JP4809963B2 - Bone filling material - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a bone grafting material, and more particularly to a bone grafting material having an excellent ability to promote bone formation.
[0002]
[Prior art]
In recent years, in an area such as orthopedics, the use of artificial bones for the repair of bone defects caused by various diseases has become widespread. As a material for the artificial bone, calcium phosphate ceramics are often used.
[0003]
However, although calcium phosphate ceramic materials are excellent in biocompatibility, have good osteoconductivity, and act effectively as a scaffold for osteogenesis, calcium phosphate ceramic materials alone can be used when the severity of bone defects is large. There is a problem that it is difficult to repair.
[0004]
Therefore, for such cases, there is only an option of transplanting autologous bone, and repair of bone defects is difficult when the amount of bone collection is limited.
[0005]
From such a background, a material having a higher bone forming ability, that is, having an osteoinductive activity is required for a case having a high severity of bone defect. As such a material, a material that combines a cell growth factor that induces bone formation and a carrier made of a ceramic material has been proposed.
[0006]
For example, JP-A-7-2691 discloses a composite material of transforming growth factor (TGF-β) and hydroxyapatite (HAP) / tricalcium phosphate (TCP), and a composite of TGF-β and calcium sulfate. JP-A-7-172111 discloses a composite material of fibroblast growth factor (FGF) and HAP, TCP, or tetracalcium phosphate (TeCP). JP-A-7-246235 discloses a material. In addition, the composite material of BMP and HAP / TCP is disclosed in JP-T-8-505548, in which a transplant made of a composite material of TGF-β and TCP promotes bone formation or induces bone. Each is disclosed.
[0007]
In order to promote bone formation, a material in which an osteoinductive factor and its carrier are combined 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 interfere with the activity of the osteoinductive factor. In addition, the carrier itself must have bone conduction ability and be absorbed by the progress of bone formation in the transplanted portion.
[0008]
JP-A-7-88174 discloses the use of collagen or polylactic acid glycolic acid as a BMP carrier. Collagen, polylactic glycolic acid, and the like are biodegradable, and among the above-mentioned conditions as a carrier, the decomposition / absorption properties are satisfied, but the osteoconductivity is poor, and this is insufficient.
[0009]
On the other hand, the above-mentioned calcium phosphate ceramics are excellent in osteoconductivity and can be said to be a preferable carrier in this respect. However, among calcium phosphates, the most common HAP as an artificial bone is difficult to be absorbed in a living body and is not preferable in this respect. On the other hand, β-tricalcium phosphate (β-TCP) has excellent absorbability and is the most preferable material as a carrier when combined with the property of osteoconductivity.
[0010]
[Problems to be solved by the invention]
β-TCP has been used alone as a bone substitute material for a long time. However, according to a report by Altermatt et al. (Eur. J. Pediatr. Surg. 2, 180-182), it was observed that porous β-TCP was applied to bone cysts, and the material was still used for up to 7 years. Has been confirmed to remain in the filling part.
[0011]
β-TCP basically has the property of being absorbed, but there are cases where it remains for a long period of time in this way. Show.
[0012]
In practice, the purity of β-TCP becomes a problem. β-TCP is generally produced by a dry method in which calcium carbonate and calcium hydrogen phosphate are subjected to a solid phase reaction, or a wet method in which Ca ions and P ions are reacted.
[0013]
However, the dry method has the disadvantage that the reaction is inhomogeneous, a little unreacted material remains, and generally the generated powder has poor sintering characteristics. In the wet method, the temperature and pH need to be finely adjusted, and the ratio of Ca and P may be slightly deviated from the stoichiometric value or may contain a small amount of by-products.
[0014]
Moreover, it can be said that the property of the material is greatly influenced by the process to be manufactured. If there is a problem in the manufacturing process, a desired result cannot be obtained in the application stage and the practical use stage. In the disclosure example shown in the prior art, this point is not considered at all.
[0015]
The present invention has been made in view of the above circumstances, and an object thereof is to provide a bone prosthetic material having excellent bone formation promoting ability.
[0016]
[Means for Solving the Problems]
In order to solve the above-mentioned problems, the present inventor has conducted extensive studies, and as a result, the properties of β-TCP, in particular, the manufacturing process and the pore properties are factors that affect the osteoconductivity and absorbability. It was also found that an ideal bone prosthetic material that promotes bone formation can be provided by the combination of β-TCP and an osteoinductive factor. The present invention is based on such knowledge.
[0017]
That is, the present invention provides a bone grafting material for promoting bone formation characterized by containing porous β-tricalcium phosphate (β-TCP) and an osteoinductive factor.
[0018]
The bone filling material according to the present invention configured as described above has an excellent ability to promote bone formation.
[0019]
Β-TCP used for the bone grafting material of the present invention is porous β-TCP having high purity and excellent osteoconductivity and absorbability. The porous β-TCP has continuous ventilation holes, the porosity of 60 to 80%, the volume ratio of all pores having a pore diameter of 50 to 1000 μm is 30 to 70%, and the volume ratio of all pores having a pore size of 5 μm or less is 10 to 40. % Is desirable.
[0020]
If the porosity is less than 60%, sufficient communicating pores cannot be secured, and if it exceeds 80%, the strength tends to decrease and it becomes difficult to handle.
[0021]
Macropores with a pore size of 50-1000 μm contribute to the invasion of cells involved in bone formation and angiogenesis, and micropores with a pore size of 5 μm or less contribute to promoting chemical action such as ease of absorption. To do. More preferably, the macropores have a pore diameter of 100 to 400 μm, and the micropores have a pore diameter of 1 μm or less.
[0022]
When the volume ratio of the macropores is lower than the above value and the volume ratio of the micropores is higher than the above value, the area into which the cells enter decreases, the volume ratio of the macropores is higher than the above value, and the volume ratio of the micropores is above the above value. If it is lower than the value, it tends to be difficult to absorb the fine portion, which is not preferable.
[0023]
High purity β-TCP produced by a wet pulverization method is excellent as a component of a material used as an alternative material for bone tissue. In this wet pulverization 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 an aqueous slurry of 10% by weight. This is wet pulverized with a ball mill, dried at 80 ° C., for example, and then calcined at 720 to 1150 ° C., preferably 720 to 900 ° C. for 1 to 10 hours or more to obtain β-TCP. is there.
[0024]
According to this method, the ratio of Ca and P can be controlled by the weighing value of the raw material, and β-TCP having high purity and excellent sinterability can be obtained.
[0025]
Porous β-TCP having excellent osteoconductivity and absorbability can be produced, for example, by the method described in Japanese Patent No. 2597355. That is, a peptizer and a foaming agent are added to the β-TCP powder obtained by the wet pulverization method as described above, wet foamed, dried, and fired at a temperature of 950 to 1050 ° C. Is what you get.
[0026]
As the peptizer to be used, for example, a water-soluble polymer compound composed of a polyacrylic acid derivative such as ammonium polyacrylate can be used.
[0027]
Also, as the foaming agent, polyoxyethylene alkyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene alkyl allyl ether, polyoxyethylene alkylamine, polyethylene glycol fatty acid ester, decaglycerin monolaurate, alkanolamide, and polyethylene Nonionic surfactants such as glycol and polypropylene glycol copolymers, or those obtained by adding ethylene oxide to these nonionic surfactants can be used.
[0028]
The drying is desirably performed at a temperature of about 40 ° C. for 10 to 20 hours, and the baking is performed at a temperature increase rate of 100 to 300 ° C./hour up to 1000 to 1300 ° C., and at this temperature for 0.5 to 1 hour. It is desirable to carry out by holding.
[0029]
By the method as described above, the volume ratio of all pores having continuous ventilation holes, the porosity of 60 to 80%, the pore diameter of 50 to 1000 μm is 30 to 70%, and the total pores of 5 μm or less is 10 to 40. % Porous porous β-TCP can be obtained.
[0030]
On the other hand, osteoinductive factors include bone morphogenetic factor (BMP), transforming growth factor (TGF-β), fibroblast growth factor (FGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), etc. Further, two or more of these may be combined. These cell growth factors have a strong effect on cell proliferation and differentiation in the process leading to differentiation from mesenchymal cells to osteoblasts and bone formation.
[0031]
Since BMP-2, 4, 5, and 7 as BMP and bFGF as FGF all show high osteoinductive activity, it is particularly desirable to use these.
By compounding such β-TCP and an osteoinductive factor into a bone prosthetic material, a bone prosthetic material that favorably promotes bone formation can be obtained.
[0032]
In addition, although the quantity of the osteoinductive factor in a bone grafting material changes with seed | species, it is desirable that it is normally several micrograms / g-several tens mg / g.
[0033]
In addition, when β-TCP and these osteoinductive factors are combined, the retention of the osteoinductive factor is achieved by adding at least one of atelocollagen, hyaluronic acid, fibrin glue, and gelatin that are decomposed and absorbed in vivo. Is even more desirable in this respect. The addition amount of these substances is preferably 0.5 ml / g to 3 ml / g.
[0034]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, various embodiments of the present invention will be described.
[0035]
(First embodiment)
The calcium carbonate powder and calcium hydrogen phosphate dihydrate were weighed at a molar ratio of 1: 2, put into a ball mill pot together with pure water, and mixed and ground in a ball mill for about 1 day. The resulting slurry was dried at about 80 ° C. and then fired at 750 ° C. The obtained powder was a high-purity β-TCP having a β-TCP single phase in an X-ray diffraction pattern and excellent in sinterability.
[0036]
To this β-TCP powder, pure water, an ammonium acrylate peptizer, and a polyoxyethylene alkylphenyl ether surfactant were added, mixed and stirred to prepare a foamed slurry. The foamed slurry was dried and then fired at 1050 ° C. to obtain a β-TCP porous body.
[0037]
This porous body had a distribution in two regions of a porosity of 75% and a pore diameter of 100 to 400 μm and 1 to 0.1 μm.
To 1 cc of this porous body, 10 to 1000 μg of rhBMP-2 dissolved in a buffer solution was added and freeze-dried to obtain a bone filling material.
[0038]
The bone prosthetic material thus produced can promote bone formation, and promote early bone renewal by promoting BMP osteoblast differentiation and β-TCP as a scaffold for bone formation. In addition, β-TCP had the performance as an ideal bone prosthetic material that is absorbed over time.
[0039]
(Second Embodiment)
In the same manner as in the first embodiment, β-TCP powder was synthesized to produce a porous body. This porous body was pulverized into granules having a particle diameter of 0.5 to 3 mm, and 10 g of bFGF per 1 g of the granules and 1 ml of a 3% sodium hyaluronate solution were mixed to prepare a bone filling material.
[0040]
The bone prosthetic material manufactured in this way can promote bone formation and promote bone renewal at an early stage by the action of bone induction of bFGF and the bone formation scaffold of β-TCP. β-TCP had the performance as an ideal bone filling material that is absorbed over time.
[0041]
(Third embodiment)
In the same manner as in the first embodiment, β-TCP powder was synthesized to produce a porous body. This porous body was pulverized into granules of 1 to 5 mm, and 10 g of TGF-β per 1 g of the granules was mixed with 1 ml of 3% atelocollagen solution to gel the collagen to obtain a bone filling material.
[0042]
The bone prosthetic material thus produced can promote bone formation, and promotes bone renewal at an early stage by the action of TGF-β as an osteoinductive function and β-TCP as a scaffold for bone formation. At the same time, β-TCP has the performance as an ideal bone grafting material that is absorbed over time.
[0043]
【The invention's effect】
As described above in detail, according to the present invention, in the bone grafting material formed by combining porous β-TCP and an osteoinductive factor, β-TCP, which is a carrier of the osteoinductive factor, has excellent bone conduction. By having the ability and bioresorbability, it is possible to provide a bone prosthetic material having an excellent ability to promote bone formation.

Claims (3)

Porous β-phosphate having a porosity of 60 to 80%, a volume ratio of 50 to 1000 μm among all pores of 30 to 70%, and a volume ratio of 1 μm or less of pores of all pores of 10 to 40% Tricalcium (β-TCP),
An osteoinductive factor mixed with the porous β-tricalcium phosphate;
A bone filling material that promotes bone formation, comprising: The bone grafting material according to claim 1, which further promotes bone formation, wherein at least one selected from the group consisting of atelocollagen, hyaluronic acid, fibrin glue and gelatin is further mixed .   The bone substitute material according to claim 1 or 2, wherein the osteoinductive factor is at least one selected from the group consisting of BMP, TGF-β, FGF, IGF and PDGF.