JP2001137328A - Bone prosthesis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a bone prosthesis having a superior bone formation accelerating ability. SOLUTION: A bone prosthesis contains porous β-tricalcium phosphate (β-TCP) and a bone inducing factor. The β-TCP has communicative pores and a porosity of 60-80%. The ratio of the total volume of pores having diameters of 50-1,000 μm to that of all pores is 30-70% and the ratio of the total volume of pores having diameters of <=5 μm to that of all pores is 10-40%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a bone filling material,
In particular, it relates to a bone substitute having an excellent ability to promote bone formation.

[0002]

2. Description of the Related Art In recent years, in the field of orthopedic surgery and the like, the use of artificial bones for repairing bone defects caused by various diseases has become widespread. As a material for the artificial bone, calcium phosphate-based ceramics are often used.

[0003] However, calcium phosphate-based ceramic materials are excellent in biocompatibility, have good osteoconductivity, and effectively act as scaffolds for bone formation. There is a problem that it is difficult to repair the ceramic material alone.

[0004] Therefore, in such a case, it is difficult to repair the bone defect when there is only an option of transplanting the autologous bone and the amount of the collected bone is limited.

[0005] From such a background, a material having a higher osteogenic ability, that is, a material having an osteoinductive activity is required for a case where the severity of a bone defect is high. As such a material, a material in which a cell growth factor for inducing osteogenesis and a carrier made of a ceramic material are combined has been proposed.

For example, Japanese Patent Application Laid-Open No. 7-2691 discloses that
A composite material of transforming growth factor (TGF-β) and hydroxyapatite (HAP) / tricalcium phosphate (TCP) and a composite material of TGF-β and calcium sulfate are disclosed in JP-A-7-117211. A composite material of fibroblast growth factor (FGF) and HAP, TCP or tetracalcium phosphate (TeCP) is disclosed in
JP-A-246235 discloses a composite material of BMP and HAP / TCP, and JP-A-8-505548 discloses a TG.
It is disclosed that an implant made of a composite material of F-β and TCP promotes bone formation or induces bone, respectively.

[0007] In order to promote bone formation, a material obtained by combining an osteoinductive factor and its carrier is effective. However, it is important that the material used as the carrier satisfies the following conditions. That is, the carrier must not only retain the osteoinductive factor, but also be highly biocompatible and not hinder the activity of the osteoinductive factor. In addition, it is necessary that the carrier has osteoconductivity and that the carrier itself is absorbed as the formation of bone at the implanted portion progresses.

[0008] JP-A-7-88174 discloses a BMP.
It is disclosed that collagen or polylactic glycolic acid is used as a carrier for the above. Collagen, polylactic glycolic acid, etc. are biodegradable and satisfy the degrading and resorbing properties of the above-mentioned carrier conditions, but have poor osteoconductivity and are insufficient in this respect.

On the other hand, the above-mentioned calcium phosphate-based ceramics have excellent osteoconductivity and can be said to be a preferred carrier in this respect. However, in calcium phosphate,
HAP, which is the most common artificial bone, is hardly absorbed in a living body and is not preferable in this respect. In contrast,
β-Tricalcium phosphate (β-TCP) has excellent absorbability and is the most preferred material for a carrier when combined with the osteoconductive properties.

[0010]

[Beta] -TCP has been used as a bone substitute alone by itself. However, a report by Altermatt et al. (Eur.
J. Pediatr. Surg. 2,180-182)
According to the above, porous β-TCP was applied to bone cysts and observed with follow-up, and it was confirmed that the material still remained in the prosthetic part even for a maximum of seven years.

Although β-TCP basically has the property of being absorbed, the fact that β-TCP sometimes remains for a long period of time means that it is only necessary to use β-TCP as a material. It is not.

In practice, the purity of β-TCP is a problem. β-TCP is generally prepared by a solid-phase reaction between calcium carbonate and calcium hydrogen phosphate in a dry state,
It is produced by a method of reacting ions with P ions.

[0013] However, the dry method has the disadvantage that the reaction is heterogeneous, some unreacted substances remain, and the powder generally produced has poor sintering characteristics. In the wet method, fine adjustment of the temperature and the pH is required, and the ratio of Ca and P may slightly deviate from the stoichiometric value, or a small amount of by-products may be contained.

The properties of the material can be said to be greatly affected by the manufacturing process. If there is a problem in the manufacturing process, a desired result cannot be obtained in an application stage or a practical stage. This point is not considered at all in the disclosure example shown in the prior art.

The present invention has been made in view of the above circumstances,
An object of the present invention is to provide a bone substitute having an excellent ability to promote bone formation.

[0016]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have made intensive studies and as a result, the properties of β-TCP, particularly the manufacturing process and the porosity, affect the osteoconductivity and resorption. And β-T based on these factors.
It has been found that a composite of CP and an osteoinductive factor can provide an ideal bone substitute for promoting bone formation. The present invention is based on such findings.

That is, the present invention provides a bone substitute for promoting bone formation, which comprises porous β-tricalcium phosphate (β-TCP) and an osteoinductive factor.

The bone substitute according to the present invention thus constituted has an excellent ability to promote bone formation.

Β-TCP used in the bone replacement material of the present invention
Is a porous β-TCP having high purity and excellent osteoconductive and resorbable properties. Porous β-TCP has continuous pores, a porosity of 60 to 80%, and a pore diameter of 50 to 1000 μm.
It is preferable that the volume ratio of all pores of 30 to 70% and 5 μm or less is 10 to 40%.

If the porosity is less than 60%, the communicating pores cannot be sufficiently secured. If the porosity exceeds 80%, the strength tends to decrease and the handling tends to be difficult, which is not preferable.

Macropores having a pore diameter of 50 to 1000 μm contribute to the entry of cells involved in bone formation, angiogenesis, and the like, and micropores having a pore diameter of 5 μm or less promote chemical actions such as ease of absorption. Contribute to More preferably, the pore size of the macropores is 100 to 400 μm, and the pore size of the micropores is 1 μm or less.

When the volume ratio of macropores is lower than the above value and the volume ratio of micropores is higher than the above value, the area into which cells enter is reduced, the volume ratio of macropores is higher than the above value, and the volume of micropores is higher. If the ratio is lower than the above value, the absorption in the fine portion tends to be difficult, which is not preferable.

High-purity β-TCP produced by a wet grinding method is excellent as a component of a material used as a substitute for bone tissue. In this wet grinding method, calcium carbonate and calcium hydrogen phosphate dihydrate are weighed so that the molar ratio of Ca and P is 1.5, and pure water is added to these powders to form a 10% by weight aqueous slurry. This is wet-pulverized by a ball mill and dried at, for example, 80 ° C.
Baking at 150 ° C., preferably 720 to 900 ° C. for 1 to 10 hours or more to obtain β-TCP.

According to this method, C is determined by the weighed value of the raw material.
The ratio of a to P can be controlled, and β-TCP having high purity and excellent sinterability can be obtained.

Porous β having excellent osteoconductivity and absorbability
-TCP can be produced, for example, by the method described in Japanese Patent No. 2597355. That is,
The β-TCP powder obtained by the wet grinding method as described above
A deflocculant and a foaming agent are added, and the mixture is wet foamed, dried, and fired at a temperature of 950 to 1050 ° C. to obtain a porous body.

As the deflocculant to be used, for example, a water-soluble polymer compound comprising a polyacrylic acid derivative such as ammonium polyacrylate can be used.

Examples of foaming agents include polyoxyethylene alkyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene alkyl allyl ether, polyoxyethylene alkylamine, polyethylene glycol fatty acid ester, decaglycerin monolaurate, and alkanolamide. And nonionic surfactants such as polyethylene glycol and polypropylene glycol copolymer, or those obtained by adding ethylene oxide to these nonionic surfactants.

The drying is preferably carried out at a temperature of about 40 ° C. for 10 to 20 hours, and the firing is carried out at a rate of 100 to 300 ° C./hour up to 1000 to 1300 ° C. It is desirable to carry out by holding for ~ 1 hour.

According to the above-described method, continuous pores are provided, the porosity is 60 to 80%, and the pore diameter is 50 to 1000 μm.
The porous β-TCP having a porous property in which the volume ratio of the total pores is 30 to 70% and the volume ratio of the total pores of 5 μm or less is 10 to 40% can be obtained.

On the other hand, osteoinductive factors include bone morphogenetic factor (BMP), transforming growth factor (TGF-β), fibroblast growth factor (FGF), and insulin-like growth factor (IG).
F), platelet-derived growth factor (PDGF), and the like, and two or more of these may be used in combination. These cell growth factors strongly act on the proliferation and differentiation of cells in the process of differentiation from mesenchymal cells to osteoblasts and bone formation.

As BMP, BMP-2, 4, 5, 7
However, it is particularly desirable to use bFGF as an FGF, since these all exhibit high osteoinductive activity. By mixing such a β-TCP and an osteoinductive factor to form a composite to form a bone replacement material, a bone replacement material that favorably promotes bone formation can be obtained.

Although the amount of the osteoinductive factor in the bone substitute varies depending on the species, it is usually several μg / g to several tens mg / g.
It is desirable that

When β-TCP is combined with these osteoinductive factors, at least one of atelocollagen, hyaluronic acid, fibrin glue, and gelatin, which is degraded and absorbed in vivo, is added to form a complex. Is further improved, which is more desirable. The addition amount of these substances is desirably 0.5 ml / g to 3 ml / g.

[0034]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, various embodiments of the present invention will be described.

(First Embodiment) Calcium carbonate powder and calcium hydrogen phosphate dihydrate are weighed at a molar ratio of 1: 2, put into a ball mill pot together with pure water, and then ball milled for about 1 day. It was mixed and ground. The obtained slurry was dried at about 80 ° C. and then calcined at 750 ° C. The obtained powder showed a single phase of β-TCP in the X-ray diffraction pattern, and was a high-purity β-TCP excellent in sinterability.

To this β-TCP powder, pure water, ammonium acrylate-based deflocculant, and polyoxyethylene alkylphenyl ether-based surfactant were added, and mixed and stirred to prepare a foamed slurry. The foamed slurry is dried and then fired at 1050 ° C. to obtain β-TCP
A porous body was obtained.

This porous body had a porosity of 75% and a pore size distribution in two regions of 100 to 400 μm and 1 to 0.1 μm. To 1 cc of the porous material, 10 to 1000 μg of rhBMP-2 dissolved in a buffer solution was added and freeze-dried to obtain a bone replacement material.

The bone substitute thus produced can promote bone formation, promote BMP differentiation into osteoblasts, and act as a scaffold for β-TCP bone formation.
While promoting new bone formation at an early stage, β-TCP had the ability to be absorbed over time as an ideal bone replacement material.

(Second Embodiment) In the same manner as in the first embodiment, a β-TCP powder was synthesized to produce a porous body. This porous body is pulverized into granules having a particle size of 0.5 to 3 mm, and bFGF is used in an amount of 10 to 500 μg per 1 g of the granules.
Mix 1 ml of 3% sodium hyaluronate solution,
It was used as a bone substitute.

The bone substitute prepared in this manner can promote bone formation, and has the osteoinductive ability of bFGF and β-
Due to the effect of TCP as a scaffold for bone formation, bone regeneration was promoted at an early stage, and β-TCP was absorbed over time, thus having the performance as an ideal bone replacement material.

(Third Embodiment) In the same manner as in the first embodiment, β-TCP powder was synthesized to produce a porous body. The porous material was pulverized into granules of 1 to 5 mm, and 10 g of TGF-β was mixed with 1 g of the granules, and 1 ml of a 3% atelocollagen solution was mixed with the granules to gel the collagen to obtain a bone replacement material.

[0042] The bone replacement material thus produced can promote bone formation, and has the osteoinductive ability of TGF-β and β
Due to the effect of -TCP as a scaffold for bone formation, bone regeneration was advanced at an early stage, and β-TCP had an ability to be absorbed over time as an ideal bone replacement material.

[0043]

As described above in detail, according to the present invention, in a bone replacement material comprising a composite of porous β-TCP and an osteoinductive factor, β
-Since TCP has excellent osteoconductivity and bioabsorbability, it is possible to provide a bone replacement material having excellent bone formation promoting ability.

Claims (5)

[Claims] Claims: 1. A porous β-tricalcium phosphate (β-TC
A bone substitute for promoting bone formation, which comprises P) and an osteoinductive factor. 2. Promote bone formation characterized by containing a porous β-TCP, an osteoinductive factor, and at least one selected from the group consisting of atelocollagen, hyaluronic acid, fibrin glue and gelatin. Bone replacement material. 3. The porous β-TCP is obtained by wet-grinding at least one selected from the group consisting of calcium carbonate, calcium hydrogen phosphate and calcium hydrogen phosphate dihydrate, followed by drying and firing. Β-TCP powder obtained by
The bone filling material according to claim 1 or 2, wherein the bone filling material is a porous body or a porous granule obtained by foam-forming in a wet manner using a surfactant, drying and firing. 4. The porous β-TCP has continuous pores, a porosity of 60 to 80%, and a pore diameter of 50 to 1000 μm.
The bone filling material for promoting bone formation according to claim 1 or 2, wherein the volume ratio of all pores is 30 to 70%, and the volume ratio of all pores having a pore diameter of 5 µm or less is 10 to 40%. . 5. The osteoinductive factor is BMP, TGF-β,
The bone replacement material according to claim 1 or 2, wherein the bone replacement material is at least one selected from the group consisting of FGF, IGF, and PDGF.