JPH06102527B2 - Hydroxyapatite with high biocompatibility - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to apatite useful as an artificial bone, an artificial tooth root, an aggregate for an apatite cement and the like.

[0002]

2. Description of the Related Art Conventionally, apatite does not cause a rejection reaction or necrosis of a living body even when implanted in a living body, and has a property of easily assimilating and adhering to a hard tissue of a living body. It is used as a raw material.

The apatite currently used for this purpose is called stoichiometric apatite, and its crystal composition is a crystal represented by Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ (hereinafter referred to as composition formula). It is a sexual substance. This substance is contained in human bones and teeth, and its composition ratio is slightly different from that of biological apatite, which plays a role in maintaining its strength.However, it is originally composed of similar chemical components to human bones, etc. However, since it is not found to be harmful, it is considered to be a desirable substance as an implant material.

However, it is known that this stoichiometric hydroxyapatite has a long osteoinduction period of 4 to 5 weeks from the time it is implanted in the living body to the time when it adheres to the hard tissue of the living body and starts to be joined. Because this property is associated with patient distress,
It has become one of the drawbacks of current apatite.

On the other hand, it has been experimentally known that the bone induction period can be shortened to about one week when calcium silicate glass, calcium silicate calcium glass or the like is embedded in a living body. By comparing the length of this osteoinduction period, it is even considered that this stoichiometric hydroxyapatite has low biocompatibility as compared with these glasses.

[0006] The long-term toxicity of bringing a glass containing a silicic acid component into a living body is not sufficiently known at this stage. Under such circumstances, it is desirable to avoid as much as possible the introduction of silicic acid, which is a completely foreign substance to the living body. Therefore, it is desired to search for apatite having higher biocompatibility.

An object of the present invention is to solve the above problems in the prior art and to provide apatite having a higher biocompatibility and suitable as a material for implant materials.

[0008]

Apatite is a name given to a group of crystal phases that are similar to each other, and its chemical composition is diverse. Even if the chemical composition is limited to apatite composed of a combination of three components represented by CaO, P ₂ O ₅ , and H ₂ O, the Ca / P molar ratio and the H ₂ O content may vary depending on the synthesis conditions.

When this apatite is used as an implant material, it must have high biocompatibility, be stable in the living body for a long period of time, and be hardly absorbed by living tissues. In other words, it is a condition that its solubility is low, and in other words, that it is thermodynamically stable.

In the case of a combination of CaO, P ₂ O ₅ and H ₂ O,
Conventionally, the only thermodynamically stable apatite is the stoichiometric hydroxyapatite. This stoichiometric ratio hydroxyapatite can exist stably in a living body for a sufficiently long period of time and will not dissolve and disappear. Due to this situation, stoichiometric hydroxyapatite is currently used as a material for implant materials. That is, it can be considered that the material is suitable as an implant material if it is thermodynamically stable.

Therefore, in order to achieve the object of the present invention, any apatite that is thermodynamically stable and excellent in biocompatibility may be used. Therefore, as a result of intensive research to find such apatite, the present inventor has found here apatite having a novel chemical composition that can meet the above conditions.

That is, its chemical composition is Ca ₁₀ _x (N
a, H) x (PO ₄ ) ₆ (OH) ₂ _x · nH ₂ O (however, 0.05 <
x <0.4, n = 2x) (hereinafter referred to as a composition formula).

[0013]

It was confirmed by the following experiment that the apatite having the composition of this compositional formula is thermodynamically stable and excellent in biocompatibility.

(1) Stoichiometric ratio It has been found that when hydroxyapatite is embedded in a living body, a composition change occurs, and sodium ions and hydrogen ions are mainly taken in from the living body to form calcium-deficient hydroxyapatite. It took about 4 to 12 weeks for this composition change to progress in the living body. This time is in agreement with the osteoinduction period required for the stoichiometric hydroxyapatite embedded in the living body to start binding with living tissue. That is, it was found that the stoichiometric hydroxyapatite can bind to biological tissue after the composition of the composition formula is changed. Therefore, it has been found that apatite having a composition represented by the composition formula has high biocompatibility and easily binds to living tissue.

(2) When the stoichiometric hydroxyapatite is suspended in a phosphoric acid-sodium phosphate pH buffer aqueous solution and held for a long time, the hydroxyapatite phase having the compositional formula is thermodynamically combined with the aqueous phase. It can be found that equilibrium is reached. From this, it can be confirmed that the apatite having the composition of the composition formula is a thermodynamically stable phase, and therefore its solubility is sufficiently low.

In the composition formula, the value of x has a range, but the value of x may vary depending on the synthesis conditions, but if it is within the above range (0.05 <x <0.4), it can be used in cell culture or the like. It means that the biocompatibility shown is significantly higher than that of stoichiometric hydroxyapatite having the composition shown in the formula.

In the composition formula, (Na, H) x means H
It means that the sum of ions and Na ions is x. When x is within the above range, a better biocompatibility than the stoichiometric hydroxyapatite can be expected regardless of the amount ratio of Na ions and H ions and n.

Next, examples of the present invention will be described.

[0019]

Example 1 Stoichiometric ratio hydroxyapatite powder synthesized by hydrolysis of dicalcium phosphate in air
The powder was kept at 00 ° C. for 2 hours to remove defects in the crystal and obtain a powder having a thermodynamically stable crystal phase. 1 in a condition in which the powder was immersed in aqueous NaH ₂ PO ₄ concentration of 0.1F
As a result of holding at 40 ° C. and 2.5 atmospheric pressure for 300 hours, a part of calcium ions was replaced with hydrogen ions and sodium ions to obtain apatite having the following composition formula.

[0020] _{Ca 9. 93 H 0. 07} Na 0. 002 (PO 4) 6 (OH) 1. 93 · 0.14H 2 O

The apatite was exhausted and enclosed in a metal capsule, and then held in argon gas at 600 ° C. and 300 MPa for 2 hours to obtain a dense sintered body.

The dense apatite body thus obtained was cut into a test piece and subjected to a cell culture test. That is, rat cancer cells were placed on this apatite test strip,
Cultured and propagated using calf serum. As a result of repeated experiments, it was confirmed that the area covered by the cells adhered and grown on the apatite test piece covered the test piece by about 40%, which was significantly larger than that of the stoichiometric hydroxyapatite used as a comparative example. It was From this result, it was determined that this apatite test piece was superior in biocompatibility to stoichiometric hydroxyapatite.

[0023]

Example 2 A stoichiometric ratio hydroxyapatite dense sintered body obtained by atmospheric pressure sintering was immersed in a sodium phosphate pH buffered aqueous solution having a pH of 7.4 at a concentration of 1 F at 40 ° C. for 2000 hours. Then, the chemical composition of the surface was measured by EPMA. As a result, the chemical composition of the surface was the composition of the following composition formula. However, water of crystallization was not measured.

[0024] _{Ca 9. 82 H 0. 18} Na 0. 004 (PO 4) 6. 01 (OH) 1. 82

This test piece was subjected to the same cell culture test as in Example 1. As a result, as in Example 1, the area covered by the cells that adhered to and grew on this test piece was significantly larger than that of the stoichiometric hydroxyapatite test piece, and therefore, the biocompatibility of this test piece was large. The properties were judged to be superior to the stoichiometric ratio hydroxyapatite.

[0026]

EFFECTS OF THE INVENTION Since the conventionally used stoichiometric ratio hydroxyapatite undergoes composition change in the living body during the induction period required to start binding to living tissue after being implanted in the living body, the present invention Hydroxyapatite has a composition that reaches the body in advance and is given to the apatite phase before the operation, so that the induction period until the tissues start to bond after the operation can be significantly shortened.

Further, the stoichiometric ratio hydroxyapatite conventionally used is the only thermodynamically stable phase, and therefore, its shape can be stably retained in the living body without being dissolved for a long period of time. Have been considered to be excellent. However, as seen in the above-mentioned examples, this stoichiometric ratio hydroxyapatite is not stable under the conditions of synthetic experiments in the living body and in the vicinity of normal pressure, and changes to the composition of the composition formula. Therefore, the hydroxyapatite of the present invention is to give the composition of the composition formula to the apatite phase in advance, so that it is possible to form a thermodynamically stable crystalline phase in the living body, and it is possible to form it in the living body for a long time. It is possible to make an implant material that can stably maintain its shape.

Therefore, it can be expected that the use of the hydroxyapatite of the present invention as an implant material will reduce the pain of patients undergoing surgery and increase the number of successful surgery.

Claims (1)

[Claims] 1. Apatite has a chemical composition of C
a ₁₀ _x (H, Na) x (PO ₄ ) ₆ (OH) ₂ _x · nH ₂ O (however,
Hydroxyapatite, characterized in that 0.05 <x <0.4, n = 2x).