JPH06296680A - Production of artificial bone material - Google Patents

Abstract

PURPOSE:To provide the artificial bone material having a relatively high mechanical strength to withstand handling and excellent bioaffinity while having a high porosity and large pore sizes. CONSTITUTION:This process for production includes a stage for preparing the amorphous body of chelate org. matter by ethylenediaminetetraacetic acid contg. phosphorus P and calcium Ca and a stage for generating foaming and a reaction to change the org. matter from the amorphous body into the crystalline body of the calcium phosphate by baking the amorphous body.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for manufacturing an artificial bone material. This material is used in orthopedics, plastic surgery, brain surgery,
It can be suitably used as a bone filling member in the medical field such as oral surgery and dentistry.

[0002]

2. Description of the Related Art Calcium phosphate compounds are known to have excellent biocompatibility, and their sintered bodies are known to be materials that are chemically bound to bone or replaced with bone. As a method for producing a calcium phosphate calcined product having high biocompatibility and high strength, the inventors of the present invention have disclosed in JP-B-60-50744 that a calcium phosphate having a calcium / phosphorus atomic ratio of 1.4 to 1.75 is mainly used. A method was devised in which 0.5 to 15% by weight of alkaline earth metal oxide-phosphate frit was added to the powder to be calcined, and then calcined. By this method, an artificial bone material having excellent biocompatibility and high mechanical strength was obtained. When these artificial bone materials were transplanted into a living body, they were chemically bonded to bone tissue, and because of their high strength, they were not easily broken and showed good results.

[0003]

However, even with these materials, it takes about one month to bond with new bone, and further improvement in biocompatibility, particularly improvement in bone growth in the early stage after surgery is desired. ing. Generally, it has long been known that living bones easily invade by introducing pores of several tens to several hundreds of μm.

On the other hand, as a method for producing a porous ceramic body such as a brick, a method of introducing a combustible pore-forming material such as an organic material or carbon into a raw material and a method of mixing a foaming agent have been used for a long time. Therefore, a porous body can be prepared by directly applying these methods to the calcium phosphate system.

However, in these conventional methods for producing a porous body, in the case of an apatite system, it is difficult for the particles to sinter, so that the skeleton as a porous body does not grow sufficiently. As a result, the obtained porous body has a remarkably low strength, and when it is touched or rubbed with a finger, the particles fall off or are damaged. Therefore, post-processing by grinding cannot be performed, and further, it is difficult to handle and the operability during bone replacement surgery is significantly reduced.

[0006] An object of the present invention is to provide a method for producing an artificial bone material having a high porosity and a large pore size, and having a relatively high mechanical strength capable of withstanding handling and having excellent biocompatibility. Is.

[0007]

Means for Solving the Problems The artificial means is characterized in that it comprises a step of preparing an amorphous body of an organic substance containing phosphorus P and calcium Ca and a step of firing the amorphous body. It is in the method of manufacturing bone material. Hereinafter, the present invention will be described in detail. In the present invention, first, phosphorus P and calcium C
An amorphous substance of an organic substance containing a (hereinafter referred to as “phosphorus / calcium-containing organic substance”) is prepared.

The starting material is not particularly limited as long as it is possible to prepare an amorphous form of a phosphorus-calcium-containing organic material such as various inorganic salts of Ca and P, organic salts, metal alkoxides, alkyl metals, chelate compounds, and the like. , Can be used. It is preferable to use an inorganic salt or an organic salt from the viewpoints of easiness of operation and control and manufacturing cost.

For example, as inorganic salts, nitrates, chlorides,
Bromide, iodide, chlorate, chlorite, nitrite,
Sulfite and the like can be used, and as the organic salt, acetate, oxalate, lactate, tartrate, citrate, benzoate, isobutyrate, maleate and the like can be used.
However, in order to prepare an amorphous substance of a phosphorus-calcium-containing organic substance, a substance having sufficient solubility in a reaction solvent (water or an organic solvent) is preferable, and a carbonate or a sulfate is not preferable because the reaction is slow.

Amorphous organic compounds are prepared from these starting materials. When a metal alkoxide or an alkyl metal is used as a starting material, a transparent amorphous solid can be obtained simply by dissolving and mixing the Ca material and the P material in an organic solvent, drying and concentrating. When an inorganic salt or an organic salt is used, the respective salts of Ca and P are dissolved in water and then a chelating agent is added to cause a reaction. Here, the chelating agent means a polydentate ligand which forms a chelate compound by coordinating with a metal ion. Dimethylglyoxime, dithizone, oxine, acetylacetone, glycine, EDTA, NTA and the like are used, and ED is particularly preferable from the viewpoint of high solubility and reactivity.
It was TA (ethylenediaminetetraacetic acid). Prepared C
When a transparent reaction solution containing a and P is heated and decompressed to remove water as a solvent, a transparent amorphous solid is obtained.

The amorphous body thus obtained contains at least one selected from a mixture of an organic phosphorus compound and an organic calcium compound, a reaction product of an organic phosphorus compound and an organic calcium compound, and an organic phosphorus / calcium compound. It is the main component.

This amorphous body is heated to 700 to 130 in an electric furnace.
Firing to a temperature of about 0 ° C. gives a foamed porous body. When observing this porous body, there are many large pores of at least several tens to several hundreds of μm, and other than that, several μm.
There are many pores on the entire surface. Despite having such a large porosity, the obtained porous body has a relatively high strength with no particles falling off even if it is rubbed with a finger, and is not damaged by normal handling. Indicated. Upon firing, the amorphous body became a foamed porous body and was crystallized into a calcium phosphate-based crystalline body.

What was important here was to prepare an amorphous substance of a phosphorus-calcium-containing organic substance and use it as a precursor for firing. For example, when only an inorganic salt was used without using a chelating agent, an inorganic amorphous body or a crystal body with low crystallinity was obtained, but even if it was fired under various firing conditions, a porous body was obtained at all. It was not possible to do this, and it only burst when fired at a rapid temperature rise.

It should be noted that, instead of firing the amorphous body as it is, it is crushed to about several mm and put in a heat-resistant container (for example, made of alumina) and fired. A monolithic porous body is obtained. However, when finely pulverized (for example, 1 mm or less), the porosity decreases. The rate of temperature increase is an important factor for controlling the pore size and the amount of pores of the porous body.
Pore size and porosity tend to increase. A preferable rate of temperature rise is 5 ° C./minute or more, more preferably 10 ° C./minute or more.

The calcium / phosphorus (Ca / P) atomic ratio of the amorphous substance of the organic substance containing phosphorus / calcium is 1.4 to 1.75.
And in this case 700 to 1300
When it is fired up to ° C, a hydroxyapatite phase (HAP: Ca / P = 1.67) or a tertiary calcium phosphate phase (TCP: Ca / P = 1.5) having excellent biocompatibility can be obtained. More preferably, calcium / phosphorus (Ca / Ca / Ca / Ca / Ca /) is used so that the amorphous body becomes a mixed crystal phase of HAP phase and TCP phase.
P) atomic ratio. When the material consisting of this mixed crystal phase is filled in the living body with bone, tricalcium phosphate is eluted into the living body to promote the growth of bone tissue, and due to the elution of TCP, new pores other than the pores generated during foaming are newly formed. This is because it facilitates the invasion and growth of bone tissue. The composition ratio of the HAP phase and the TCP phase is Ca / of the mixing ratio of the starting materials.
It can be controlled by the P ratio.

The crystal phase constituent ratio of hydroxyapatite and tricalcium phosphate is identified by a known X-ray diffraction method. Specifically, using CuKα rays, the peak height I _HAP of the (2,1,1) plane of hydroxyapatite and the (0,2,10) plane and the (2,1,7) plane of tricalcium phosphate are used. It can be calculated from the peak height I _{TCP of} C _TCP = {I _TCP / (I _HAP + I _TCP )} × 100 (%) C _TCP : Content of tricalcium phosphate

[0017]

The foaming phenomenon of the production method of the present invention is a unique phenomenon observed only when the above-mentioned amorphous organometallic compound is used. In a general porous body manufacturing method, a foaming agent is added to a slurry containing raw material powders to foam a foamed molded body, and then a method of preparing a porous body that retains a foamed shape by firing is It has been known since ancient times. However,
The foaming mechanism of the present invention is completely different from this, in which the amorphous substance of the phosphorus-calcium-containing organic material itself foams during the firing process, and further controls the Ca / P ratio and the crystalline phase after firing. Then, it is most suitable for artificial bone material.

The reason why the foamed porous body is produced in the present invention is not clear at present, but it is presumed as follows.
Probably due to the thermal decomposition-densification-crystallization behavior of the amorphous substance of phosphorus-calcium-containing organic substance during firing. That is,
The amorphous substance of phosphorus-calcium-containing organic matter is oxidized, burned or decomposed by firing to once become an amorphous metastable inorganic substance, and the densification-crystallization behavior peculiar to this metastable product is obtained. Is believed to be the cause of the unique foaming phenomenon of the present invention.

This metastable material exhibits viscous flow behavior during firing, and as the viscous flow and sintering progress, foaming occurs while releasing combustion gas of organic matter and H ₂ O gas generated by polymerization of OH groups from the inside. To do. As a result, a porous structure is constructed. After that, the metastable substance is considered to crystallize into HAP and TCP. Then, once crystallized, the material movement mechanism changes from the viscous flow mechanism to the diffusion mechanism, so that the shape is maintained.

In this respect, the amorphous substance prepared from the inorganic salt is
This differs from the fact that calcination easily crystallizes. That is, if the substance is crystallized before foaming and the substance transfer mechanism becomes a diffusion mechanism, the gas does not foam even if the gas is released from the inside and bursts when the gas pressure is high. Therefore, the above metastable state cannot be obtained from an inorganic raw material, and is specifically obtained only when an amorphous substance of a phosphorus-calcium-containing organic substance is used as in the present invention.

The reason why the strength of the artificial bone material obtained in the present invention is relatively high is that, unlike the conventional case where a foaming agent is added to a raw material slurry (baking a foamed molded body), the artificial bone material is densified during baking. It is speculated that foaming proceeded at the same time to form a strong skeleton.

[0022]

【Example】

-Example 1- 0.39 mol of calcium nitrate was dissolved in 1 liter of distilled water. 0.39 mol of ethylenediaminetetraacetic acid ammonium salt (EDTA) was added to this solution and stirred for 1 hour to cause a reaction. To this reaction solution, ammonium phosphate was added.
After adding 26 mol and further stirring until it became a transparent solution, it was dried at 120 ° C. to obtain a transparent solid. When this solid was analyzed by X-ray diffractometry, it was an amorphous substance.

This amorphous material was placed in an electric furnace and the temperature rising rate was 1
The temperature was raised at 0 ° C./min, and the temperature was maintained at 1100 ° C. for 2 hours, followed by firing. The fired product was a porous body having a porosity of about 70%, and even if it was rubbed with a finger, the particles did not fall off and showed a strength sufficient to withstand handling. The fired product had a large number of pores of several tens to several hundreds μm and several pores of several μm as shown in FIG. The crystal phase was analyzed by X-ray diffractometry and found to be tricalcium phosphate. Therefore, it became clear that this fired product can be applied to an artificial bone having both excellent biocompatibility and required strength.

-Example 2- The transparent solid amorphous material prepared in Example 1 was crushed into granules of about 5 mm in a Meno-mortar and then charged into a cylindrical container made of alumina, and the granules were placed on it. Cover with a plate made of alumina,
Firing was performed by raising the temperature in an electric furnace at a temperature rising rate of 5 ° C./min and holding at 1200 ° C. for 2 hours.

The fired product was a columnar porous body which was integrated and foamed to a porosity of about 65%. Similar to Example 1, the fired product had a large number of pores of several tens to several hundreds μm and several μm, and exhibited a strength sufficient to withstand handling, and its crystal phase was a tricalcium phosphate phase. Therefore,
It has become clear that this calcined product can be applied to an artificial bone having both excellent biocompatibility and required strength.

Example 3 0.40 mol of calcium nitrate was dissolved in 1 liter of distilled water, and 0.65 mol of ethylenediaminetetraacetic acid ammonium salt (EDTA) was added to this solution and stirred for 1 hour to react. To this reaction solution, 0.25 mol of ammonium phosphate was added, and the mixture was further stirred until it became a transparent solution, and then dried at 120 ° C to obtain a transparent solid. When this solid was analyzed by X-ray diffractometry, it was an amorphous substance.

This amorphous material was crushed into granules of about 5 mm in the same manner as in Example 2, then charged into a cylindrical container made of alumina, and an alumina plate was covered on the container, and the temperature rising rate was 5 ° C.
Firing was performed by heating at 1 / min and holding at 1100 ° C. for 2 hours. The fired product is an integrated porous body having a porosity of about 65%, and the fired product is several tens to several hundreds μ.
It has a large number of pores of m and several μm, and even if it is rubbed with a finger, the particles do not fall off and the strength is sufficient to withstand handling. The crystal phase was 70% hydroxyapatite phase-30% tricalcium phosphate phase. Therefore, it became clear that this calcined product can be applied to an artificial bone having extremely excellent biocompatibility and required strength.

Comparative Example 1 Almost the same as in Example 1, except that 0.39 mol of calcium nitrate was dissolved in 1 liter of distilled water and then ethylenediaminetetraacetic acid ammonium salt (EDTA) was not added.
0.26 mol of ammonium phosphate was added as it was.
A white precipitate was formed instantaneously, and when dried, it became a gel-like almost amorphous body. The amorphous body is put into an electric furnace and the temperature rising rate is 1
The temperature was raised at 0 ° C./minute and the temperature was maintained at 1100 ° C. for 2 hours, but no foaming occurred at all.

[0029]

EFFECTS OF THE INVENTION According to the production method of the present invention, a living body having a high porosity and a large pore diameter of several tens to several hundreds of μm, and a relatively high mechanical strength capable of withstanding handling, and having a good biocompatibility. An artificial bone material can be obtained.

[Brief description of drawings]

FIG. 1 shows the material structure of the fired product of Example 1,
(A) is a scanning electron micrograph with a magnification of 50 and (B) is a magnification of 500.

Claims (6)

[Claims] 1. A method for producing an artificial bone material, comprising: a step of preparing an amorphous body of an organic material containing phosphorus P and calcium Ca; and a step of firing the amorphous body. 2. An amorphous substance of an organic substance containing phosphorus P and calcium Ca is a mixture of an organic phosphorus compound and an organic calcium compound, a reaction product of an organic phosphorus compound and an organic calcium compound, and an organic phosphorus / calcium compound. The method for producing an artificial bone material according to claim 1, wherein the main component is one or more selected from the following. 3. The method for producing an artificial bone material according to claim 1, wherein the step of firing causes foaming and a reaction of changing an amorphous substance of an organic substance into a crystalline substance of calcium phosphate. . 4. Calcium / phosphorus (Ca /) in an amorphous body
The method for producing an artificial bone material according to claim 1, wherein the P) atomic ratio is 1.4 to 1.75. 5. The method for producing an artificial bone material according to claim 1, wherein the amorphous substance of the organic substance is a chelate compound. 6. The method for producing an artificial bone material according to claim 5, wherein the chelate compound is an ethylenediaminetetraacetic acid compound.