KR100559171B1 - Mixture for Producing a Bioactive Bone Cement and Method for Producing a Bioactive Bone Cement Using the Same - Google Patents

Abstract

The present invention relates to a method for producing bioactive bone cement using the mixture, characterized in that it contains PMMA powder and CaO-SiO ₂ gel. In the present invention, a method for producing PMMA / CaO-SiO ₂ bone cement and PMMA / CaO-SiO ₂ bone prepared by the above method, characterized in that MMA solution is added to the mixture containing CaO-SiO ₂ gel and PMMA powder. Provide cement.

The PMMA / CaO-SiO ₂ bone cement according to the present invention can be used as an adhesive for fixing metals, polymers, ceramics, etc. to bone, and at the same time, it can be used under load because it is strongly bonded to the bone in a short time.

PMMA, Bone Cement, Bioactive, Implants

Description

Mixture for Producing a Bioactive Bone Cement and Method for Producing a Bioactive Bone Cement Using the Same             

Figure 1 shows the manufacturing process of PMMA / CaO-SiO ₂ bone cement.

FIG. 2 shows an X-ray diffraction pattern of a sample obtained by mixing bone cement prepared by mixing PMMA powder and 20CaO-80SiO ₂ gel powder in a weight ratio of 95: 5 in an analogous liquid by a thin film X-ray diffractometer.

Figure 3 is a scanning electron micrograph of the structural changes of the surface when the bone cement prepared by mixing the PMMA powder and 20CaO-80SiO ₂ gel powder in a weight ratio of 95: 5.

FIG. 4 illustrates an X-ray diffraction pattern of a sample obtained by mixing bone cement prepared by mixing PMMA powder and 20CaO-80SiO ₂ gel powder in a weight ratio of 70:30 in an analogous liquid by a thin film X-ray diffraction analyzer.

FIG. 5 is a scanning electron micrograph of a structural change of a surface when bone cement prepared by mixing PMMA powder and 20CaO-80SiO ₂ gel powder in a weight ratio of 70:30 is added to an analogous liquid.

Field of invention

The present invention relates to a mixture for producing bioactive bone cement and a method for producing bioactive bone cement, and more particularly, bone cement mainly composed of CaO-SiO ₂ prepared by PMMA and sol-gel method. It relates to a mixture for preparation and a method for producing bone cement, characterized by adding MMA solution to the mixture.

Background of the Invention

Our skeleton is made up of 206 bones. These bones support our bodies and protect important organs such as the brain and internal organs, as well as allow each movement to work independently.

In recent years, as the aging society progresses, the damage to bone tissue due to diseases such as osteoporosis and automobile accidents is increasing. Materials for repairing these damaged bone tissues have long been studied. Alumina (Al ₂ O ₃ ), metal stainless steel and metal titanium (Ti), which are hydrophilic materials without eluting harmful components in the body, have been used for this purpose.

However, since these materials do not chemically bond directly to the bones of living bodies, the surface of the material is made porous or deliberately irregularities in order to enhance the binding ability to the bones, so that they are fixed by a mechanical method that allows the bones to grow therein. However, bone cement has begun to be used as an attempt to anchor implants to surrounding bone tissue, as long as it takes longer than 2-3 months for such bonding to be achieved.

When preserving complex bone defects or fixing metal artificial joints to natural bones, mixing powder and liquid gives fluidity for several minutes, then hardens and binds to nearby bones Cement materials that exhibit mechanical properties are preferred. If it is such a material, it will also be possible to inject | pour this into a affected part with a syringe, and repair the bone defect part resulting from osteoporosis etc ..

In order to achieve this, a method of hardening MMA (methyl methacrylate) monomer by polycondensation or mixing various ceramic powders with water, aqueous sodium phosphate solution, organic acid or polymer solution, etc. come.

Properties Required for Bio Cement

As a property of the cement used in the living body, an appropriate time until it is injected into the affected part and hardens, and high strength of the cement injected into the affected part after filling is important. This curing time and strength vary greatly depending on the use ratio (separation ratio) of the powder and the liquid agent during cement kneading. In general, when the separation ratio is high, the curing time is short and a high strength cured product is obtained. However, if this is too high, the workability for injecting the affected part will be difficult, and a compact filling will be impossible.

Therefore, while securing the fluidity of the cement paste, it becomes important to harden it at a time suitable for the work and to achieve high strength. In general building cement, the said objective is achieved by using water-soluble agents, such as surfactant. However, it is difficult to use such a substance from the viewpoint of the stability of the substance to be used in the biological cement, and it is preferable to achieve this by controlling the form of the powder itself.

On the other hand, PMMA (polymethylmethacrylate) bone cement, which is most commonly used in the conventional clinical, is known to not directly show the property of binding to bone, that is, bioactivity (bioactivity). Therefore, in order for the bone cement to be stable in the long term in the living body, above all, it is required that the bone cement has a bioactivity that chemically bonds with natural bone.

Bioactive Bone Cement

In general, when an artificial material is embedded in a bone defect, the living body surrounds it with a fibrous coating to isolate it from surrounding bone. Inorganic solids, however, do not form these fibrous coatings, but are in direct contact with the surrounding bones, creating strong chemical bonds with them. This kind of ceramics is called bioactive ceramics.

Until now, in addition to the Na ₂ O—CaO—SiO ₂ —P ₂ O ₅ based glass (Bioglass: Bioglass), various kinds of glass, crystallized glass, and sintered ceramics are known to bind to bone. Among them, bioglass has the property of binding to bone in a short time, and is used as artificial middle bone and periodontal filler.The sintered crystalline apatite (Ca ₁₀ (PO ₄ ) ₆ (OH ₂ )) crystalline does not contain anything other than bone component. It is used as a bone filler because it does not have properties, and crystalline sintered β-3CaO · P ₂ O ₅ can be replaced with bone.

Oxygen-fluorine-apatite _{(Ca 10 (PO 4) 6} (O, F 2)) and β- wollastonite (β-wollastonite: CaO · SiO 2) which MgO-CaO-SiO ₂ -P ₂ O ₅ -CaF ₂ precipitate The system crystallized glass AW has excellent mechanical strength (curve strength of 215 MPa) and bone bonding speed, so it has been put into practical use as an artificial vertebra, intervertebral disc, iliac bone, filler, and the like.

After that, Na ₂ OK ₂ O-MgO-CaO-SiO ₂ -P ₂ O _{5 type} crystallized glass which precipitated apatite (Ca ₁₀ (PO ₄ ) ₆ (O, F ₂ )) in a glass called ceravital Implant-L1 precipitated apatite and wollastonite with slightly different composition from AW, apatite and gold mica ((Na, K) Mg ₃ (AlSiO ₁₀ ) F ₂ ) were added to Na ₂ OK ₂ O-MgO-CaO-Al ₂ O ₃ -SiO ₂ -P ₂ O ₅ -F system crystallized glass Bioburit, crystalline natural calcite, crystallized glass obtained by depositing magnetite (Fe ₂ O ₃ ) and β- wollastonite in glass It is known to show a strong binding property to the bone directly, that is, bioactivity without making a sexual coating.

These ceramics, which have been known to bind bones to date, have all materials including crystalline apatite sintered bodies except for crystalline natural calcite and crystalline β-3CaO · P ₂ O ₅ , which show significant surface decomposition in vivo. It is known to form an apatite layer on its surface within which it binds to bone ( J. Non-Cryst. Solids, 120, 138-51, 1990; Biomaterials, 12, 155-63, 1991).

This apatite layer contains simulated body fluid (mM): Na ⁺ 142.0, K ⁺ 5.0, Mg ²⁺ 1.5, Ca ²⁺ 2.5, Cl _{^{- 147.8, HCO 3 -..}} . 4.2, HPO 4 2- 1.0, SO 4 2- 0.5) (J. Am Ceram Soc, 78, is formed on the ceramic surface in 1769-74, 1995).

According to the structural analysis, the apatite contains CO ₃ ^2- ions, and the Ca / P ratio is smaller than the Ca / P ratio (1.67) of the hydroxide apatite (Ca ₁₀ (PO ₄ ) ₆ (OH ₂ )) and formed of fine particles. It is similar to apatite of living bone in that it is. On the surface of this apatite, osteoblasts that produce bone are more likely to proliferate and differentiate than fibroblasts that form a fibrous coating.

As a result, bones extending from the surroundings can directly contact the surface apatite. When this occurs, a chemical bond is created between the bone apatite and the surface apatite, causing the artificial material to bond to the bone. Thus, it can be said that the essential condition for the artificial material to bind to the living bone is to form an apatite layer having a property similar to the living bone on its surface when embedded in the living body.

Currently, cement is most commonly used to fix artificial materials to surrounding bones or to fill bone defects. PMMA DDS is a mixture of PMMA powder and MMA monomer liquid and then hardened in vivo. Often, zirconium oxide or barium sulfate powder was mixed with powder to enhance the opacity of X-rays.

Both mixed pastes have fluidity that can be freely formed for about 4 minutes and have a compressive strength of 90 MPa. However, in this cement, the polycondensation heat near 100 degreeC may damage surrounding tissue at the time of hardening, and an unreacted monomer may pass through a blood vessel and damage a heart. In addition, a problem has been reported that a large shrinkage caused by polycondensation and a relatively thick fibrous coating formed around the cement cause loosening of the fixing of the artificial material to the bone.

Conventional PMMA cement itself does not bind to living bones. Thus, in order to reduce the calorific value of the living bone and to give it the property of binding to bone, the cerebital crystallized glass powder bioactive to the PMMA cement ( J. Biomed. Mater. Res., 13, 89-99, 1979) Alternatively, attempts have been made to mix aquatic apatite fibers (11, p20, 1989). As a result, as the amount of bioactive ceramic powder increases, the amount of heat generated decreases, and the ratio of the interface where cement directly bonds with bone increases. In the case of apatite fibers, fracture toughness was also improved. However, when the amount of the bioactive ceramics powder is increased, there is a problem that the hardening property in a short time is reduced and does not directly bond with the bone.

Accordingly, the present inventors have diligently reduced the calorific value of bone cement and gave the property of binding to bone. As a result, PMMA powder was mixed with CaO-SiO ₂ gel powder having the property of attaching to living bone, and then MMA solution was added. It was confirmed that the prepared cement cement had excellent biocompatibility, and thus the present invention was completed.

It is an object of the present invention to provide a mixture for producing bioactive bone cement having a property of directly reducing calorific value and binding directly to bone, and a method for producing bioactive bone cement using the mixture.

In order to achieve the above object, the present invention provides a mixture for producing bioactive bone cement, characterized in that it contains PMMA powder and CaO-SiO ₂ gel.

The present invention also provides a PMMA / CaO-SiO ₂ prepared in the bone cement preparation and the method of the PMMA / CaO-SiO ₂ bone cement, characterized in that the addition of the curing solution to the mixture.

In the present invention, CaO-SiO ₂ gel is obtained by adding and stirring TEOS (tetraethoxysilane: Si (C ₂ H ₅ O ₄ )) to a mixed aqueous solution of Ca (NO ₃ ) .4H ₂ O and PEG It may be, wherein the curing solution may be characterized in that the MMA solution.

In addition, in the CaO-SiO ₂ gel, CaO: SiO ₂ is preferably in the range of 2:98 to 30:70 in a molar ratio. If CaO ratio is 2% or less, it cannot be expected to act as a bioactive bone cement that can be attached to bone. If the CaO ratio is 30% or more, there is a problem that it is difficult to produce CaO-SiO ₂ gel by the sol-gel method.

In the present invention, the content of CaO-SiO ₂ is preferably from 3 to 90% by weight relative to the sum of the PMMA powder, and CaO-SiO ₂ gel. Adding more than 90% by weight of CaO-SiO ₂ has a problem that does not cure, when mixing less than 3% by weight has a disadvantage in that it takes longer to bond with the bone (4 weeks or more after the meal).

In the present invention, instead of bioactive cerbital crystallized glass powder or hydroxyapatite fiber, a gel containing CaO-SiO ₂ produced by the sol-gel method as a main component is used.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and the scope of the present invention will not be construed as being limited by these examples.

Example 1: CaO-SiO ₂  Preparation of Gel

CaO-SiO ₂ gels of various compositions as shown in Table 1 were prepared by hydrolysis of TEOS (tetraethoxysilane: Si (C ₂ H ₅ O ₄ )) in an aqueous solution and then polycondensation.

After dissolving polyethylene glycol (PEG) having a molecular weight of 10,000 in distilled water in which Ca (NO ₃ ) .4H ₂ O was dissolved, nitric acid (62 wt%) was added as a catalyst in this solution.

TEOS was added while vigorously stirring the solution, stirred until the solution was clear and then stirred for an additional 5 minutes. After transferring the solution to a plastic container, the lid was sealed with a tape and placed in an oven at 40 ° C. to make a wet gel, and then aged in an oven at 40 ° C. for 18 hours.

The wet gel thus obtained was washed with 1 mol / dm ³ nitric acid solution for 6 hours to remove the water-soluble PEG in the gel. At this time, the nitric acid solution was replaced every 2 hours. The wet gel washed with nitric acid solution was dried in a 40 ° C. oven for 6 days, and then heat-treated in a furnace using a siliconite heating element. At this time, the temperature increase rate was raised to 200 ~ 1300 ℃ at 100 ° C / h, and then maintained at that temperature for 2 hours, followed by heat treatment. After cooling, the furnace temperature reached room temperature, the sample was taken out and stored in a desiccator. It was used as a raw material.

TABLE 1 Amount of starting raw material to prepare xCaO- (100-x) SiO ₂ gels.

CaO-SiO ₂ Gel Starting material amount (g) TEOS [Si (OCH ₂ CH ₃ ) ₄ ] Ca (NO ₃ ) ₂ .4H ₂ O PEG 62% HNO ₃ 100 SiO ₂ 6.5100 - 0.70 0.8100 5CaO-95SiO ₂ 6.1845 0.365 0.665 0.7695 10CaO-90SiO ₂ 5.8590 0.730 0.630 0.7290 15CaO-85SiO ₂ 5.5335 1.095 0.595 0.6885 20CaO-80SiO ₂ 5.2080 1.460 0.560 0.6480 25CaO-75SiO ₂ 4.8825 1.825 0.525 0.6075 30CaO-70SiO ₂ 4.5570 2.190 0.490 0.5670

Example 2: PMMA / CaO-SiO ₂  Manufacture of cement

The xCaO- (100-x) SiO ₂ gel prepared in Example 1 was weighed and the PMMA powder was mixed for 30 minutes using magnetic induction (FIG. 1). At this time, the mixing ratio of PMMA powder and xCaO- (100-x) SiO ₂ is shown in Table 2.

[Table 2] Mixing composition of PMMA powder and xCaO- (100-x) SiO ₂

sample PMMA (g) xCaO- (100-x) SiO ₂ (g) 100P 10 - 95P-5 C * 9.5 0.5 90P-10 C 9 One 85P-15 C 8.5 1.5 80P-20 C 8 2 75P-25 C 7.5 2.5 70P-30 C 7 3 65P-35 C 6.5 3.5 60P-40 C 6 4 55P-45 C 5.5 4.5 50P-50 C 5 5 45P-55 C 4.5 5.5 40P-60 C 4 6 35P-65 C 3.5 6.5 30P-70 C 3 7 25P-75 C 2.5 7.5 20P-80 C 2 8 15P-85 C 1.5 8.5 10P-90 C One 9 5P-95 C 0.5 9.5 100 C - 10

* P represents PMMA and C represents xCaO- (100-x) SiO ₂ .

About 0.971 g of the powder mixture as shown in Table 2, 0.029 g of benzoyl peroxide as a curing initiator was added and mixed again by induction of 30 minutes. The curing solution (hereinafter referred to as MMA solution) was prepared by mixing 0.008 g of dimethyl-para-toluene (N, N-dimethyl- p- tolune) based on 0.992 g of liquid MMA. MMA solution was added to the powder mixture to form a cement, which was then put into a mold to form a cylinder, and the time until curing was measured to be a setting time. The ratio of the powder mixture and the MMA solution in cement production was 2: 1 by weight ratio.

Example 3: Evaluation of Bioactivity Using Analog Fluids

For in vitro testing, analogs with ionic concentrations equal to the inorganic ions concentrations in human plasma, as shown in Table 3, were prepared using NaCl, NaHCO ₃ , KCl, K ₂ HPO ₄ · 3H ₂ O, MgCl ₂ · 6H ₂ O, 1N HCl, CaCl ₂ , Na ₂ SO _{4 It} was prepared by adding in the distilled water of the polyethylene beaker. At this time, the reagent was added to the first reagent after confirming that the first reagent is completely dissolved.

Finally, the pH of the solution in the beaker was adjusted to 7.25 at 36.5 ° C. using Tris-buffer (Tris-hydroxymethyl aminomethane: (CH ₂ OH) ₃ CNH ₂ ) and 1N-HCl solution. After putting 30 ml of simulated body fluid into a polystyrene bottle, a sample having a size of 10 x 15 x 1.5 mm ³ was cut out of the complex and deposited therein. After closing the lid, the polystyrene bottle was placed in an incubator adjusted to a temperature of 36.5 ° C., which is a human body temperature, and left for a certain period of time.

After the sample was immersed in the analog liquid at 36.5 ° C. for a certain period of time, the sample was taken out, washed well with distilled water, and then dried in air. The surface was subjected to thin film X-ray diffraction, FT-IR reflection spectroscopy and scanning electron microscopy.

In the case of thin film X-ray diffraction analysis, the sample surface was fixed to 1 ° with respect to the incident beam. FT-IR reflection spectroscopy fixed the reflection angle at 75 ° in the above case. Both measurement techniques are known to enable surface analysis of about 1 μm thickness.

TABLE 3

Ion Concentrations (mM) in Human Body Fluid and Analog Fluid (SBF) Na ⁺ K ⁺ Mg ²⁺ Ca ²⁺ Cl ^- HCO ₃ ^- HPO ₄ ^2- SO ₄ ^2- body fluids 142.0 5.0 1.5 2.5 147.8 4.2 1.0 0.5 SBF 142.0 5.0 1.5 2.5 147.8 4.2 1.0 0.5

FIG. 2 is an X-ray diffraction pattern of a sample obtained by adding bone cement prepared by mixing PMMA powder and 20CaO-80SiO ₂ gel powder in a weight ratio of 90:10 to an analogous liquid by a thin film X-ray diffraction analyzer. Prior to incorporation into the analogous fluid, only amorphous diffraction patterns due to diffraction of PMMA bone cement can be seen. There is no change in the diffraction pattern even after one week of deposition, but two weeks after the deposition of the analogous liquid, the diffraction pattern due to apatite appears. Therefore, it was found that bone cement prepared by mixing PMMA powder and 20CaO-80SiO ₂ gel powder in a weight ratio of 90:10 forms apatite in the analog liquid.

Figure 3 is a photograph taken by scanning electron microscopy of the structural change of the surface when the bone cement prepared by adding 10wt% 20CaO-80SiO ₂ gel powder instead of PMMA powder into the analog solution. The spherical PMMA powder and 20CaO-80SiO ₂ gel powder can be seen on the surface before being deposited in the analogous fluid, but two weeks after the deposition, leaflike apatite particles are formed.

FIG. 4 is an X-ray diffraction pattern of a sample obtained by mixing bone cement prepared by mixing PMMA powder and 20CaO-80SiO ₂ gel powder in a weight ratio of 70:30 in an analogous liquid by a thin film X-ray diffraction analyzer. Prior to addition to the analogous fluid, only amorphous diffraction patterns due to diffraction of PMMA bone cement can be seen as in FIG. However, one week after the deposition, it can be seen that the diffraction pattern due to the apatite appears. Therefore, it was found that increasing the amount of 20CaO-80SiO ₂ gel powder added to PMMA powder accelerated the formation of apatite on the surface of the analog liquid.

5 is a photograph taken with a scanning electron microscope of the structural change of the sample surface after the bone cement prepared by mixing PMMA powder and 20CaO-80SiO ₂ gel powder in a weight ratio of 70:30 in the analogous liquid. Compared with FIG. 3, it was found that apatite completely covered the surface of bone cement as 20CaO-80SiO ₂ gel powder was added at a weight ratio of 10% to 30%. These results indicate that increasing the 20CaO-80SiO ₂ gel powder from 10% to 30% by weight relative to PMMA powder can also speed up the formation of apatite and thus the speed of binding to bone.

PMMA / CaO-SiO ₂ bone cement according to the present invention can bind to bone because it forms apatite on its surface when deposited in analogous fluid. In addition, it can be used as an adhesive for fixing metals, polymers, ceramics, etc. to the bone, and can be used under load because it is strongly bonded to the bone in a short time. In addition, since it has fluidity as in the conventional PMMA bone cement, it can be used as an injectable bone substitute injected into a part damaged by osteoporosis or the like.

Therefore, the bone cement according to the present invention can be used not only for fixing the implants such as artificial joints in orthopedic surgery, but also for the repair of bones and teeth, the maintenance of defects, and orthopedic surgery, brain surgery, plastic surgery, oral surgery, etc. It is possible to apply to the drug, it is also possible to use as a drug carrier useful in the drug delivery system (DDS).

Simple modifications and variations of the present invention can be readily used by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.

Claims (7)

Mixture for preparing bioactive bone cement containing PMMA powder and 3 to 90% by weight of CaO-SiO ₂ gel prepared by the following steps: (a) adding and stirring TEOS (tetraethoxysilane: Si (C ₂ H ₅ O ₄ )) to a mixed aqueous solution of Ca (NO ₃ ) .4H ₂ O and PEG; (b) placing the stirred mixture in an oven at about 40 ° C. to make a wet gel and to mature for at least 10 hours; And (c) removing PEG from the aged gel and drying in an oven at about 40 ° C. delete delete The mixture of claim 1, wherein CaO: SiO ₂ of the CaO—SiO ₂ gel is in a molar ratio of 2:98 to 30:70. Method for producing PMMA / CaO-SiO ₂ bone cement, characterized in that the curing by adding MMA solution to the mixture of claim 1 or 4. delete delete

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