TW201909933A - 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 the composition of a calcium phosphate compound and collagen in order to prevent a substituting bone from being falling into small pieces even when constant shear force is applied, thereby facilitating the 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.

Description

 Particle aggregate for replacing bone, manufacturing method thereof and extrusion container containing the same  

The present invention relates to a particle aggregate for replacing bone and a method for producing the same, and more particularly to the following particle aggregate for replacing bone and a method for producing the same: it optimizes the composition of the calcium phosphate compound and collagen even if it is subjected to The constant shear force does not become a small piece, which helps to provide replacement bone to the bone defect or extraction site that needs to be filled.

An alternative bone is a material that is implanted to reinforce or fill a fractured or defected portion of a bone. So far, autologous bone, allogeneic bone, xenogenic bone and synthetic bone have been introduced.

Among them, autologous bone is the most ideal material, which has almost no immune side effects and has excellent bone regeneration characteristics. However, the disadvantage of autologous bone is that the harvest requires a second surgery and the amount that can be harvested is limited. The advantage of allogeneic bone is that it is easy to supply and the donor does not require secondary surgery. However, a disadvantage of allogeneic bone is its potential to transfer disease to others and may cause ethical problems. Xenogenic bones are easy to supply and manufacture. Disadvantages of xenogeneic bone, however, are that animal diseases may be transferred to humans and the osteoinductive capacity is significantly reduced. The advantage of synthetic bone is that it is easy to supply and can be manufactured in various forms, and the possibility of an inflammatory reaction is low. However, synthetic bone has disadvantages in that absorption in the body is slow and bone induction ability is remarkably lowered.

Among the above materials, although synthetic bone has disadvantages, research on manufacturing new synthetic bone which is easy to provide in various forms has been actively carried out to improve osteoinductive ability by promoting in vivo absorption of synthetic bone.

The replacement bone made of conventional synthetic bone has been supplied to the bone defect site or the extraction site in the form of a powder or a fixed block. In the case where the replacement bone is in the form of a powder, there is a disadvantage in that additional measures are required to prevent the replacement bone from separating after being supplied to the bone defect site or the tooth extraction site. In the case where the replacement bone is massive, there are disadvantages in that the replacement bone cannot effectively adapt to various forms of the bone defect site or the tooth extraction site.

In order to solve these problems, it has been attempted to add collagen to conventional synthetic bone to provide flexibility. U.S. Patent No. 7,819,263 (registered on May 13, 2007) and European Patent Publication No. 0621,044 (published on Oct. 26, 1994) discloses the use of 11 to 43 parts by weight of collagen and 200 to 100,000 parts by weight of collagen. An invention in which a protein is mixed with 100 parts by weight of a calcium phosphate compound, respectively.

However, in this case, the viscosity of the mixed solution is excessively increased due to excessive collagen, so that it is difficult to uniformly disperse the synthetic bone. Therefore, there is a great demand in the industry for synthetic replacement bones having a variable shape.

Patent Document 1: U.S. Patent No. 7,819,263 (registered on May 13, 2007).

Patent Document 2: European Patent Publication No. 0612104 (published on October 26, 1994).

The present invention provides a particle aggregate for a substitute bone having a desired level of viscoelasticity by adding collagen to synthetic bone composed of a calcium phosphate compound, thereby effectively adapting various forms of the bone defect site and the tooth extraction site, while simultaneously Even if it is subjected to shearing force, it will not become a small piece.

The present invention also provides a method of producing a particle aggregate for replacing bone.

According to an exemplary embodiment, the particle aggregate for replacing bone comprises: 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, even more preferably 1.1. To 2.5 parts by weight of collagen.

Further, the particles can be produced by spray-drying fine particles of a calcium phosphate compound, then sintering the fine particles to aggregate them to form large particles, and then coating the surface with collagen.

Further, the particles may have an average particle diameter of from 0.05 to 2 mm, preferably from 0.08 to 1.5 mm, more preferably from 0.1 to 1 mm.

Further, the ratio of the average surface area to the average particle diameter of the particles, i.e., the average surface area/average particle diameter of the particles may be from 0.3 to 45 mm, preferably from 0.6 to 25 mm, more preferably from 1 to 15 mm.

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

Further, the sintering may be carried out at 500 ° C to 800 ° C, preferably 550 ° C to 750 ° C, more preferably 600 ° C to 700 ° C for 60 to 90 minutes.

In addition, the shear resistance index of the particle aggregate for replacing bone of the present invention may be 50×10 ^-9 to 2000×10 ^-9 , preferably 100×10 ^-9 to 1000×10 ^-9 , more preferably 200× 10 ^-9 to 600 × 10 ^-9 .

According to another exemplary embodiment, the particle aggregate of the present invention may further comprise an osteogenic promoting factor.

According to another exemplary embodiment, the calcium phosphate compound may be selected from the group consisting of tricalcium phosphate, β-tricalcium phosphate, calcium dihydrogen phosphate, biphasic calcium phosphate, heptacalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, Calcium metaphosphate, carbonate apatite (calcium deficiency hydroxyapatite), hydroxyapatite, oxyapatite, and combinations thereof.

In addition, collagen can be obtained from mammals, preferably cattle, and better calves.

According to another exemplary embodiment, the osteogenic factor may be selected from the group consisting of transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), bone morphogenetic 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 (PGF), granulocyte colony-stimulating factor (G-CSF), ascorbate 2-phosphate, activin, statin, and combinations thereof.

According to another exemplary embodiment, the extrusion container of the present invention can accommodate particle aggregates for replacing bone.

According to another exemplary embodiment, the extrusion container may be a syringe.

According to another exemplary embodiment, the method for producing a particle aggregate for replacing bone includes the following steps: (A) by adding 0.7 to 2.5 parts by weight, preferably 0.8 to 2.3 parts by weight, to 100 parts by weight of water, More preferably 0.9 to 2.1 parts by weight of collagen, and 0.02 to 0.06 parts by weight, preferably 0.03 to 0.05 parts by weight, more preferably 0.035 to 0.045 parts by weight of hydrogen chloride to produce a collagen mixed solution; (B) by collagen Dissolved in a collagen mixed solution to produce an aqueous collagen solution; (C) by mixing 40 to 70% by weight, preferably 45 to 65% by weight, more preferably 50 to 60% by weight of the aqueous collagen solution and 30 to 60% by weight Preferably, 35 to 55% by weight, more preferably 40 to 50% by weight, of the calcium phosphate compound is used to make a mixture for replacing bone; (D) frozen to replace the mixture of bone; and (E) by freeze drying for Instead of a frozen mixture of bone, a particle aggregate for replacing bone is made.

According to another exemplary embodiment, the method of manufacturing the particle aggregate for replacing bone of the present invention may further include filling the mixture for replacing the bone in the extrusion container after the step (C) and before the step (D) A step of.

Further, the calcium phosphate compound of the step (C) can be formed into a large particle by spray drying the fine particles of the calcium phosphate compound and then sintering the fine particles to aggregate them.

Further, the particles may have an average particle diameter of from 0.05 to 2 mm, preferably from 0.08 to 1.5 mm, more preferably from 0.1 to 1 mm.

Further, the ratio of the average surface area to the average particle diameter of the particles may be from 0.3 to 45 mm, preferably from 0.6 to 25 mm, more preferably from 1 to 15 mm.

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

Further, the sintering may be carried out at 500 ° C to 800 ° C, preferably 550 ° C to 750 ° C, more preferably 600 ° C to 700 ° C for 60 to 90 minutes.

In addition, the shear resistance index of the particle aggregate for replacing bone of the present invention may be 50×10 ^-9 to 2000×10 ^-9 , preferably 100×10 ^-9 to 1000×10 ^-9 , more preferably 200× 10 ^-9 to 600 × 10 ^-9 .

Further, the method for producing a particle aggregate for replacing bone of the present invention may further include an osteogenic factor.

In addition, the calcium phosphate compound may be selected from the group consisting of tricalcium phosphate, β-tricalcium phosphate, calcium dihydrogen phosphate, biphasic calcium phosphate, heptacalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, calcium metaphosphate, and phosphorus carbonate. Gray stone (calcium-deficient hydroxyapatite), hydroxyapatite, oxyapatite, and combinations thereof.

In addition, collagen can be obtained from mammals, preferably cattle, and better calves.

In addition, the osteogenic factor may be selected from the group consisting of transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), bone morphogenetic protein (BMP), vascular endothelial growth factor (VEGF), and 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 (PGF), granulocyte colony-stimulating factor (G-CSF), Ascorbic acid-2-phosphate or a salt thereof, activin, statin, and combinations thereof.

Further, the freeze-drying of the step (E) may be carried out at -90 ° C to -50 ° C, preferably -80 ° C to -60 ° C, more preferably -75 ° C to -65 ° C.

Further, the freeze-drying of the step (E) may be carried out for 24 to 96 hours, preferably 30 to 84 hours, more preferably 36 to 72 hours.

Further, the method for producing a particle aggregate for replacing bone of the present invention may further include a sterilization step after the step (E).

Alternatively, the sterilization may be sterilization using gamma rays.

Meanwhile, the particle aggregate of the present invention for replacing bone is characterized by being manufactured by the above-described manufacturing method.

An advantage of the particle aggregate for replacing bone according to the present invention is that since synthetic bone is made of a raw material such as a calcium phosphate compound and collagen instead of living bone, it contributes to its supply, which can be manufactured in various forms, And the possibility of an inflammatory reaction is low. In addition, by optimizing the composition of the calcium phosphate compound and collagen, the problem that the excessive increase in the viscosity of the mixed solution makes it difficult to uniformly disperse the synthetic bone is solved. Most importantly, with this optimization of composition, even if subjected to a constant shearing force, the replacement bone does not become a small piece, so it is easy to supply the replacement bone to the bone defect site or the extraction site to be filled.

1‧‧‧ Subject

2‧‧‧Put

3‧‧‧Washers

4‧‧‧ cover

1 is a connection diagram showing an embodiment of an extrusion container accommodating the particle aggregate of the present invention for replacing bone; FIG. 2 is a perspective view showing a main body constituting the extrusion container of FIG. 1; Fig. 4 is a perspective view showing a gasket constituting the extrusion container of Fig. 1; Fig. 5 is a perspective view showing a lid constituting the extrusion container of Fig. 1; A diagram of another embodiment of an extrusion container for replacing a particle aggregate of bone; FIG. 7 is a view showing a state in which a part of the particle aggregate of the present invention for replacing bone is discharged from an extrusion container, and then Separating from the container of the embodiment of Fig. 6 by opening the lid and performing extrusion; Fig. 8 is a photograph showing the absorbability of the particle aggregate of the present invention for replacing bone; and Fig. 9 is a view showing a commercially available conventional Photograph of the absorbency of calcium phosphate compound aggregates.

Hereinafter, preferred embodiments of the present invention will be described in detail. In the following description, numerous specific details are set forth It is to be understood that the specific details of the invention are to be understood as a In addition, the detailed description of known functions and structures contained herein will be omitted in the following description of the present invention when the subject matter of the present invention is unclear.

In addition, the term "comprising" or "comprising" is used to include any component (or component) without limitation, and is not to be construed as excluding the addition of additional components (or components).

In the present invention, the "shear resistance index" is defined by the following formula: shear resistance index = (mass of collagen / mass of calcium phosphate compound) × average particle diameter of fine particles of calcium phosphate compound / (particle Average surface area / average particle size of the particles).

The particle aggregate for replacing bone of the present invention is characterized in that it comprises 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, even more preferably 1.1. To 2.5 parts by weight of collagen.

Here, the particles may be produced by spray drying fine particles of a calcium phosphate compound, then sintering the fine particles to aggregate them to form large particles, and then coating the surface with collagen.

Thus, since the calcium phosphate compound forms particles rather than being in a fine particle state, it is promoted to be mixed with collagen, and is more easily injected by an extrusion container. In particular, the present invention can change the shape of the replacement bone by adding collagen to the calcium phosphate compound, thereby allowing the bone defect site and the extraction site to be completely filled without voids, thereby increasing the rate of bone regeneration.

However, if the relative content of the collagen and the calcium phosphate compound is less than the above range, when a shearing force is applied thereto by hand kneading, the particle aggregate tends to become a small piece. Therefore, the aggregate must be handled with care to significantly reduce the operator's operability. On the contrary, as described above, when the relative content exceeds the above range, the viscosity of the mixed solution of the calcium phosphate compound is excessively increased due to excessive collagen, so that it is difficult to uniformly disperse the substitute bone.

The particles in which the fine particles of the calcium phosphate compound are aggregated to form large particles may have an average particle diameter of 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 shearing force can be ensured, so that the operator can easily change the shape of the replacement bone by simple movement of the finger.

Further, the ratio of the average surface area to the average particle diameter of the particles, i.e., the average surface area/average particle diameter of the particles may be from 0.3 to 45 mm, preferably from 0.6 to 25 mm, more preferably from 1 to 15 mm. When the ratio of the average surface area to the average particle diameter is within the above range, the above resistance to shearing force can be similarly ensured, so that the operability of the operator can be ensured.

The fine particles of the calcium phosphate compound constituting the particles may have an average particle diameter of 10 to 1000 nm, preferably 30 to 500 nm, more preferably 50 to 100 nm. When the average particle diameter is within the above range, a desired porosity level can be obtained while preventing economical reduction.

The fine particles of the calcium phosphate compound are spray-dried and sintered to form pellets having a sintering temperature of from 500 ° C to 800 ° C, preferably from 550 ° C to 750 ° C, more preferably from 600 ° C to 700 ° C, and the sintering time may be from 60 to 90 minutes. When the sintering temperature and the sintering time are within the above range, particles in the above average particle diameter range and average surface area to average particle diameter ratio range can be obtained while preventing economical reduction.

In addition, the shear resistance index of the particle aggregate for replacing bone of the present invention may be 50×10 ^-9 to 2000×10 ^-9 , preferably 100×10 ^-9 to 1000×10 ^-9 , more preferably 200× 10 ^-9 to 600 × 10 ^-9 .

The shear resistance index defined above is a dimensionless variable which indicates that when the shearing force is applied, the particle aggregate of the present invention for replacing bone remains in an aggregated state without becoming a small block: shear resistance index = (mass of collagen / mass of calcium phosphate compound) × average particle diameter of fine particles of calcium phosphate compound / (average surface area of particles / average particle diameter of particles).

Taking into account the meaning of each variable, first, as the ratio of the amount of collagen protein to the mass of the calcium phosphate compound becomes larger, the resistance of the aggregate to shear force becomes stronger due to the viscoelasticity of the collagen itself. Therefore, the ratio of the mass of collagen to the mass of the calcium phosphate compound is proportional to the shear resistance index.

Next, as the average particle diameter of the fine particles of the calcium phosphate compound becomes larger, the surface area of the fine particle-aggregated particles becomes smaller, so that the collagen is more distributed on the surface of the particles than inside the particles, so that the shear force is The resistance becomes stronger. Therefore, the average particle diameter of the fine particles of the calcium phosphate compound is proportional to the shear resistance index.

Finally, as the ratio of the average surface area of the particles to the average particle size of the particles becomes larger, collagen is less distributed on the surface of the particles than inside the particles, making it less resistant to shear forces. Therefore, the average surface area of the particles is inversely proportional to the shear resistance index.

When the shear resistance index of the particle aggregate for replacing bone of the present invention is within the above range, since the aggregate does not become a small block when the bone defect portion or the tooth extraction portion is completely filled without leaving a void at the time of filling, Easy to program. Particularly when the shear resistance index is within the above range, the procedure becomes simpler, since the operator can obtain a desired shape of the particle aggregate for replacing the bone by simply applying a simple force with a finger.

The calcium phosphate compound can be used without limitation as long as it is a compound which can be used as a substitute for bone in the field of the present invention, and the calcium phosphate compound can be selected, for example, from tricalcium phosphate, ?-tricalcium phosphate, calcium dihydrogen phosphate, and biphasic Calcium phosphate, heptacalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, calcium metaphosphate, carbonate apatite (calcium deficiency hydroxyapatite), hydroxyapatite, oxyapatite, and combinations thereof.

In addition, collagen may be used without limitation as long as it is a material which can be used as a substitute for bone in the field of the present invention, and collagen can be obtained, for example, from a mammal, preferably a cow, and more preferably a calf.

The particle aggregates of the present invention for replacing bone may also include an osteogenic factor to further increase the rate of bone regeneration to reduce the inconvenience of the patient.

The osteogenic factor can be used without limitation as long as it is a factor which can be used in the field of the present invention, and the osteogenic factor can be selected, for example, from transforming growth factor-β (TGF-β), fibroblast growth. Factor (FGF), bone morphogenetic 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 (PGF), granulocyte colony stimulating factor (G-CSF), ascorbyl-2-phosphate or a salt thereof, activin, statin, and combinations thereof.

At the same time, the extrusion container of the present invention is characterized by containing agglomerates of particles for replacing bone. The operator squeezes all or part of the particle aggregate of the present invention for replacing the bone contained in the extrusion container with a finger, kneads the extruded particle aggregate into a desired shape, and then aggregates the particles of a desired shape by pressing The body is pushed into the bone defect site or the region of the tooth extraction site to fill the region of the bone defect site or the tooth extraction site so that there is no void.

In the present invention, the extrusion container is not limited as long as it can provide the particle aggregate of the present invention for replacing bone by an extrusion method, and the extrusion container can be, for example, a syringe.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a connection diagram showing an embodiment of an extrusion container for accommodating a particle aggregate of the present invention for replacing bone, and Figs. 2 to 5 are views showing a main body (1) and a push rod constituting the extrusion container of Fig. 1, respectively. 2), perspective view of the gasket (3) and the cover (4).

In addition, Fig. 6 is a view showing another embodiment of an extrusion container for accommodating the particle aggregate of the present invention for replacing bone, and Fig. 7 is a view showing a state in which a part of the particle aggregate for replacing bone of the present invention is It is discharged from the extrusion container and then separated from the container of the embodiment of Fig. 6 by opening the lid and performing extrusion.

Meanwhile, the method for producing a particle aggregate for replacing bone of the present invention starts from the step of 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% by weight to 100 parts by weight of water. The collagen is mixed, and 0.02 to 0.06 parts by weight, preferably 0.03 to 0.05 parts by weight, more preferably 0.035 to 0.045 parts by weight, of hydrogen chloride is used to produce a collagen mixed solution. If the amount of hydrogen chloride is less than the above range, the solubility of collagen is insufficient to completely dissolve the above amount of collagen. On the contrary, if the amount exceeds the above range, it is harmful to the human body due to high acidity.

When the collagen mixed solution is produced as described above, the collagen in the mixed solution is dissolved to produce an aqueous collagen solution. Then, by mixing 40 to 70% by weight, preferably 45 to 65% by weight, more preferably 50 to 60% by weight, of the aqueous collagen solution and 30 to 60% by weight, preferably 35 to 55% by weight, more preferably 40 to 50% A weight percent calcium phosphate compound is used to make a mixture for replacing bone.

The calcium phosphate compound can form a large particle by spray-drying fine particles of the calcium phosphate compound and then sintering the fine particles to aggregate.

If the relative content of the collagen and the calcium phosphate compound is less than the above range, as described above, when the shearing force is applied to the aggregate of the particles by hand kneading, the aggregate of the particles easily becomes a small block. Therefore, the aggregate must be handled with care to significantly reduce the operator's operability. In contrast, as described above, when the relative content exceeds the above range, the viscosity of the mixed solution of the calcium phosphate compound is excessively increased due to excessive collagen, so that it is difficult to uniformly disperse the substitute bone.

The mixture of the replacement bone in which the calcium phosphate compound and collagen are mixed is then frozen, and then freeze-dried to produce the particle aggregate of the present invention for replacing bone. Freeze drying can be carried out at -90 ° C to -50 ° C, preferably -80 ° C to -60 ° C, more preferably -75 ° C to -65 ° C. When the freeze-drying temperature is within the above range, excessive increase in drying time can be prevented while preventing economical reduction. Further, the freeze-drying can be carried out for 24 to 96 hours, preferably 30 to 84 hours, more preferably 36 to 72 hours. When the freeze-drying time is within the above range, the particle aggregates can be completely dried while preventing economical reduction.

The method for producing a particle aggregate for replacing bone of the present invention may further include a step of filling the mixture for replacing the bone in the extrusion container before the freezing step, and a sterilization step after the freeze-drying step. Sterilization may be carried out without limitation as long as it is a sterilization method which can be used in the field of the invention, for example, it may be sterilization using gamma rays.

Meanwhile, the particle aggregate of the present invention for replacing bone is characterized by being manufactured by the above-described manufacturing method.

Hereinafter, embodiments of the invention will be described.

Example

Example 1: Particle aggregates for replacing bone

To 500 ml of distilled water to which 7 ml of 0.5 N HCl had been added, 10 g of collagen powder (COLLAGEN SOLUTIONS, Netherlands) was further added, followed by thorough dissolution to prepare an aqueous collagen solution. 5 g of the collagen aqueous solution was mixed with 5 g of β-tricalcium phosphate particles having an average particle diameter of 500 μm and an average surface area of 3.5 mm 2 , which was β-adhered to an average particle diameter of 70 nm at 600 ° C. The tricalcium phosphate fine particles were prepared by sintering for 90 minutes, and then the mixture was filled into an extrusion vessel. The filler was frozen and then freeze-dried at -75 ° C for 60 hours to obtain a particle aggregate of the present invention for replacing bone. The viscoelasticity and calculated shear resistance index of the particle aggregates measured by a viscoelasticity meter (Malvern, UK) are shown in Table 1 below.

Example 2: Hydroxyapatite

The same procedure as in Example 1 was carried out except that hydroxyapatite (CGBio, Korea) was used instead of β-tricalcium phosphate. The viscoelasticity and shear resistance index of the thus obtained particle aggregates are shown in Table 1 below.

Example 3: Adding osteogenic factor

The same procedure as in Example 1 was carried out except that 0.25 mg of BMP-2 (Daewoong Pharmaceutical Co., LTD, Korea) was added to distilled water. The viscoelasticity and shear resistance index of the thus obtained particle aggregates are shown in Table 1 below.

Comparative Example 1: Excessive use of collagen

The same procedure as in Example 1 was carried out except that 20 g of collagen powder was used. The viscoelasticity and shear resistance index of the thus obtained particle aggregates are shown in Table 1 below. The result of inclusion of collagen in an amount outside the scope of the present invention is an excessive increase in viscoelasticity (decreased measurement), and the shear resistance index is also outside the scope of the present invention. Further, since the viscoelasticity is too high, the viscosity of the mixed solution of the calcium phosphate compound is excessively increased, and it is difficult to uniformly disperse the substitute bone.

Comparative Example 2: Micro-use of collagen

The same procedure as in Example 1 was carried out except that 1 g of collagen powder was used. The viscoelasticity and shear resistance index of the thus obtained particle aggregates are shown in Table 1 below. The result of containing collagen in an amount less than the range of the present invention is that the viscoelasticity is too low (measured value is increased), and the shear resistance index is also outside the scope of the present invention. Further, due to the remarkably low viscoelasticity, the particle aggregate tends to become a small block when the shearing force is applied by hand kneading the particle aggregate. Therefore, the aggregate must be handled with care to significantly reduce the operator's operability.

Test Examples 1 and 2: Absorbency

The absorbance of the particle aggregate for replacing bone and the commercially available conventional calcium phosphate compound aggregate (Hansbiomed, Korea) in Example 1 was measured, as shown in Figs. 8 and 9. Absorbance is measured by taking the degree of absorption of the blue liquid by the aggregate. Figure 8 is a photograph of the aggregate in Example 1, and Figure 9 is a photograph of a commercially available aggregate. As can be seen from Figures 8 and 9, the absorbency of the present invention is superior to that of the prior art, which increases the rate of bone regeneration by activating the transport of blood through the blood, thereby solving the replacement of the bone by the blood. Open question.

Manufacturing Example 1: Particle Aggregate for Replacement of Bone (1)

To 500 ml of distilled water to which 7 ml of 0.5 N HCl had been added, 10 g of collagen powder (COLLAGEN SOLUTIONS, Netherlands) was further added, followed by thorough dissolution to prepare an aqueous collagen solution. 5 g of an aqueous collagen solution was mixed with 5 g of β-tricalcium phosphate having an average particle diameter of 500 μm and an average surface area of 32 mm 2 , which was subjected to β-phosphoric acid having an average particle diameter of 70 nm at 600 ° C. The tricalcium fine particles were sintered for 90 minutes, and then the mixture was filled into an extrusion vessel. The filler was frozen and then freeze-dried at -75 ° C for 60 hours to obtain a particle aggregate for replacing bone.

Manufacturing Example 2: Particle agglomerates for replacing bones (2)

The same procedure as in Production Example 1 was carried out except that β-tricalcium phosphate particles having an average surface area of 0.03 mm 2 were used to produce particle aggregates for replacing bone.

Manufacturing Example 3: Particle agglomerates for replacing bones (3)

The same procedure as in Production Example 1 was carried out except that β-tricalcium phosphate particles having an average particle diameter of 0.01 mm were used to produce particle aggregates for replacing bone.

Manufacturing Example 4: Particle aggregates for replacing bones (4)

The same procedure as in Production Example 1 was carried out except that β-tricalcium phosphate particles having an average particle diameter of 5 mm were used to produce a particle aggregate for replacing bone.

Manufacturing Example 5: Particle aggregates for replacing bones (5)

The same procedure as in Production Example 1 was carried out to produce a particle aggregate for replacing bone, except that β-tricalcium phosphate fine particles having an average particle diameter of 3 nm were used.

Manufacturing Example 6: Particle agglomerates for replacing bones (6)

The same procedure as in Production Example 1 was carried out to produce a particle aggregate for replacing bone except that β-tricalcium phosphate fine particles having an average particle diameter of 10 μm were used.

Manufacturing Example 7: Particle agglomerates for replacing bone (7)

The same procedure as in Production Example 1 was carried out except that sintering was performed at 400 ° C to produce a particle aggregate for replacing bone.

Manufacturing Example 8: Particle agglomerates for replacing bone (8)

The same procedure as in Production Example 1 was carried out except that sintering was performed at 1100 ° C to produce a particle aggregate for replacing bone.

Manufacturing Example 9: Particle agglomerates for replacing bone (9)

The same procedure as in Production Example 1 was carried out to produce a particle aggregate for replacing bone except that sintering was performed for 30 minutes.

Manufacturing Example 10: Particle Aggregate for Replacement of Bone (10)

The same procedure as in Production Example 1 was carried out except that sintering was carried out for 2 hours to produce a particle aggregate for replacing bone.

Manufacturing Example 11: Particle agglomerates for replacing bone (11)

The same procedure as in Production Example 1 was carried out except that 0.1 N HCl was used to produce a particle aggregate for replacing bone.

Manufacturing Example 12: Particle Aggregate for Replacement of Bone (12)

The same procedure as in Production Example 1 was carried out except that 5N HCl was used to produce a particle aggregate for replacing bone.

Test Examples 3 to 14: Viscoelasticity and Shear Resistance Index

The viscoelasticity and calculated shear resistance index of the particle aggregates in Production Examples 1 to 12 measured by a viscoelasticity meter (Malvern, UK) are shown in Table 2 below.

Although the preferred embodiments of the present invention have been described above, the present invention is not limited to the specific embodiments described above, and those skilled in the art should understand that various changes and modifications can be made without departing from the spirit of the invention. . Therefore, the scope of the invention should not be construed as being limited to the above-described embodiments, but should be determined by the scope of the appended claims and the equivalents of the claims.

Claims (8)

 A particle aggregate for replacing bone comprising: 100 parts by weight of a calcium phosphate compound; and 0.5 to 3 parts by weight of collagen.    The particle aggregate according to claim 1, which further comprises an osteogenic factor.    The particle aggregate according to claim 1, wherein the calcium phosphate compound is selected from the group consisting of tricalcium phosphate, β-tricalcium phosphate, calcium dihydrogen phosphate, biphasic calcium phosphate, heptacalcium phosphate, tetracalcium phosphate, and octacalcium phosphate. Calcium pyrophosphate, calcium metaphosphate, carbonate apatite (calcium deficiency hydroxyapatite), hydroxyapatite, oxyapatite, and combinations thereof.    The particle aggregate according to claim 2, wherein the osteogenic factor is selected from the group consisting of transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and 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 (PGF), granules Cell colony stimulating factor (G-CSF), ascorbyl-2-phosphate or a salt thereof, activin, statin, and combinations thereof.    An extrusion container accommodating the particle aggregate for replacing bone as recited in any one of claims 1 to 4.    The extrusion container of claim 5, wherein the extrusion container is a syringe.    A method for producing a particle aggregate for replacing bone, comprising the steps of: (A) preparing collagen by adding 0.7 to 2.5 parts by weight of collagen and 0.02 to 0.06 part by weight of hydrogen chloride to 100 parts by weight of water; a mixed solution; (B) preparing an aqueous collagen solution by dissolving collagen in the aforementioned collagen mixed solution; (C) by using 40 to 70% by weight of an aqueous collagen solution and 30 to 60% by weight of a calcium phosphate compound Mixing to prepare a mixture for replacing bone; (D) freezing the aforementioned mixture for replacing bone; and (E) fabricating a particle aggregate for replacing bone by freeze-drying the frozen mixture for bone replacement.    The manufacturing method as recited in claim 7, which further comprises, after the step (C) and before the step (D), filling the aforementioned mixture for replacing the bone in the extrusion container.