bone formation was fast, and partial bone formation had already occurred in 6th round, and ossification had progressed in 9th round.

(Example 2) The porous hydroxyapatite material prepared in Example 1 was molded into 5 x 5 x 3 mm, and then p
After washing with a phosphate buffer of H = 7.4 for 2 to 3 days, bone morphogenetic proteins were added and the mice were subcutaneously implanted as in Example 1. As a result, invasion of cells was faster than that of the equivalent product of Example 1, and the outer peripheral portion of the test piece was almost calcified after 3 weeks.

Example 3 A molded body obtained after rubber pressing in the manufacturing process of Example 1 was manufactured in the same manner,
This was crushed and granules having a particle diameter of 300 to 500 μm were collected by sieving. The granules of porous hydroxyapatite were obtained by again evaporating the resin from the granules in the same post-process as in Example 1 and further sintering. Bone morphogenetic protein was added to the obtained granules, and they were implanted subcutaneously on the back of mice. As a result, cells were invaded into all stomata after 1 week, and ossification occurred after 2 weeks.
In addition, the absorption of the granular porous body is occurring, suggesting that the conversion into complete bone is performed very quickly.

(Comparative Example 1) Natural bone-derived hydroxyapatite block obtained by burning bovine bone was measured in a size of 5 × 5 × 3 mm.
Each test piece was formed subcutaneously on the back of a mouse, and the subsequent process was observed in the case of forming only the block, adding the bone marrow cells to the block, and adding the bone morphogenetic protein. As a result, in the case of only the block, the cells have already penetrated into the inside after 3 weeks as compared with the equivalent product of Example 1, and the invasion of the cells is very fast. However, bone formation was fast, and bone formation did not occur even after 9 weeks. In addition, the effect of addition of bone marrow cells was not observed. Further, when the bone morphogenetic protein was added, the invasion of cells was faster than in the case of only the block, and there was a part of ossification after 9 weeks, but the bone formation rate was significantly inferior to that in Example 1. Was there.

[0017]

As described above, according to the bone forming porous calcium phosphate material of the present invention, a molded body made of calcium phosphate having a uniform size of 100 to 300 μm diameter is used. Spherical pores are continuously formed three-dimensionally with a porosity of 50 to 80%, and since the surface of the pores is composed of fine irregularities, bone is cultivated in a short period of time. Further, if the hydroxyapatite single phase is used as the calcium phosphate, the bone growth rate is further improved. Further, the bone growth rate can be further improved by retaining the bone morphogenetic protein in the pores of the calcium phosphate material.

[Brief description of drawings]

FIG. 1 is a photograph of a ceramic structure of pore surfaces in an example of the present invention.

Claims (4)

[Claims] 1. A molded body composed of calcium phosphate, wherein spherical spherical pores having a uniform size of 100 to 300 μm are continuously formed three-dimensionally with a porosity of 50 to 80%. The porous calcium phosphate material for bone formation, characterized in that the surface of the pores is composed of fine irregularities 2. A granule composed of calcium phosphate particles having a particle size of 300 to 1000 μm, wherein 50 to 80% of the spherical particles have a uniform size of 100 to 300 μm. Porous calcium phosphate material for bone formation characterized in that it is formed three-dimensionally continuously at a constant rate, and that the surface of the pores is composed of fine irregularities 3. The porous calcium phosphate material for bone formation according to claim 1, wherein the calcium phosphate is composed of hydroxyapatite [Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ] single phase. 4. The bone-forming porous calcium phosphate material according to claim 1, wherein the bone-forming factor is retained in the pores.