JPS62231669A - Method for producing biomaterial coated with hydroxyapatite - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for producing a biomaterial coated with hydroxyapatite, and in particular a method for producing an implant material coated with hydroxyapatite and having excellent biocompatibility. It is related to.

[Conventional technology and its problems]

In recent years, the use of implant materials such as artificial bones, artificial joints, and artificial tooth roots has become common, and the materials used include metal materials such as titanium and stainless steel, and ceramic materials such as alumina and zirconia.

However, while these materials have excellent mechanical strength and durability, they have poor compatibility with living organisms and have problems in adhesion to bone tissue.

To improve this drawback, 1 synthetic apatite was added to 90%
In recent years, materials such as materials fired at 0 to 1200°C, materials made by adding Sing to hydroxyapatite and sintering them, and materials made of hydroxyapatite and bioglass have been developed.

However, while these hydroxyapatite and bioglass are superior to conventional ones in terms of biocompatibility, their mechanical strength is inferior to ceramic materials such as metals, alumina, and zirconia, and they crack when used for long periods of time. There are problems such as generation of carbon dioxide and release of material components, and it is not satisfactory as an implant material.

Moreover, these materials need to be sintered at a high temperature to increase their strength after molding, which causes a change in the composition of hydroxyapatite and deteriorates the biocompatibility inherent in apatite, which is not preferable.

Recently, in order to particularly strengthen the mechanical strength of such hydroxyapatite, methods of coating the core material of metal implants with hydroxyapatite powder by thermal spraying (for example, Japanese Patent Publication No. 52-82893) and coating methods by sputtering (for example, Publication No. 58-109049) has been proposed. However, these methods cannot be called ideal coating methods. In other words, in the case of thermal spraying, decomposition occurs, resulting in changes in the composition and crystal structure of hydroxyapatite, and in the case of thermal spray gun components.
There are problems with the presence of metal atoms, which are unfavorable for biocompatibility, such as the mixing of u into the sprayed layer and the presence of bonding agents such as NiAl.

On the other hand, the sputtering method requires the preparation of a special hydroxyapatite as a target material, the deposition rate is slower than other methods, so the production efficiency is not good, and it is difficult to produce complex three-dimensional shapes. It has disadvantages such as difficulty in uniform coating.

As described above, these coating methods have various drawbacks and require special equipment, so that they are inevitably expensive in terms of manufacturing costs.

Therefore, in order to develop a material with excellent properties such as mechanical strength, durability, and biocompatibility required for an implant material under such circumstances, the present inventors developed an inexpensive and simple method for applying ceramic materials. We have conducted intensive research on a method of coating highly pure hydroxyapatite.

As a result, we have been able to coat the surfaces of materials with excellent strength properties, such as metals and ceramics, with adhesives, binders, etc. without using special manufacturing equipment. The present invention was completed based on the discovery that it is possible to easily and firmly form a high-purity product without using any other ingredients.

[Means for solving problems]

The present invention is based on a solution of phosphoric acid and calcium nitrate, Ca/PO, dissolved in a solvent selected from methanol, ethylene glycol, propylene glycol, and glycerin so that the molar ratio is in the range of 1.5 to 1.75. Apply it to the material,
This is a method for producing a biomaterial coated with hydroxyapatite, which involves firing.

〔Example〕

To explain in detail the method for manufacturing the hydroxyapatite coating material of the present invention, first, phosphoric acid and calcium nitrate are used as raw materials for hydroxyapatite.

Hydroxyapatite can generally be obtained by reacting calcium salt with phosphoric acid or its salt and firing,
In the present invention, the effects of the present invention are exhibited only in combination with phosphoric acid and calcium nitrate.

That is, if calcium lactate, calcium acetate, or the like is used as a material other than these, the component composition at the time of coating becomes non-uniform, and therefore it becomes difficult to obtain a homogeneous coating material of the present invention.

Phosphoric acid and calcium nitrate are used after being dissolved in a solvent selected from methanol, ethylene glycol, propylene glycol, and glycerin, but these vary depending on the type of solvent used, and are usually used separately when applying to the substrate. It is preferable to mix both.

In other words, although it depends on the type of solvent, if both are dissolved in the same solvent, calcium phosphate will precipitate over time, resulting in a non-uniform solution, so remove the base as soon as possible. It is necessary to apply it to the material.

In addition, methanol, ethylene glycol, and
The concentration of the solvent selected from propylene glycol and glycerin varies depending on the proportion of phosphoric acid and nitrate used, the type of base material, and the drying and baking process, which will be described later. During dissolution,
It is used so that it is 50% or more, preferably 70% or more.

-i: The lower the concentration of these solvents, that is, the higher the water content, the better the stability of the solution when phosphoric acid and calcium nitrate are dissolved in the same solvent; The properties will be poor and the coating will be non-uniform.

Therefore, it is preferable that the concentration of the solvent used when dissolving the solute is as high as possible. Other solvents include ethanol,
The use of propatool, butanol, acetone, etc. does not result in a homogeneous solution of phosphoric acid and calcium nitrate, and the coating applied to the substrate is non-uniform.

Regarding the usage ratio of phosphoric acid and calcium nitrate,
When applying to the base material, the Ca/PO4 molar ratio is 1.5~
Use it so that it is within the range of 1.75. In this case, in the method of using phosphoric acid and calcium nitrate separately dissolved in the above-mentioned solvent, when coating, it is sufficient to mix the two so that the molar ratio falls within the above-mentioned range.

Furthermore, if the Ca/PO4 molar ratio deviates from the above-mentioned range and is less than 1.50, hydroxyapatite with good crystallinity cannot be converted, the amorphous component increases, and the film strength decreases.

Furthermore, when it exceeds 1.75, the crystallinity of hydroxyapatite similarly decreases, and the alkali component becomes excessive, resulting in a decrease in affinity with living organisms.

Therefore, the Ca/PO4 molar ratio is particularly important in the present invention.

Note that the concentration of phosphoric acid and calcium when applied to the base material is based on the hydroxyapatite (Ca5(PO4)i) produced.
o As a general rule, it is desirable to set the content within the range of 5 to 20% by weight.

That is, if it is less than 5% by weight, the resulting apatite film will become thinner and it will be necessary to repeat the coating process, and if it exceeds 20% by weight, the liquid composition during coating will become unstable and non-uniform, resulting in the inhomogeneous coating of the present invention. It becomes difficult to obtain a suitable coating film.

In this way, ethylene glycol, propylene glycol,
Phosphoric acid and calcium nitrate dissolved in a solvent selected from glycerin can be applied at a concentration of 1.5-1.
75, and then applied to the substrate.

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

In addition, methods for applying the apatite coating include dipping,
It can be carried out by conventional means such as a roll coater, a spray method, a spacing method, or a doctor blade method.

Although the thickness of the coating layer varies depending on the intended use of the product, it has been confirmed through animal experiments that a 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 used solvent.

As for the drying method, normal drying methods such as room temperature drying, heating and standing drying, and hot air drying may be used, but if extreme heating is performed, the solvent will rapidly volatilize and the coating film will become non-uniform, which is undesirable. (Although it varies depending on the type of solvent used, drying is usually carried out at about 200'C or less until the solvent evaporates slowly.)

The coated substrate after drying is then fired to remove 'f1 separated water, bound water, residual solvent and nitrate groups in the coating film,
A strong film of hydroxyapatite is formed on the base material.

Firing is carried out at a temperature of 450 to 800°C, and the excellent implant material of the present invention cannot be obtained outside this range.

That is, if the firing temperature is lower than 450° C., the release and removal effect of nitrate radicals derived from calcium nitrate will not be sufficient, leading to elution of nitrate ions in the living body, embrittlement of the coating film, etc. Moreover, if it exceeds 800'C, it is not preferable because it changes the composition of the hydroxyapatite produced and deteriorates its affinity with living organisms.

The atmosphere during firing is air or reduced pressure, but in order to further strengthen the biocompatibility of the hydroxyapatite coating, firing at a low temperature is desirable, and firing under reduced pressure is usually recommended.

Regarding the firing time, 10 minutes or more is usually required, but firing time and temperature are generally in a contradictory relationship.
10 minutes or more is required at 800°C.

The hydroxyapatite film deposited on the base material in this way has a uniform and dense coating layer, and maintains the same mechanical strength and impact resistance as the base material due to strong bonding with the base material. Moreover, since it has a hydroxyapatite composition, it has a property of being highly biocompatible.

Therefore, it exhibits excellent properties when applied as an implant material to artificial bones, artificial joints, artificial tooth roots, etc.

[Example 1] Calcium nitrate (tetrahydrate, special grade reagent) and phosphoric acid solution (8
5z special grade reagent) was separately dissolved in 99.5X (all values indicate weight % unless otherwise specified; the same applies hereinafter) and methanol (special grade reagent) in the proportions shown in Table 1. This was left at room temperature for one week, and then predetermined amounts of each method were mixed to prepare a coating solution. (Table 1) Separately, 495 g of the above-mentioned calcium nitrate (tetrahydrate) and 145 g of phosphoric acid solution were simultaneously dissolved in 760 g of methanol, but this solution 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 the solvents of methanol, ethylene glycol, propylene glycol, and glycerin (each used as a reagent) in the proportions shown in Table 2. did.

This solution was allowed to stand at room temperature for one week, and then predetermined amounts of each method were mixed to prepare a coating solution. (Table 2) Also, for comparison,
Coating solutions were similarly prepared using other calcium salts instead of calcium nitrate, various other phosphates instead of phosphoric acid, and other solvents.

[Example 3] A polycrystalline alumina plate of 15 x 40 x 1 mm was used as an underground substrate, and hydroxy7 batite (sample! 1h7) was applied to a thickness of 2 to 3 μm by the dipping method.
00℃, 400℃, 550℃, 600℃1650℃,
It was baked for 30 minutes in the air at temperatures of 700°C, 800°C, and 1000°C, and its fixability was evaluated by scratch strength. To measure the scratch strength, Shinraikagaku Al Surface Measurement 4i was used.
TYPI! -11HIDON-14 type was used, and the results are shown in Table 3.

From this result, baking temperature of at least 400℃ is required to form a uniform, dense, and strong coating of hydroxyapatite on polycrystalline alumina plates, and the optimum baking temperature is 70℃.
It has been found that 0 to 800°C is desirable. On the other hand, about 900
Although baking at temperatures above 0.degree. C. has strong adhesion, the hydroxyl groups of hydroxyapatite are removed, resulting in uneven coating, making it somewhat difficult to obtain a uniform coating.

Results similar to those in Example 3 were obtained for samples 1 to 4 and samples 8 to 12.

However, samples N15 to Kan6 all showed lower values due to this. This is the mixed solution Ca/PO4
This is thought to be due to the fact that the former has a stoichiometric molar ratio, while the latter has a non-stoichiometric molar ratio, resulting in decreased crystallinity.

[Example 4] An apatite-coated polycrystalline implant baked at the optimal baking temperature as shown in Example 3 was produced (size: 5 x lOx 1 mm, hydroxyapatite coating liquid: 9, baking was performed under the following conditions). =700”CX30m
Implants were performed in healthy peagle-sized femurs (1n in air). After 3 months, the animals were exsanguinated, tissue specimens were prepared, and tissue reactions were observed using a microscope and fluorescence.

As a result, no inflammatory reaction was observed in the tissues in contact with the implant, and no abnormal bone resorption occurred. New bone and fibrous tissue were observed to be in direct contact with the implant surface.

[Comparative Example 1] Hydroxyapatite coating liquid Na12 as in Example 4
An animal experiment was conducted by baking a polycrystalline alumina implant blunt for 30 minutes at 1000° C. in the air. As a result of observation of the tissue specimen, a significant inflammatory reaction was observed in the tissue in contact with the implant. On the other hand, only a slight amount of new bone formation was observed.

〔Effect of the invention〕

As described above, the present invention has the ability to stably retain a hydroxyapatite coating liquid for a long time, which is highly biocompatible and firmly adheres to bone tissue, and by changing the type and mixing ratio of the solvent, Since the shape and particle size of the colloidal particles can be freely controlled, the component composition during coating can be made uniform, and the coating has extremely excellent properties in terms of operability. In addition, since the hydroxyapatite according to the present invention exists in a homogeneous and stable colloidal dispersion state in a solvent, the baking temperature of hydroxyapatite is 200 to 300°C higher than the normal temperature.
It is possible to bake at low temperatures, and there is little risk of changing the composition of the hydroxyapatite produced or reducing its biocompatibility.

Furthermore, since the coating method according to the present invention does not require any special equipment or coating method, it has the great advantage of being extremely economical and being applicable to almost all shapes.

Therefore, the biomaterial coated with hydroxyapatite by the production method according to the present invention has almost no denaturation as apatite and has high purity, so it is extremely useful for constructing dental and medical implant members.

Claims (2)

[Claims] (1) Methanol,
A method for producing a biomaterial coated with hydroxyapatite, which comprises applying a solution dissolved in a solvent selected from ethylene glycol, propylene glycol, and glycerin to a base material and firing the solution. (2) The 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.