JPH072181B2 - Method for producing biomaterial coated with hydroxyapatite - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a biomaterial coated with hydroxyapatite, and particularly to a method for producing an implant material coated with hydroxyapatite and having excellent biocompatibility. Is.

[Conventional technology and its problems]

In recent years, the use of implant materials such as artificial bones, artificial joints, and artificial tooth roots has been generalized, and metal materials such as titanium and stainless steel and ceramic materials such as alumina and zirconia are used as the materials thereof.

However, while these materials are excellent in mechanical strength and durability, they are poor in affinity with living organisms and have a problem in fixing to bone tissue.

To improve this defect, synthetic apatite is added to 900
For materials fired at ~ 1200 ° C and hydroxyapatite
In recent years, materials obtained by adding SiO ₂ and sintering, and further materials made of hydroxyapatite and bioglass have been developed.

However, while these hydroxyapatite and bioglass are superior to conventional ones in terms of biocompatibility, they are inferior in mechanical strength to ceramic materials such as metal, alumina, and zirconia, and crack in long-term use. However, it is not satisfactory as an implant material because of the problems such as the occurrence of blemishes and the release of material components.

Further, since these materials increase in strength after molding, it is necessary to sinter at a high temperature, the composition change of hydroxyapatite occurs, and the biocompatibility originally possessed by apatite is deteriorated, which is not preferable.

Recently, in particular, in order to reinforce the mechanical strength of such hydroxyapatite, a coating method of spraying hydroxyapatite powder onto a core material of a metal implant (for example, Japanese Patent Publication No. 52-82893) or a coating method by sputtering (for example, Japanese Patent Publication No. 58-109049) has been proposed. However,
These methods are not very ideal coating methods. That is, in the case of the thermal spraying method, decomposition occurs, resulting in alteration of the composition and crystal structure of hydroxyapatite, mixing of W and Cu, which are constituent materials of the thermal spray gun, into the thermal spray layer, and a bonding agent such as NiAl. There is a problem of existence of a metal atom which is unfavorable for biocompatibility, such as intervening.

On the other hand, in the sputtering method, first, it is necessary to prepare a special hydroxyapatite as a target material, and the deposition rate is slower than other methods, so the production efficiency is not good, and a complicated three-dimensional shape is obtained. It has drawbacks such as difficulty in uniform coating.

As described above, these coating methods have various drawbacks and require special equipment, so that they have to be expensive in terms of manufacturing cost.

Therefore, in order to develop a material having excellent properties such as mechanical strength, durability, and biocompatibility required as an implant material in such a situation, the inventors of the present invention use an inexpensive and simple method for a ceramic material. An intensive study was conducted on a method of coating high-purity hydroxyapatite.

As a result, a hydroxyapatite coating with rich biocompatibility, which was thought to be impossible until now, could be applied to other components such as adhesives and binders on the surface of materials such as metals and ceramics, which have excellent strength characteristics, without using special manufacturing equipment. The inventors have found that it is possible to easily and firmly form with high purity without using, and have completed the present invention.

[Means for solving problems]

The present invention uses phosphoric acid and calcium nitrate in a Ca / PO ₄ molar ratio of 1.
A biomaterial coated with hydroxyapatite, characterized in that the solution is dissolved in a solvent selected from methanol, ethylene glycol, propylene glycol, and glycerin so as to be in the range of 5 to 1.75, and is applied to a substrate, followed by firing. Is a manufacturing method.

〔Example〕

The method for producing the hydroxyapatite coating material of the present invention will be described in detail. First, phosphoric acid and calcium nitrate are used as raw materials for hydroxyapatite.

Hydroxyapatite can be generally obtained by reacting a calcium salt with phosphoric acid or a salt thereof, and firing,
In the present invention, the effect of the present invention is exhibited only in the combination with phosphoric acid and calcium nitrate.

That is, in addition to these, the use of calcium lactate, calcium acetate, etc. makes the composition of the components non-uniform during coating, thus making it difficult to obtain the homogeneous coating material of the present invention.

Phosphoric acid and calcium nitrate are used by dissolving them in a solvent selected from methanol, ethylene glycol, propylene glycol, and glycerin.These are different depending on the type of solvent used, and they are usually used separately, and when applied to a substrate. It is preferable to mix both.

That is, although it depends on the type of solvent, when both are dissolved in the same solvent and used, calcium phosphate precipitates over time and a heterogeneous solution is formed. It is necessary to apply it to the material.

Also used as solvent are methanol, ethylene glycol,
The concentration of the solvent selected from propylene glycol and glycerin varies depending on the use ratio of phosphoric acid and calcium nitrate described below, the type of base material, the drying and firing steps, but usually during the dissolution of phosphoric acid and calcium nitrate. ,
It is used in an amount of 50% or more, preferably 70% or more.

In general, the lower the concentration of these solvents, that is, the higher the amount of water, the better the liquid stability when phosphoric acid and calcium nitrate are dissolved in the same solvent, but the drying property when coating and drying the substrate is improved. It becomes worse and the coating becomes non-uniform.

Therefore, it is preferable to use the solvent in a region where the concentration of the solute when dissolved is as high as possible. As another solvent, ethanol,
The use of propanol, butanol, acetone, etc. does not give a homogeneous phosphoric acid and calcium nitrate solution and the coating applied to the substrate is non-uniform.

Speaking of the usage ratio of phosphoric acid and calcium nitrate,
It is used so that the molar ratio of Ca / PO ₄ is from 1.5 to 1.75 when applied to the substrate. In this case, in the method in which phosphoric acid and calcium nitrate are separately dissolved in the above-mentioned solvent and used, both may be mixed and used so as to be in the above molar ratio range at the time of coating.

In addition, the range of Ca / PO ₄ molar ratio deviates from the above range, and is 1.50.
When it is below the range, hydroxyapatite with good crystallinity cannot be obtained, the amount of amorphous components increases, and the film strength decreases.

Further, when it exceeds 1.75, the crystallinity of hydroxyapatite is similarly lowered, and the alkali component becomes excessive, so that the affinity with living body is lowered.

Therefore, the Ca / PO ₄ molar ratio is of particular importance in the present invention.

The concentration of phosphoric acid and calcium when applied to the base material is the hydroxyapatite produced [Ca ₅ (PO ₄ ) ₃ OH].
As a general rule, it is desirable to set it in the range of 5 to 20% by weight.

That is, if it is less than 5% by weight, the formed apatite coating becomes thin and it is necessary to repeat the coating process.
When it exceeds the above range, the liquid composition at the time of application becomes unstable and becomes non-uniform, and it becomes difficult to obtain the uniform coating film of the present invention.

In this way ethylene glycol, propylene glycol,
Phosphoric acid and calcium nitrate dissolved in a solvent selected from glycerin are prepared so as to have a Ca / PO ₄ molar ratio of 1.5 to 1.75 at the time of coating, and then coated on a substrate.

In the present invention, the material of the base material is not particularly limited, and materials generally usable as implant materials, for example, metals such as titanium and stainless steel, ceramics such as alumina, zirconia, and mullite can be used.

Further, as a method for depositing the apatite coating, a dipping method,
It can be carried out by an ordinary means such as a roll coater, a spray method, a brush coating method or a doctor blade method.

It was confirmed from animal experiments that the thickness of the coating layer varies depending on the purpose of use of the product, but that the thickness of 0.1 to 100 μm is optimal for use as a biomaterial.

The substrate coated with phosphoric acid and calcium nitrate is then dried to volatilize the solvent used.

Regarding the drying method as well, ordinary drying means such as room temperature drying, heating static drying, hot air drying and the like may be used, but if heating is performed radically, the solvent volatilizes rapidly and the coating film becomes non-uniform, which is not preferable. Usually, drying is performed at about 200 ° C or lower until the solvent evaporates slowly, although it depends on the type of solvent used.

The dried coated substrate is then calcined to remove free water, bound water, residual solvent and nitrate radicals in the coating film and form a strong coating of hydroxyapatite on the substrate.

The firing is performed in the range of 450 to 800 ° C., and the excellent implant material of the present invention cannot be obtained outside this range.

That is, when the baking temperature is lower than 450 ° C., the effect of releasing and removing nitrate radicals derived from calcium nitrate is not sufficient, which causes elution of nitrate ions in the living body and embrittlement of the coating film. Also
If it exceeds 800 ° C., the composition of hydroxyapatite produced is changed and the affinity with living organisms is deteriorated, which is not preferable.

The atmosphere at the time of baking is carried out in the air or under reduced pressure, but in order to further enhance the biocompatibility of the hydroxyapatite film, it is desirable to carry out baking at a low temperature, and usually baking under reduced pressure is recommended.

Regarding the firing time, usually 10 minutes or more is required,
The firing time and the temperature are generally in a contradictory relationship, and it is necessary to have 120 minutes or more at 500 ° C, 30 minutes or more at 550 ° C, and 10 minutes or more at 800 ° C in the atmosphere.

The hydroxyapatite coating applied to the substrate in this way has a uniform and dense coating layer, and the strong bond with the substrate maintains mechanical strength and impact resistance similar to the substrate. In addition, since it has a hydroxyapatite composition, it has the property of being highly biocompatible.

Therefore, it exhibits excellent properties when applied to an artificial bone, an artificial joint, an artificial tooth root, etc. as an implant material.

Example 1 Calcium nitrate (tetrahydrate, special grade reagent) and phosphoric acid solution (85
% Special grade reagents) were separately dissolved in 99.5% (all are% by weight unless otherwise specified. The same applies hereinafter) and methanol (special grade reagents) in the proportions shown in Table 1. This was left at room temperature for one week, and then each liquid was mixed in a predetermined amount to prepare a coating liquid. (Table 1) Separately, 495 g of calcium nitrate (tetrahydrate) and 145 g of phosphoric acid solution were simultaneously dissolved in 760 g of methanol. This product gradually precipitated 24 hours after preparation, and the coating solution Could not be used as.

[Example 2] Calcium nitrate (tetrahydrate, special grade reagent) and phosphoric acid solution (special grade reagent) were dissolved in a solvent of methanol, ethylene glycol, propylene glycol, and glycerin (each used as a reagent) at a ratio shown in Table 2. did.

This solution was left at room temperature for one week, and then each solution was mixed in a predetermined amount to prepare a coating solution. (Table 2) Further, for comparison, coating solutions were prepared in the same manner for other calcium salts in place of calcium nitrate, other various phosphate salts in place of phosphoric acid, and other solvents.

[Example 3] A 15 x 40 x 1 mm polycrystalline alumina plate was used as an underground substrate, and hydroxyapatite (sample No. 7) was applied to a thickness of 2 to 3 µm by a dipping method, and the temperature was set to 300 ° C, 400 ° C, 550 ° C. ℃, 60
30 ° C in air at 0 ° C, 650 ° C, 700 ° C, 800 ° C, 1000 ° C
After baking for minutes, the settlement property was evaluated by scratching strength. For measuring scratch strength, surface measuring machine TYPE-H manufactured by Shinto Kagaku Co., Ltd.
EIDON-14 type was used, and the results are shown in Table 3.

From this result, the baking temperature for the uniform, dense and strong coating of hydroxyapatite on the polycrystalline alumina plate needs to be 400 ° C or higher, and the optimum baking temperature is 700-80
It has been found that 0 ° C is desirable. On the other hand, baking at a temperature of about 900 ° C. or higher has a strong adhesive force, but due to the elimination of hydroxyl groups of hydroxyapatite, unevenness is caused and it is somewhat difficult in terms of uniform coating.

The same results as in Example 3 were obtained with Samples No. 1 to No. 4 and Samples No. 8 to 12.

However, the samples No. 5 to No. 6 all showed low numerical values. It is considered that this is because the Ca / PO ₄ molar ratio of the mixed solution is stoichiometric in the former and non-stoichiometric in the latter, and the crystallinity is lowered. .

[Example 4] As shown in Example 3, an apatite-coated polycrystalline implant baked at the optimum baking temperature was produced (size: 5 x 10 x 1 mm, hydroxyapatite coating solution: No. 9, baking conditions). Implantation was carried out on the femur of a healthy beagle dog. After 3 months, the blood was killed by exsanguination, a tissue sample was prepared, and the tissue reaction was observed with a microscope and fluorescence.

As a result, no inflammatory reaction was observed in the tissue in contact with the implant, and no abnormal bone resorption occurred. Then, it was observed that new bone and fibrous tissue were in direct contact with the implant surface.

[Comparative Example 1] In the same manner as in Example 4, a hydroxyapatite coating solution No. 12 was used to bake a polycrystalline alumina implant in the atmosphere at 1000 ° C for 30 minutes, and an animal experiment was conducted. As a result of observation of the tissue specimen, a remarkable inflammatory reaction was observed in the tissue in contact with the implant. On the other hand, new bone formation was only slightly observed.

[Effects of the Invention] As described above, according to the present invention, it is possible to stably retain a hydroxyapatite coating liquid that is rich in biocompatibility and firmly adheres to bone tissue for a long time, and the type and mixing ratio of the solvent can be changed. By changing the shape, the shape and particle size of the apatite colloidal particles can be freely controlled, so that the component composition at the time of coating can be made uniform, and the operability of coating is extremely excellent. Further, since the hydroxyapatite according to the present invention exists as a homogeneous and stable colloidal dispersion state in a solvent, it can be baked at a temperature lower than the baking temperature of ordinary hydroxyapatite by 200 to 300 ° C. There is little risk of changing the composition of the product or decreasing the biocompatibility.

Furthermore, the coating method according to the present invention does not require any special device or coating method, and therefore has a great advantage that it is extremely economical and can be applied to almost all shapes.

Therefore, the biomaterial coated with hydroxyapatite by the production method according to the present invention hardly changes as apatite and has high purity, which is extremely useful for the construction of dental and medical implant members.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kazushi Kamiyama 11-17 Kugahonmachi, Fushimi-ku, Kyoto-shi, Kyoto Kyocera Corporation Fushimi Research Institute (72) Inventor Yoichi Nishio Karasuma Nishiiri, Shiokoji-ku, Kyoto-shi, Kyoto Kyoto Implant Research Institute (72) Inventor Hajime Hajime 2 Midoricho, Beppu-cho, Kakogawa-shi, Hyogo Taki Kagaku Co., Ltd. (72) Inventor Yoshiharu Ishikawa Midori-cho, Beppu-cho, Kakogawa-shi, Hyogo Taki Kagaku Co., Ltd. In the company

Claims (2)

[Claims] 1. A Ca / PO ₄ molar ratio of phosphoric acid and calcium nitrate.
As a range of 1.5 to 1.75, methanol, ethylene glycol, propylene glycol, a solution of a solution dissolved in a solvent selected from glycerin is applied to a base material, and the biomaterial coated with hydroxyapatite characterized by baking. Production method. 2. A method for producing a biomaterial coated with hydroxyapatite according to claim 1, wherein the firing temperature is in the range of 450 to 800 ° C.