KR20190017513A - Granule aggregate for substituting bone and manufacturing method thereof - Google Patents

Abstract

Provided are granule aggregate for a substituting bone and a manufacturing method thereof. More particularly, provided are granule aggregate for a substituting bone which optimizes compositions of a calcium phosphate compound and collagen in order to prevent the substituting bone from being fallen into small pieces even when constant shear force is applied, thereby facilitating supply of the substituting bone to a bone defect portion or a tooth extraction portion both of which require filling, and a manufacturing method thereof. The granule aggregate for the substituting bone comprises 100 parts by weight of the calcium phosphate compound and 0.5 to 3 parts by weight of collagen.

Description

TECHNICAL FIELD [0001] The present invention relates to an alternate bone grains aggregate and a method for manufacturing the same. BACKGROUND ART < RTI ID = 0.0 >

The present invention relates to an alternative bone grains aggregate and a method for producing the same, and more particularly, to a bone graft substitute granule and a method of manufacturing the same, which can optimize the composition of a calcium phosphate compound and collagen to prevent a bone substitute from being falsified even under a constant shearing force, And to a method for producing the same.

The replacement bone is a material that is implanted to reinforce or fill the fractured bone damage site or the extraction site. So far, autogenous bone, allogeneic bone, heterogeneous bone, and synthetic bone have been introduced.

Double autogenous bone is the most ideal material because it has few immunological side effects and has good bone regeneration. However, it requires secondary surgery for harvesting and has a disadvantage that the amount of harvest is limited. Allogeneic bone has the advantage that it is easy to supply and does not require the second operation of the donor part, but it can cause the possibility of disease transmission and ethical problems of others. Although heterogeneous bone is easy to supply and manufacture, there is a disadvantage that the disease transmission possibility and bone induction ability of animal are considerably deteriorated. Synthetic bone is easy to supply and can be manufactured in various forms and has a low possibility of inflammatory reaction, but it has a disadvantage in that the in vivo absorption is slow and the bone inducing ability is significantly lowered.

Among these materials, research on the production of new synthetic bone has been actively carried out to improve the bone inducing ability by promoting in vivo absorption of synthetic bone easily supplied in various forms despite its disadvantages.

The replacement bone with the conventional synthetic bone was supplied in the form of a powder or a fixed block in the bone defect or foot area. In the case of the powder form, there is a disadvantage that additional additional measures are required to prevent the bone defect or the foot portion from being separated after being supplied. In the case of the block form, there is a disadvantage that it can not be efficiently coped with various forms of the bone defect portion or the extraction portion.

In order to solve these problems, there has been an attempt to add flexibility to conventional synthetic bone by adding collagen. US Patent No. 7189263 (registered on May 13, 2007) and European Patent Publication No. 0621044 (published on October 26, 1994) 11 to 43 parts by weight and 200 to 100,000 parts by weight of collagen are mixed per 100 parts by weight of the calcium compound.

However, in this case, the viscosity of the mixed solution excessively increases due to the excessive amount of collagen, so that it is difficult to uniformly disperse the synthetic bone, and thus there is a great demand in the industry for a composite synthetic bone having a variable shape.

United States Patent No. 7189263 (registered on May 13, 2007) European Patent Publication No. 0621044 (published October 26, 1994)

SUMMARY OF THE INVENTION The present invention has been conceived in order to solve the above-mentioned problems, and it is an object of the present invention to provide a calcium phosphate compound composite collagen which is effective in coping with various types of bone defects and foot fragments by adding collagen, The present invention also provides an alternative granular granule aggregate having an appropriate level of viscoelasticity so as not to be crumbled even when the granules are crushed.

It is still another object of the present invention to provide a method for producing the granular aggregates for alternate bone grafting.

In order to achieve the above-mentioned object, the alternate bone grains aggregate of the present invention,

100 parts by weight of a calcium phosphate compound, and

0.5 to 3 parts by weight, preferably 0.7 to 2.8 parts by weight, more preferably 0.9 to 2.6 parts by weight, still more preferably 1.1 to 2.5 parts by weight of collagen

And a control unit.

The granules may be prepared by spray-drying and calcining the calcium phosphate compound microparticles, aggregating the microparticles together to form macroparticles, and then coating the surface with collagen.

The average particle diameter of the granules may be 0.05 to 2 mm, preferably 0.08 to 1.5 mm, and more preferably 0.1 to 1 mm.

The average surface area, that is, the average surface area / average particle diameter of granules with respect to the average particle diameter of the granules may be 0.3 to 45 mm, preferably 0.6 to 25 mm, more preferably 1 to 15 mm.

The average particle diameter of the calcium phosphate compound fine particles may be 10 to 1000 nm, preferably 30 to 500 nm, more preferably 50 to 100 nm.

The sintering may be performed at 500 to 800 ° C, preferably 550 to 750 ° C, more preferably 600 to 700 ° C for 60 to 90 minutes.

The shear stress resistance index of the alternative bone grains aggregated aggregate of the present invention is in the range of 50 x 10 ^-9 to 2000 x 10 ^-9 , preferably 100 x 10 ^-9 to 1000 x 10 ^-9 , more preferably 200 x ^10-9 600 x 10 < ^-9 >.

In addition, the alternative bone graft aggregate of the present invention is characterized by further comprising an osteogenesis promoting factor.

The calcium phosphate compound may be at least one selected from the group consisting of tricalcium phosphate,? -Tricalcium phosphate, monocalcium phosphate, biphasic calcium phosphate, hepta calcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, calcium metaphosphate, Hydroxyapatite, calcium apatite (calcium deficient hydroxyapatite), hydroxyapatide, oxyapatite, and mixtures thereof.

And, the collagen can be obtained from a mammal, preferably a small animal, more preferably a small animal.

The bone formation promoting factors may be selected from the group consisting of transforming growth factor-beta (TGF-beta), fibroblast growth factor (FGF), bone morphogenic protein (BMP) A growth factor such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), platelet-derived growth factor , Nerve growth factor (NGF), hepatocyte growth factor (HGF), placental growth factor (PGF), granulocyte colony stimulating factor (G-CSF) May be selected from the group consisting of ascorbate 2-phosphate, activin, inhibin and mixtures thereof.

Meanwhile, the extrusion container of the present invention is characterized in that the granular aggregate for alternate bone is accommodated.

Further, the extrusion container may be a syringe.

On the other hand, the method for producing alternate bone graft aggregates of the present invention

(A) To 100 parts by weight of water

0.7 to 2.5 parts by weight, preferably 0.8 to 2.3 parts by weight, more preferably 0.9 to 2.1 parts by weight of collagen, and

0.02 to 0.06 part by weight, preferably 0.03 to 0.05 part by weight, more preferably 0.035 to 0.045 part by weight of hydrogen chloride is added to prepare a collagen mixture solution,

(B) Dissolving collagen in the collagen mixture to prepare an aqueous collagen solution,

(C) More preferably 50 to 60 wt%, and calcium phosphate compound 30 to 60 wt%, preferably 35 to 55 wt%, more preferably 40 to 70 wt%, preferably 45 to 65 wt% Mixing 40 to 50% by weight to prepare a mixture for alternate osteoporosis,

(D) Freezing the alternative bone marrow mixture, and

(E) And lyophilizing the frozen alternate osseous mixture to produce alternate bone grains for alternate bone grafts.

In addition, the method for producing an alternative bone graft aggregate of the present invention may further comprise filling the extruded container with the alternative bone-containing mixture prior to the step (C) and after the step (D).

The calcium phosphate compound of the step (C) can be macerated by spraying and drying the calcium phosphate compound fine particles and sintering the fine particles to aggregate them together.

The average particle diameter of the granules may be 0.05 to 2 mm, preferably 0.08 to 1.5 mm, and more preferably 0.1 to 1 mm.

And, the average surface area with respect to the average particle diameter of the granules may be 0.3 to 45 mm, preferably 0.6 to 25 mm, more preferably 1 to 15 mm.

The average particle diameter of the calcium phosphate compound may be 10 to 1000 nm, preferably 30 to 500 nm, more preferably 50 to 100 nm.

The sintering may be performed at 500 to 800 ° C, preferably 550 to 750 ° C, more preferably 600 to 700 ° C for 60 to 90 minutes.

The shear stress resistance index of the alternative bone grains aggregated aggregate of the present invention is in the range of 50 x 10 ^-9 to 2000 x 10 ^-9 , preferably 100 x 10 ^-9 to 1000 x 10 ^-9 , more preferably 200 x ^10-9 600 x 10 < ^-9 >.

The method for producing an alternative bone graft aggregate of the present invention further comprises a bone formation promoting factor.

The calcium phosphate compound may be at least one selected from the group consisting of tricalcium phosphate,? -Tricalcium phosphate, monocalcium phosphate, biphasic calcium phosphate, hepta calcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, calcium metaphosphate, Hydroxyapatite, calcium apatite (calcium deficient hydroxyapatite), hydroxyapatide, oxyapatite, and mixtures thereof.

And, the collagen can be obtained from a mammal, preferably a small animal, more preferably a small animal.

The bone formation promoting factors include transforming growth factor-beta, fibroblast growth factor (FGF), bone morphogenic protein (BMP), vascular endothelial growth factor A growth factor such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), platelet-derived growth factor , Nerve growth factor (NGF), hepatocyte growth factor (HGF), placental growth factor (PGF), granulocyte colony stimulating factor (G-CSF) May be selected from the group consisting of ascorbate 2-phosphate, activin, inhibin and mixtures thereof.

The lyophilization of the step (E) may be performed at -90 to -50 캜, preferably -80 to -60 캜, more preferably -75 to -65 캜.

The lyophilization of the step (E) may be performed for 24 to 96 hours, preferably 30 to 84 hours, more preferably 36 to 72 hours.

Further, the method for manufacturing the alternative bone grains aggregate of the present invention may further include the step of sterilizing after the step (E).

The sterilization may be sterilization using a gamma ray.

On the other hand, the alternative bone grains aggregate for replacement of the present invention is characterized by being manufactured by the above-mentioned production method.

The alternative granule granule aggregates according to the present invention are advantageous in that they can be supplied in a variety of forms and have a low possibility of an inflammation reaction by using synthetic bone such as calcium phosphate compound and collagen as raw materials instead of bones of an organism. Further, by optimizing the composition of the calcium phosphate compound and the collagen, the viscosity of the mixed solution is excessively increased, thereby solving the problem that it becomes difficult to uniformly disperse the synthetic bone. Above all, it is advantageous to facilitate the supply of the replacement bone to the bone defect part or the foot part requiring filling because the alternative bone is not flawed even when a constant shear force is applied through such composition optimization.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a view of an embodiment of an extrusion vessel for receiving alternate bone grains of alternate bone grafts of the present invention.
FIG. 2 is a perspective view showing a body constituting the extrusion container of FIG. 1; FIG.
Fig. 3 is a perspective view showing a push rod constituting the extrusion container of Fig. 1; Fig.
4 is a perspective view showing a gasket constituting the extrusion container of FIG.
5 is a perspective view showing a lid constituting the extrusion container of FIG.
FIG. 6 is a photograph of another embodiment of an extrusion container accommodating alternate bone grains aggregates of the present invention. FIG.
FIG. 7 is a photograph showing a state in which a part of the granular substitute granule of the present invention is discharged from the extrusion container and then separated from the container by opening the lid and performing extrusion in the embodiment of FIG.
FIG. 8 is a photograph showing the absorbency of alternate bone graft aggregates according to the present invention. FIG.
9 is a photograph showing absorbency of a commercially available conventional calcium phosphate compound aggregate.

Hereinafter, preferred embodiments of the present invention will be described in detail. In the following description, numerous specific details, such as specific elements, are set forth in order to provide a thorough understanding of the present invention, and it is to be understood that the present invention may be practiced without these specific details, It will be obvious to those who have knowledge of. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

Additionally, reference throughout this specification to "including" or "containing", unless otherwise specified, refers to including any and all components (or components) Can not be interpreted as excluding.

In the present invention, the term 'shear resistance index' is defined by the following formula:

Shear force resistance index = (mass of collagen / mass of calcium phosphate compound) x average particle diameter of calcium phosphate compound fine particles / (average surface area of granules / average particle diameter of granules).

The alternate bone grains aggregate of the present invention is prepared by mixing 100 parts by weight of a calcium phosphate compound and 0.5 to 3 parts by weight, preferably 0.7 to 2.8 parts by weight, more preferably 0.9 to 2.6 parts by weight, and even more preferably 1.1 to 2.5 parts by weight of collagen, By weight.

The granules may be prepared by spray-drying the fine calcium phosphate compound particles and then sintering the fine particles to aggregate them into large particles, and then coating the surface with collagen. As such, the calcium phosphate compound forms a granule rather than a fine particle state, thereby facilitating mixing with collagen, and the administration through the extrusion container becomes much simpler. Particularly, the present invention makes it possible to change the shape of the replacement bone by adding collagen to the calcium phosphate compound, which can completely fill the bone defect portion and the extraction portion without voids, thereby improving the bone regeneration speed.

However, when the relative content of collagen to the calcium phosphate compound is less than the above range, the granular aggregates are easily rubbed when the shear force is applied by rubbing them with hands, so the aggregates must be handled with care, do. On the other hand, when the relative content exceeds the above range, the viscosity of the mixed solution mixed with the calcium phosphate compound due to excessive collagen is excessively increased as described above, which makes it difficult to uniformly disperse the alternative bone.

The average particle diameter of the granules in which the calcium phosphate compound fine particles are aggregated to form a large particle size may be 0.05 to 2 mm, preferably 0.08 to 1.5 mm, more preferably 0.1 to 1 mm. When the average particle diameter is within the above range, resistance to the shear force can be ensured. Thus, the operator can easily change the shape of the alternative bone with a simple operation of sliding the finger with the finger.

The average surface area, that is, the average surface area / average particle diameter of granules with respect to the average particle diameter of the granules may be 0.3 to 45 mm, preferably 0.6 to 25 mm, more preferably 1 to 15 mm. When the average surface area with respect to the average particle diameter is within the above range, resistance to the shear force described above can be similarly secured, and the workability of the operator can be secured.

The average particle diameter of the fine particles of the calcium phosphate compound constituting the granules may be 10 to 1000 nm, preferably 30 to 500 nm, more preferably 50 to 100 nm. When the average particle diameter is within the above-mentioned range, it becomes possible to obtain a desired level of porosity while suppressing excessive economic drop.

The sintering temperature at the time of granulating the calcium phosphate compound microparticles by spray drying and sintering is 500 to 800 ° C, preferably 550 to 750 ° C, more preferably 600 to 700 ° C, and the sintering time may be 60 to 90 minutes have. When the sintering temperature and the sintering time are within the above ranges, the average particle diameter range of the granules And a granule having an average surface area range with respect to the average particle diameter can be obtained.

The shear stress resistance index of the alternative granular granule aggregates of the present invention is in the range of 50 × 10 ^-9 to 2000 × 10 ^-9 , preferably 100 × 10 ^-9 to 1000 × 10 ^-9 , more preferably 200 × 10 ^-9 To 600 x 10 < ^-9 >

The shear resistance index is defined as a non-dimensional parameter, as described above, indicating the extent to which the alternative bone grained granulous aggregate of the present invention retains aggregation without being fickled when a shear force is applied:

Shear force resistance index = (mass of collagen / mass of calcium phosphate compound) x average particle diameter of calcium phosphate compound fine particles / (average surface area of granules / average particle diameter of granules).

The significance of each variable is that the larger the value of the collagen mass relative to the mass of the calcium phosphate compound, the stronger the resistance of the aggregate to the shear force due to the viscoelasticity of the collagen itself, and therefore the mass of the collagen with respect to the mass of the calcium phosphate compound, It is proportional to the resistance index.

As the average particle diameter of the following calcium phosphate compound microparticles increases, the surface area of the granules in which the fine particles are aggregated becomes smaller. As a result, the collagen is more distributed on the granule surface than in the inside of the granule, The average particle size of the compound microparticles is proportional to the shear resistance index.

Finally, as the average surface area of the granules with respect to the average particle diameter of the granules is lower than that of the granules, the collagen is less distributed on the surface of the granules as compared with the inside of the granules and the resistance against the shearing force is weakened. The average surface area of the granules is inversely proportional to the shear resistance index.

When the shear force resistance index of the alternative bone grains aggregated granule according to the present invention is within the above range, it is possible to proceed easily because the aggregate is not crushed while filling the bone defect portion or the foot portion with no space separated during filling. In particular, when the range is within the above range, the practitioner can easily grasp the alternate bone grains of alternate granules with their fingers to form a desired shape.

The calcium phosphate compound is not limited as long as it is a compound that can be used as a substitute in the technical field of the present invention. Examples of the calcium phosphate compound include tricalcium phosphate,? -Tricalcium phosphate, monocalcium phosphate, biphasic calcium phosphate, May be selected from the group consisting of calcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, calcium metaphosphate, carbonated apatite (calcium deficient hydroxyapatite), hydroxyapatide, oxyapatite, have.

The collagen can be used as any material that can be used as an alternative bone in the technical field of the present invention, and can be obtained, for example, in a mammal, preferably a cow, more preferably a cow.

The alternative bone graft aggregate of the present invention may further include an osteogenesis promoting factor, thereby further increasing the bone regeneration rate and reducing the inconvenience of the patient.

The bone formation promoting factor may be any factor that can be used in the technical field of the present invention. For example, transforming growth factor-beta (TGF-β), fibroblast growth factor ), Bone morphogenic protein (BMP), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), hepatocyte growth factor (HGF), placental growth factor , Granulocyte colony stimulating factor (G-CSF), ascorbate 2-phosphate, activin, inhibin, and mixtures thereof. have.

Meanwhile, the extrusion container of the present invention is characterized in that the granular aggregate for alternate bone is accommodated. The practitioner pushes all or a part of the alternative granular granule aggregate of the present invention accommodated in the extrusion container into a finger, and pushes the granular granule into the desired shape, pushes the granule into the bone defect portion or the foot portion,

In the present invention, the extrusion container is not limited as long as it is capable of providing an alternative bone grains aggregate of the present invention by an extrusion method, and may be, for example, a syringe.

Fig. 1 is a coupling view showing an embodiment of an extrusion container for accommodating alternate bone grains for alternate bone grafting according to the present invention. Fig. 2 to Fig. 5 respectively show a body 1, a plunger 2, A gasket 3 and a lid 4 according to an embodiment of the present invention.

FIG. 6 is a photograph of an embodiment of the extrusion container accommodating the alternate bone grains for alternate bone grafts of the present invention. FIG. 7 is a photograph of the alternative granule granules of the present invention by opening the lid and performing extrusion in the embodiment of FIG. And a part of the agglomerate is taken out of the extrusion container and then separated from the container.

Meanwhile, the method for producing an alternative bone grains aggregate for alternate bone grafting according to the present invention comprises adding 0.7 to 2.5 parts by weight, preferably 0.8 to 2.3 parts by weight, more preferably 0.9 to 2.1 parts by weight of collagen, 0.02 to 0.06 part by weight of hydrogen chloride, , Preferably 0.03 to 0.05 part by weight, more preferably 0.035 to 0.045 part by weight of the collagen mixture is added to the collagen mixture. If the amount of hydrogen chloride is less than the above range, the solubility of collagen is not sufficient and the collagen in the amount described above can not be completely dissolved. On the other hand, if the amount exceeds the above range, high acidity results in deleterious effects on the human body.

When the collagen mixture solution is prepared as described above, collagen in the mixture solution is dissolved to prepare an aqueous collagen solution. And more preferably 40 to 70 wt%, preferably 45 to 65 wt%, more preferably 50 to 60 wt%, and calcium phosphate compound 30 to 60 wt%, preferably 35 to 55 wt%, of the above collagen aqueous solution 40 to 50% by weight are mixed to prepare an alternative ointment mixture.

The calcium phosphate compound can be macerated by spraying and drying the calcium phosphate compound fine particles and sintering the fine particles to aggregate them.

If the relative content of the collagen to the calcium phosphate compound is less than the above range, the aggregate should be handled with care since the granule aggregate is easily rubbed when the shear force is applied by hand rubbing as described above, Lt; / RTI > On the other hand, when the relative content exceeds the above range, the viscosity of the mixed solution mixed with the calcium phosphate compound due to excessive collagen is excessively increased as described above, which makes it difficult to uniformly disperse the alternative bone.

The alternate osseous mixture, which is a mixture of calcium phosphate compound and collagen, is then frozen and then lyophilized to produce the alternate bone granulation aggregate of the present invention. The freeze-drying can be performed at -90 to -50 캜, preferably -80 to -60 캜, more preferably -75 to -65 캜. When the temperature is within the above range, It is possible to prevent excessive stretching. The lyophilization may be performed for 24 to 96 hours, preferably 30 to 84 hours, more preferably 36 to 72 hours. When the amount is within the above range, the granular aggregate can be completely dried while suppressing excessive economic drop It becomes.

The method for manufacturing an alternative bone graft aggregate according to the present invention may further comprise the step of filling the extruded container with the alternative bone mixture before the freezing step, . The sterilization can be used without limitation as long as it is a sterilization method that can be used in the technical field of the present invention, for example, sterilization using gamma rays.

On the other hand, the alternative bone grains aggregate for replacement of the present invention is characterized by being manufactured by the above-mentioned production method.

Hereinafter, embodiments of the present invention will be described.

Example

Example  1: Alternative bone grains for alternate bone grafting

10 g of collagen powder (COLLAGEN SOLUTIONS, the Netherlands) was added to 500 mL of distilled water to which 7 mL of 0.5 N HCl had been added and sufficiently dissolved to prepare an aqueous collagen solution. 5 g of the above-mentioned collagen aqueous solution was mixed with 5 g of beta -tricalcium phosphate granules having an average particle size of 500 mu m and an average surface area of 3.5 mm < ² > prepared by sintering the beta -tricalcium phosphate fine particles having an average particle size of 70 nm at 600 DEG C for 90 minutes And then filled in the extrusion container. The packing was frozen and lyophilized at -75 [deg.] C for 60 hours to obtain alternate bone granulation aggregates of the present invention. The viscoelasticity of the granular aggregates was measured with a viscoelasticity meter (Malvern, UK) and the shear resistance index was calculated and shown in Table 1 below.

Example 2: Hydroxyapatite

The same procedure as in Example 1 was carried out, and hydroxyapatite (CisioBio, Korea) was used in place of? -Tricalcium phosphate. The viscoelastic and shear resistance indexes of the thus-prepared granular aggregates are shown in Table 1 below.

Example 3: Addition of an osteogenesis promoting factor

The same procedure as in Example 1 was followed, and 0.25 mg of BMP-2 (Daewoong Pharm, Korea) was added to the distilled water. The viscoelastic and shear resistance indexes of the thus-prepared granular aggregates are shown in Table 1 below.

Comparative Example 1: Excessive use of collagen

The procedure of Example 1 was followed and 20 g of the collagen powder was used. The viscoelastic and shear resistance indexes of the thus-prepared granular aggregates are shown in Table 1 below. Including collagen in quantities exceeding the scope of the present invention resulted in an excessively high viscoelasticity (measured values were reduced) and shear resistance index was also outside the scope of the present invention. Further, the viscosity of the mixture solution mixed with the calcium phosphate compound becomes too high due to the excessive viscoelasticity, and it is difficult to uniformly disperse the alternative bone.

Comparative Example 2: Using a trace amount of collagen

The same procedure as in Example 1 was carried out, and 1 g of the collagen powder was used. The viscoelastic and shear resistance indexes of the thus-prepared granular aggregates are shown in Table 1 below. As a result of including collagen in an amount that is less than the range of the present invention, the resultant viscoelasticity is too low (the measured value is high) and the shear resistance index is out of the scope of the present invention. And, because of the remarkably low viscoelasticity, when the granule agglomerate is rubbed by the hand, it is easily broken when the shear force is applied, so the agglomerate has to be treated with care, which is a problem that the workability of the practitioner is significantly lowered.

Viscoelasticity (°) Shear resistance index (× 10 ^-9 ) Example 1 4.2 536 Example 2 4.3 515 Example 3 4.5 427 Comparative Example 1 0.8 4852 Comparative Example 2 9.2 16

Test Examples 1 and 2: Absorbency

The absorbency of the alternate bone granule aggregate of Example 1 and the commercially available conventional calcium phosphate compound agglomerate (Hans BioMed, Korea) was measured and shown in FIGS. 8 and 9. FIG. 8 is a photograph of the aggregate of Example 1, and FIG. 9 is a photograph of a commercially available aggregate. FIG. 8 and 9, it can be seen that the absorbability of the present invention is superior to that of the prior art. Such a high absorbability enhances the bone regeneration rate by activating mass transfer through the blood, .

Preparation Example 1: Alternative bone graft aggregates (1)

10 g of collagen powder (COLLAGEN SOLUTIONS, the Netherlands) was added to 500 mL of distilled water to which 7 mL of 0.5 N HCl had been added and sufficiently dissolved to prepare an aqueous collagen solution. 5 g of the above-mentioned collagen aqueous solution was mixed with 5 g of beta -tricalcium phosphate granules having an average particle size of 500 mu m and an average surface area of 32 mm < ² > prepared by sintering the beta -tricalcium phosphate fine particles having an average particle size of 70 nm at 600 DEG C for 90 minutes And then filled in the extrusion container. The packing was frozen and lyophilized at -75 ° C for 60 hours to obtain alternate bone granulation aggregates.

Preparation Example 2: Alternative bone graft substitute (2)

The same procedure as in Preparation Example 1 was carried out to prepare an alternative bone grains aggregate for granulation using β-tricalcium phosphate granules having an average surface area of 0.03 mm ² .

Preparation Example 3: Alternative bone graft substitute (3)

The same procedure as in Preparation Example 1 was carried out to prepare an alternate bone grains aggregate for granulation using β-tricalcium phosphate granules having an average particle diameter of 0.01 mm.

Preparation Example 4: Alternate bone graft aggregate (4)

The procedure of Preparation Example 1 was followed and β-tricalcium phosphate granules having an average particle diameter of 5 mm were used to prepare alternate bone granule aggregates.

Preparation Example 5: Alternative bone graft aggregates (5)

The same procedures as in Preparation Example 1 were carried out to prepare alternate bone grains for alternate bone grains using β-tricalcium phosphate fine particles having an average particle size of 3 nm.

Preparation Example 6: Alternate bone graft aggregate (6)

The same procedures as in Preparation Example 1 were carried out to prepare alternate bone grains for alternate bone grains using β-tricalcium phosphate microparticles having an average particle diameter of 10 μm.

Preparation Example 7: Alternative bone graft substitute (7)

The same procedures as in Production Example 1 were carried out, and the sintering temperature was set to 400 ° C to prepare alternate granule granules for bone grafting.

Preparation Example 8: Alternate bone graft aggregate (8)

The same procedure as in Preparation Example 1 was carried out, and the sintering temperature was changed to 1100 ° C to prepare an alternative aggregate granule aggregate.

Preparation Example 9: Alternate bone graft aggregate (9)

The same procedures as in Preparation Example 1 were carried out, and a sintering time of 30 minutes was used to prepare an alternative aggregate granule aggregate.

Preparation Example 10: Alternate bone graft aggregate (10)

The procedure of Preparation Example 1 was followed, and a sintering time of 2 hours was used to prepare an alternative aggregate granule aggregate.

Preparation Example 11: Alternative bone graft aggregates (11)

The same procedure as in Preparation Example 1 was carried out to prepare an alternative bone grains aggregate for granulation using 0.1 N HCl.

Preparation Example 12: Alternate bone graft aggregate (12)

The same procedures as in Preparation Example 1 were carried out, and alternate bone granulation aggregates were prepared using 5 N HCl.

Test Examples 3 to 14: Viscoelastic and Shear Resistance Index

The viscoelastic properties of the granular aggregates prepared in Preparation Examples 1 to 12 were measured by a viscoelasticity meter (Malvern, UK), and shear resistance indexes were calculated and shown in Table 2 below.

Viscoelasticity (°) Shear resistance index (× 10 ^-9 ) Test Example 3 10.5 8 Test Example 4 2.3 2774 Test Example 5 1.6 3416 Test Example 6 12.7 5 Test Example 7 1.9 3196 Test Example 8 11.3 6 Test Example 9 8.8 21 Test Example 10 2.4 2657 Test Example 11 9.1 17 Test Example 12 2.2 2843 Test Example 13 8.6 32 Test Example 14 2.6 2481

While the present invention has been described in connection with what is presently considered to be practical exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, Of course it is possible. Accordingly, the scope of the present invention should not be construed as being limited to the above-described embodiments, but should be determined by equivalents to the appended claims, as well as the following claims.

1: Body 2:
3: gasket 4: lid

Claims (8)

100 parts by weight of a calcium phosphate compound, and
0.5 to 3 parts by weight of collagen
≪ / RTI > The method according to claim 1,
≪ RTI ID = 0.0 > 1, < / RTI > further comprising an osteogenesis promoting factor. The method according to claim 1,
Wherein the calcium phosphate compound is selected from the group consisting of calcium phosphate,? -Triccium phosphate, monocalcium phosphate, biphasic calcium phosphate, hepta calcium phosphate, tetra calcium phosphate, octacalcium phosphate, calcium pyrophosphate, calcium methaphosphate, (Calcium deficient hydroxyapatite), hydroxyapatite, oxyapatite, and mixtures thereof. ≪ RTI ID = 0.0 > 11. < / RTI > The method according to claim 1,
The bone formation promoting factors include transforming growth factor-beta (TGF-beta), fibroblast growth factor (FGF), bone morphogenic protein (BMP), vascular endothelial growth factor vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), platelet-derived growth factor (NGF), hepatocyte growth factor (HGF), placental growth factor (PGF), granulocyte colony stimulating factor (G-CSF), ascorbate Wherein the granule is selected from the group consisting of ascorbate 2-phosphate, activin, inhibin, and mixtures thereof. An extrusion container containing an alternate bone grains aggregate of any one of claims 1 to 4. The method of claim 5,
Wherein the extrusion vessel is a syringe. (A) 100 parts by weight of water
0.7 to 2.5 parts by weight of collagen, and
Adding 0.02 to 0.06 part by weight of hydrogen chloride to prepare a collagen mixture,
(B) dissolving collagen in the collagen mixture to prepare an aqueous collagen solution,
(C) mixing 40 to 70% by weight of the collagen aqueous solution and 30 to 60% by weight of a calcium phosphate compound to prepare a bone substitute mixture,
(D) freezing the alternative bone-marrow mixture, and
(E) lyophilizing said frozen alternate bone-filling mixture to produce alternate bone grains for alternate bone grains. The method of claim 7,
Further comprising filling the alternate osseous mixture into an extrusion vessel after step (C) and after step (D). ≪ Desc / Clms Page number 20 >

Images