JPH10179713A - Bioactive cement composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a bioactive cement composition having no carcinogenicity and good affinity with an osteogenetic factor by using an alumina powder containing δ-Al2 O3 crystal, γ-Al2 O3 crystal or noncrystalline alumina together with dimethacrylate monomers, a polymn. initiator, a polymn. accelerator, a polymn. inhibitor and an osteogenetic factor. SOLUTION: A hardening material containing an alumina powder, dimethacrylate monomers, a polymn. initiator, a polymn. accelerator and a polymn inhibitor acts as a carrier for an osteogenetic factor. The alumina powder used is an active alumina containing at least δ-Al2 O3 crystal, γ-Al2 O3 crystal or noncrystalline alumina. The osteogenetic factor used is not specified, and for example, a single or plural kinds selected from Vg-DDP/BMP family containing BMP-1 to 7 in TGF-β super family, 1NH-βA in Inhibin/Activin family, and TGF-β1 to β3 in TGF-βfamily are added.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the field of orthopedic surgery, neurosurgery, oral surgery, dentistry, etc.
The present invention relates to a bioactive cement composition used for bonding and fixing an implant material such as an artificial bone.

[0002]

2. Description of the Related Art Conventionally, in the fields of orthopedic surgery, neurosurgery, oral surgery, dentistry, and the like, filling and filling of a bone defect, artificial bone,
Various materials have been proposed as materials for bonding and fixing implant materials such as artificial joints and artificial roots. Among them, as bioactive cement compositions containing bone morphogenetic proteins (BMP), which are used to promote rapid binding to bone around the body, bioactive glass powder or crystallized glass powder, phosphorus It is known to use a mixture with an aqueous solution containing an acid salt as a main component as a carrier (also referred to as a support or a carrier and implanted in combination with an osteogenic factor). In addition to the above, there have been known those using, as a carrier, insoluble bone matrix, collagen, fibrin glue, fibrous glass, hydroxyapatite (HAP) of various shapes, or a composite thereof.

[0003]

The conditions to be met by a bioactive cement composition containing an osteogenic factor include (1)
No toxicity, no carcinogenicity, (2) no antigenicity, no inflammation (having biocompatibility and no inflammatory response), (3) carrier having affinity for osteogenic factors (4) good operability and workability at the time of use; (5) stable mass productivity at an industrial level;
(6) It is necessary to have mechanical strength enough to withstand a load in a living body.

However, at present, none of the various bioactive cement compositions described above satisfy all of the above conditions. For example, a material using a mixture of a bioactive glass powder or a crystallized glass powder and an aqueous solution mainly containing a phosphate as a carrier has insufficient mechanical strength after curing. The material using fibrous glass is
Since the operability and workability at the time of use are not good, a problem remains when considering a wide application to a complicated part.

[0005] Therefore, PMMA which has good operability and workability and is cured after a certain period of time to form a cured product having high mechanical strength.
Although it is conceivable to use cement as a carrier, PMMA cement has no biological activity, so that adding a bone forming factor does not provide a sufficient effect.

[0006] It is an object of the present invention to provide a bioactive cement composition which satisfies all the above-mentioned required properties.

[0007]

The bioactive cement composition of the present invention comprises alumina powder, a dimethacrylate monomer, a polymerization initiator, a polymerization accelerator, a polymerization inhibitor, and a bone forming factor, and the alumina powder has at least δ. -Al ₂ O ₃ crystal, γ-Al ₂ O ₃ crystal or amorphous alumina is included.

[0008] The bone forming factor used in the bioactive cement composition of the present invention is not particularly limited.
1, BMP-2, BMP-3, BMP-4, BMP-
5, Vg / DPP / B including BMP-6, BMP-7, etc.
MP family, Inhibin / Activin (A
ctivin) family INH-βA, TGF-β family TGF-β1, TGF-β2, TGF-β3, etc., alone or in combination. As the bone morphogenetic factor, use is made of what is called cloning, which is produced by genetic manipulation, or is extracted by an advanced purification technique, and is confirmed in advance to have no abnormality in carcinogenicity or the like.
The amount of the bone morphogenetic factor is preferably 0.1 μg or more per 100 g of cement in order to exert a sufficient effect.

In the present invention, the curable material containing the alumina powder, the dimethacrylate monomer, the polymerization initiator, the polymerization accelerator, and the polymerization inhibitor acts as a carrier for the osteogenic factor.

The alumina powder used in the present invention is different from the non-bioactive alumina powder widely used in the past. That is, the conventional alumina powder has a stable α-Al ₂ O ₃ crystal structure, but the alumina powder used in the present invention has at least δ-Al ₂ O ₃ crystal and γ-Al ₂ O ₃ crystal. Or active alumina in which amorphous alumina exists. From the viewpoint of bioactivity, it is desirable that the ratio of the δ-Al ₂ O ₃ crystal, the γ-Al ₂ O ₃ crystal, and the amorphous alumina in the alumina powder be 30% by weight or more. The smaller the alumina powder is, the higher the strength of the cured product can be obtained.
Those having a thickness of 0 μm or less are preferred. In addition, if the surface is subjected to silane coupling treatment, familiarity with the dimethacrylate monomer is improved and the strength of the cured cement is increased, and the powder surface has a hydrophobic group so that blood inhibition is eliminated, It is easy to cure.

The alumina powder used in the present invention can be prepared as follows. First, the crystal structure is α
Providing a normal alumina powder is -Al ₂ O _3. The alumina powder has an average particle diameter D ₅₀ to use those of 10μm or less. Next, the alumina powder is rapidly heated to 1500 ° C. or more, preferably 2000 ° C. or more, melted and vitrified, and then rapidly cooled. Thus, at least δ-Al ₂
A chemically unstable, that is, bioactive alumina powder containing O ₃ crystal, γ-Al ₂ O ₃ crystal or amorphous alumina can be obtained. When the particle size of the alumina powder is 10
The reason why the particle diameter is set to be not more than μm is that if the particle size is large, rapid heating and quenching becomes difficult and stable α-Al ₂ O ₃ is easily deposited,
If it exceeds 0 μm, the precipitated amount of α-Al ₂ O ₃ crystals occupies 30% by weight or more, resulting in alumina powder which is chemically stable, that is, has low bioactivity.

The dimethacrylate monomers include
2,2bis [4- (3methacryloxy-2-hydroxypropoxy) phenyl] propane (Bis-GMA)
Is particularly desirable, and in addition, 2,2-bis (4-methacryloxyphenyl) propane (BPDMA), 2,2
-Bis (4-methacryloxyethoxyphenyl) propane (Bis-MEPP), 2,2-bis (4-methacryloxypolyethoxyphenyl) propane (Bis-MP
EPP) or the like can be used. When the viscosity of the monomer is high, triethylene glycol dimethacrylate (TEGDMA) can be added. As the diluent, polymerizable monomers such as diethylene glycol dimethacrylate and ethylene glycol dimethacrylate can be used.

The powder-liquid ratio between the powder component and the monomer is as follows:
It is desirable that the powder: monomer ratio be 50:50 to 90:10 by weight.

As the polymerization initiator, benzoyl peroxide,
Tri-n-butylborane or the like can be used. The amount of the polymerization initiator to be added is preferably 0.1 to 5 parts by weight based on 100 parts by weight of the monomer. This effect is poor if the addition amount is less than 0.1 part by weight,
When the amount exceeds 5 parts by weight, the curing time becomes too short with respect to the working time, so that actual use becomes difficult.

As the polymerization accelerator, a tertiary amine such as dimethyl-P-toluidine can be used, and its addition amount is desirably 0.1 to 5 parts by weight based on 100 parts by weight of the monomer. . If the amount is less than 0.1 part by weight, it may be necessary to heat the mixture to 100 ° C. or more in order to promote the curing, and it is difficult to use the composition in an actual operation site. On the other hand, if it exceeds 5 parts by weight, the curing time is often too fast.

As a polymerization inhibitor, phenothiazine or a derivative thereof can be added. Phenothiazine and its derivatives have almost no toxicity to living organisms, and can be adjusted to the desired curing time with a relatively small amount. This is preferable as a polymerization inhibitor because it hardly affects the time. The addition amount of the polymerization inhibitor is 10 ppm to 0.2 parts per 100 parts by weight of the monomer.
Parts by weight are appropriate.

In the present invention, for example, a Ca-containing inorganic powder can be added in addition to the above components.

The Ca-containing inorganic powder is a component added to improve the adhesiveness to natural bone at the initial stage of implantation and to enable early bonding. Examples thereof include Ca-containing glass, crystallized glass, and phosphoric acid. What consists of a calcium compound, calcium carbonate, etc. can be used. In particular, Ca-containing glass and crystallized glass elute Ca ions in vivo and exhibit high bioactivity. As such a glass, in particular, in terms of weight percentage, CaO 30 to 70%, SiO ₂ 30 to 70%,
_{P 2 O 5 0~40%, 0~20} % MgO, CaF 2
0 to 5%, in particular CaO 40 to 50% SiO ₂ 3
_{0~40%, P 2 O 5 10~20} %, MgO 0~1
Glass or crystallized glass having a composition of 0% and CaF _{2 of} 0 to 2% is preferable. The calcium phosphate compounds include CaHPO ₄ , Ca ₃ (PO ₄ ) ₂ , Ca ₅ (P
O ₄ ) ₃ OH, CaP ₄ O ₁₁ , Ca (PO ₃ ) ₂ , Ca
₂ P ₂ O ₇ , Ca ₄ O (PO ₄ ) ₂ , Ca ₁₀ (PO ₄ )
₆ (OH) ₂ , Ca (H ₂ PO ₄ ) ₂ .H ₂ O, etc. as a main component. The Ca-containing inorganic powder is preferably spherical. When Ca-containing inorganic powder is added, the proportion of the powder component in the powder component is preferably in the range of 5 to 75% by weight.

In addition to the Ca-containing inorganic powder, various components such as fused silica powder, colloidal silica, and resin powder can be appropriately added as needed.

The carrier composed of the above constituents is bioactive and has an affinity for osteogenic factors. It also has good operability and workability during use, has stable industrial mass production, and maintains high mechanical strength after curing for a long period of time.

Further, the bioactive cement composition of the present invention may contain one or more kinds of chemicals, if necessary, in addition to the above-mentioned components. The added drug is released in the living body and exhibits a medicinal effect. Drugs that can be added include various antibiotics such as cephams, penicillins, aminoglucosides, macrolides, tetracyclines, and peptides, anticancer agents, anti-inflammatory agents, thyroid hormone agents, diabetes preparations, and the like. This kind of agent may be added in a necessary amount at the time of kneading when finally curing the bioactive cement composition.

The form of providing the bioactive cement composition of the present invention includes a powder-liquid system, a two-paste system, and the like. Good. It should be noted that which form to employ may be determined in consideration of various conditions, but a two-paste system is more preferable in consideration of the mixing property between the powder and the resin at the operating site. In any case, it is better to add the drug at the time of mixing, but it is also possible to add the drug in advance.

In the present invention, the timing of adding the osteogenic factor to the carrier is determined by the final kneading, such as when kneading powder and liquid systems (powder-liquid system) or when kneading pastes (two paste systems). The method of adding at the time is most preferable, but other methods include, for example, a method of adding a liquid containing a dimethacrylate-based monomer and a method of adding the liquid at the time of preparing a paste (two paste systems).

[0024]

When an appropriate amount of alumina powder, a dimethacrylate monomer, a polymerization initiator, a polymerization accelerator and a polymerization inhibitor are mixed in a proper amount, a polymerization reaction occurs at a low temperature, and curing is completed in about 3 to 15 minutes. It can be formed into a desired shape within the time until curing. In addition, the cured material not only has high mechanical strength, but also does not cause deterioration of the powder because the alumina powder does not release ions in a living body, and the strength of the cured body is not easily reduced. Moreover, the alumina powder exposed on the surface of the hardened body induces new bone and bonds with the surrounding bone.

In the bioactive cement composition of the present invention, since such a material is used as a carrier of an osteogenic factor, new bone is rapidly formed on the surface of a hardened cement by the interaction between the osteogenic factor and alumina powder. It grows and covers the surface of the cured body, and a strong bond with the surrounding bone can be obtained at an early stage.

[0026]

The present invention will be described below in detail based on examples and comparative examples.

Table 1 shows examples of the present invention (sample No. 1,
2) and Comparative Examples (Sample Nos. 3 to 5).

[0028]

[Table 1]

In the sample No. of the embodiment, 1 was prepared by the following procedure.

First, ordinary alumina powder (average particle size: 10 μm) having a crystal structure of α-Al ₂ O ₃ was prepared. Next, this powder is supplied into a flame of 2000 ° C. or more, blown off while melting, and then rapidly cooled in water,
An alumina powder containing δ-Al ₂ O ₃ crystal, γ-Al ₂ O ₃ crystal and amorphous alumina was obtained. The alumina powder thus obtained was spherical due to surface tension. As a result of X-ray diffraction, α-Al ₂
O ₃ crystals were contained, but the content was about 5 to 10% by weight.

Further, dimethacrylate monomers were mixed at a predetermined ratio.

Next, the powder and the dimethacrylate monomer mixture were equally divided, and benzoyl peroxide as a polymerization initiator was added to one of the powder and the mixture, followed by kneading to obtain a paste A. On the other hand, dimethyl-P-toluidine as a polymerization accelerator and phenothiazine as a polymerization inhibitor were added to obtain a paste B. As bone formation factors,
BMP-2 by cloning was prepared. Thereafter, both pastes (A, B) and the osteogenic factor were homogeneously kneaded in the same manner as in actual use to prepare a hardenable bioactive cement.

The composition ratio of the dimethacrylate monomer and the mixing ratio of the monomer and the powder were represented by weight ratio. Benzoyl peroxide, dimethyl-p-toluidine,
The amount of phenothiazine added is such that it cures in about 7 minutes.
2 parts by weight, 1.4 parts by weight, and 300 ppm based on 100 parts by weight of the total amount of the monomers. Further, the addition amount of the bone morphogenetic factor is shown for 100 g of the implanted sample.

Sample No. 2 is to use half of the alumina powder as C
a was replaced with a glass powder containing a. Prepared in the same manner as 1. Note that the Ca-containing glass powder is C
_{aO46.7%, SiO 2 35.6%,} P 2 O 5 1
A spherical material having a composition of 7.0% and CaF _{2 of} 0.7% and an average particle size of 4 μm was used.

In addition, the sample No. No. 3 used only ordinary alumina powder as a powder component, and No. 3 used other powders.
It was prepared in the same manner as the sample No. 1. When this alumina powder was subjected to X-ray diffraction, most of the crystals were found to be α-A
l ₂ O ₃ , δ-Al ₂ O ₃ crystal and γ-Al ₂ O ₃
The presence of crystals could not be confirmed.

Sample No. Sample No. 4 of Example except that no osteogenic factor was contained. It was prepared in exactly the same manner as in Example 1.

Sample No. 5 is a commercially available PMMA cement to which an osteogenic factor was added in the same manner as in the example.

Each sample prepared by the above procedure was evaluated for the initial stage, the bending strength at 3 months and 6 months after implantation in the living body, the condition of the surrounding bone, and the presence or absence of an inflammatory reaction of the surrounding tissue.

As is clear from the table, the N
o. Samples 1 and 2 had a flexural strength of an initial strength of 120.
MPa or more, 105MPa or more 3 months after implantation in vivo,
It was 90 MPa or more after 6 months, and it was found that the strength was hardly deteriorated. Sample No. Sample No. 1 was obtained after 2 weeks had passed. Sample No. 2 showed binding to the surrounding bone at one week, and no inflammatory reaction of the surrounding soft tissue was observed in any of the samples.

On the other hand, sample N using ordinary alumina powder
o. Despite the fact that Sample No. 3 contained an osteogenic factor, only a slight contact with the surrounding bone was observed after 8 weeks. Sample No. containing no osteogenic factor. In No. 4, the connection to the surrounding bone was observed after 4 weeks. Also P
No. 3 using MMA cement as a carrier. Regarding the sample No. 5, no connection to the surrounding bone was observed even after the lapse of 8 weeks, and necrosis of the surrounding tissue was observed due to the exothermic reaction at the time of hardening.

The bending strength was evaluated by a three-point bending test. Each sample was kneaded and hardened, and 3 × 4 × 20
The initial strength was measured by preparing a sample piece of mm, and after being implanted subcutaneously in a rat, it was taken out and measured after 3 and 6 months. For the condition of the surrounding bone, each sample after kneading was filled into the subcutaneous rat to investigate ectopic bone formation, and after hardening, it was periodically removed and observed including the surrounding tissue of the bioactive cement. Was performed with an electron microscope. As for the presence or absence of inflammatory reaction in surrounding tissues, samples were implanted under the skin of rats in the same manner as above, and the soft tissues around the samples were removed and examined for tissue necrosis using an electron microscope and an electron beam microanalyzer. Then, it is determined.

[0042]

As described above, the bioactive cement composition of the present invention satisfies all the required characteristics, and particularly, it does not cause an inflammatory reaction in the living tissue and binds to the bone around the living body. Can be promptly promoted. Further, the cement of the present invention can be applied to a site having a complicated shape, so that it can be widely used.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // (C04B 26/06 111: 00 14:30)

Claims (7)

[Claims] 1. An alumina powder comprising a alumina powder, a dimethacrylate monomer, a polymerization initiator, a polymerization accelerator, a polymerization inhibitor and a bone forming factor, wherein the alumina powder comprises at least δ-Al ₂ O ₃
A bioactive cement composition comprising crystal, γ-Al ₂ O ₃ crystal or amorphous alumina. 2. The dimethacrylate monomer is 2,2
The bioactive cement composition according to claim 1, comprising bis [4- (3 methacryloxy-2-hydroxypropoxy) phenyl] propane and triethylene glycol dimethacrylate. 3. The bioactive cement composition according to claim 1, wherein the polymerization initiator is benzoyl peroxide. 4. The bioactive cement composition according to claim 1, wherein the polymerization accelerator is dimethyl-p-toluidine. 5. The bioactive cement composition according to claim 1, wherein the polymerization inhibitor is phenothiazine. 6. The bioactive cement composition according to claim 1, wherein a Ca-containing inorganic powder is added. 7. The bioactive cement composition of claim 1, provided in a two paste system.