TW202137969A - Bone graft composition - Google Patents

Abstract

The present disclosure relates to a bone graft composition, and more particularly, to a bone graft composition including hydroxypropyl methylcellulose and a preparation method therefor. Moreover, the present disclosure relates to a bone graft composition that has an optimal composition ratio at which the dissolution rate of hydroxypropyl methylcellulose is excellent. In addition, the present disclosure relates to a bone graft composition containing hydroxypropyl methylcellulose in an amount that provides shape retainability, and a preparation method therefor. More specifically, the present disclosure relates to a bone graft composition containing hydroxypropyl methylcellulose in an amount that provides an optimum osmotic pressure and shape retainability, and a preparation method therefor.

Description

Bone graft material composition

The present invention relates to a bone graft material composition with excellent dissolution rate of hydroxypropyl methylcellulose and excellent shape maintenance and a manufacturing method thereof.

In order to reconstruct the defective bone, a variety of materials and methods can be used. For example, bone graft materials such as bone meal, bone fragments, and bone blocks can be used, or methods such as autograft, allograft, xenograft, etc. can be used to reconstruct the defective bone. .

Bone graft materials used to reconstruct defective bone can be used in orthopedics, neurosurgery, dentistry, etc. For example, it can be used for bone defect during intervertebral disc treatment to guide bone regeneration, and it can also be used for implants. Treatment and repair of oral and frontal bone defects.

In addition, Korean Granted Patent No. 10-0401941 discloses a technology related to bone graft materials and their manufacturing methods. In the case of using a mesh bone made of bioceramic powder and having a three-dimensional interconnected pore structure, the bone graft The effect may be limited in terms of biocompatibility, mechanical properties, and toxicity.

The object of the present invention is to provide a bone graft material composition including Hydroxypropyl methylcellulose having a dissolution rate suitable for bone formation and excellent in shape maintenance, and a manufacturing method thereof.

In addition, the present invention relates to a bone graft material composition including Hydroxypropyl methylcellulose suitable for bone formation. Specifically, it is desired to provide a bone graft material composition that forms an optimal osmotic pressure with other solutions, and Composition of bone graft material composition.

An embodiment of the present invention includes a bone graft material and hydroxypropyl methyl cellulose, and the hydroxypropyl methyl cellulose can form a dissolution rate of more than 50% within 48 hours.

In an example of the present invention, the bone graft material composition can include 0.15 to 6 parts by weight, 0.2 to 5 parts by weight, and 0.25 parts by weight of hydroxypropyl methylcellulose relative to 1 part by weight of the bone graft material. To 4 parts by weight or 0.3 to 3 parts by weight.

In one example of the present invention, a bone graft material composition is provided. The bone graft material is a natural source bone graft material and includes a porous structure.

An example of the present invention provides a method for manufacturing a bone graft material composition, which includes the following steps: (1) mixing a solvent and bone morphogenetic protein to prepare a bone morphogenetic protein solution; (2) mixing the bone morphogenetic protein and graft material powder to combine The bone morphogenetic protein is adsorbed to the graft material powder; (3) The graft material powder and the hydroxypropyl methyl cellulose powder on which the bone morphogenetic protein is adsorbed are mixed and stirred, and the hydroxypropyl methyl cellulose powder is made within 48 hours. And (4) freeze-drying the gel in a vacuum state to form a structure including a plurality of pores.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein the bone-forming protein may be at least one selected from the group consisting of: BMP-2, BMP-3, BMP-3b, BMP- 4. BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, its recombinant bone morphogenetic protein and its equivalent bone morphogenetic protein.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein the bone morphogenetic protein concentration of the bone morphogenetic protein solution is 0.05 to 0.15 mg/ml.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein phosphate buffer saline is used to adjust the acidity so that the pH is 4.6 to 5.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein the volume ratio of the graft material powder that adsorbs the bone-forming protein to the hydroxypropyl methylcellulose powder in the step (3) is 1:0.2 To 1:0.8.

An example of the present invention provides a method for manufacturing a bone graft material composition, which further includes a step of sterilizing the bone graft material composition by using Ethylene Oxide Gas or irradiating gamma rays.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein the concentration of the ethylene oxide gas is 450 mg/l to 1200 mg/l, or the gamma radiation dose is 10 kGy to 25 kGy.

An example of the present invention provides a bone graft material composition, wherein the force that changes the shape of the spherical object is the maximum destructive force, and the reduction ratio of the short axis after the shape change relative to the diameter of the spherical object is In the case of the minor axis change rate, the value obtained by dividing the maximum breaking force (Nmax) by the minor axis change rate is shape maintainability, and the shape maintainability is 50 or more.

Provided is a bone graft material composition, wherein the bone graft material composition is mixed with 0.3 to 3 parts by weight of hydroxypropyl methylcellulose relative to 1 part by weight of the bone graft material.

In one example of the present invention, a bone graft material composition is provided. The porous bone graft material is a natural source bone graft material and has excellent shape maintenance.

An example of the present invention provides a method for producing a bone graft material composition with excellent shape maintenance, including the following steps: (1) mixing a solvent and bone morphogenetic protein to produce a bone morphogenetic protein solution; (2) mixing the bone morphogenetic protein and Graft material powder, adsorb the bone-forming protein to the graft material powder; (3) Mix and stir the graft material powder adsorbed with the bone-forming protein and hydroxypropyl methylcellulose powder to form a gel, giving the bone graft material combination And (4) freeze-drying the gel in a vacuum state to form a structure including a plurality of pores.

An example of the present invention provides a method for producing a bone graft material composition excellent in shape maintenance, wherein the bone morphogenetic protein may be at least one selected from the group consisting of: BMP-2, BMP-3, BMP -3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15 , BMP-16, BMP-17, BMP-18, its recombinant bone morphogenetic protein and its equivalent bone morphogenetic protein.

An example of the present invention provides a method for producing a bone graft material composition excellent in shape maintenance, wherein the bone morphogenetic protein solution has a bone morphogenetic protein concentration of 0.05 to 0.15 mg/ml.

An example of the present invention provides a method for manufacturing a bone graft material composition excellent in shape maintenance, in which phosphate buffer saline is used to adjust the acidity so that the pH is 4.6 to 5.

An example of the present invention provides a method for manufacturing a bone graft material composition with excellent shape maintenance, wherein the volume of the graft material powder that adsorbs the bone-forming protein and the hydroxypropyl methylcellulose powder in the step (3) The ratio is 1:0.2 to 1:0.6.

An example of the present invention provides a method for producing a bone graft material composition with excellent shape maintenance, which further includes sterilizing the bone graft material composition by Ethylene Oxide Gas or irradiating gamma rays Processing steps.

An example of the present invention provides a method for producing a bone graft material composition with excellent shape maintenance, wherein the concentration of the ethylene oxide gas is 450 mg/l to 1200 mg/l, or the irradiation dose of the gamma ray is 10kGy to 25kGy.

An example of the present invention provides a bone graft material composition, wherein the osmotic pressure of saline is standardized to 100%, and 104 to 112% of the composition is formed within 12 to 48 hours after the saline is poured into the dissolving material of the bone graft. Osmotic pressure.

An example of the present invention provides a bone graft material composition, wherein the solubilized bone graft material is mixed with 1 part by weight of a bone graft material including hydroxypropyl methylcellulose and 0.5 to 2 parts by weight of a solvent, and the composition includes hydroxypropyl methylcellulose. The bone graft material of methyl cellulose is formed by mixing 0.3 to 3 parts by weight of hydroxypropyl methyl cellulose with respect to 1 part by weight of the bone graft material.

In one example of the present invention, a bone graft material composition is provided. The bone graft material is a natural source bone graft material.

An example of the present invention provides a bone graft material composition, characterized in that the solvent is water.

An example of the present invention provides a method for manufacturing a bone graft material composition, which includes the following steps: (1) mixing a solvent and bone morphogenetic protein to prepare a bone morphogenetic protein solution; (2) mixing the bone morphogenetic protein and graft material powder to combine The bone morphogenetic protein is adsorbed to the graft material powder; (3) the graft material powder and the hydroxypropyl methyl cellulose powder on which the bone morphogenetic protein is adsorbed are mixed and stirred to form a gel, which imparts osmotic pressure; and (4) The gel is freeze-dried in a vacuum state to form a structure including a plurality of pores.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein the bone-forming protein may be at least one selected from the group consisting of: BMP-2, BMP-3, BMP-3b, BMP- 4. BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, its recombinant bone morphogenetic protein and its equivalent bone morphogenetic protein.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein the bone morphogenetic protein concentration of the bone morphogenetic protein solution is 0.05 to 0.15 mg/ml.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein the acidity is adjusted with phosphate buffer saline, and the pH is 4.6 to 5.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein the volume ratio of the graft material powder that adsorbs the bone-forming protein to the hydroxypropyl methylcellulose powder in the step (3) is 1:0.2 To 1:0.6.

An example of the present invention provides a method for manufacturing a bone graft material composition, which further includes a step of sterilizing the bone graft material composition by using Ethylene Oxide Gas or irradiating gamma rays.

An example of the present invention provides a method for manufacturing a bone graft material composition, wherein the concentration of the ethylene oxide gas is 450 mg/l to 1200 mg/l, or the gamma radiation dose is 10 kGy to 25 kGy.

An example of the present invention provides a bone graft material composition manufactured by the method for manufacturing the bone graft material composition.

The bone graft material composition including Hydroxypropyl methylcellulose according to the present invention has excellent dissolution rate of Hydroxypropyl methylcellulose within a predetermined time, strong rigidity and non-restorability, and shape It has excellent maintainability and forms the optimal osmotic pressure with other solutions, so it has the effects of bone formation activation, biocompatibility, and ease of use.

An example of an embodiment of the present invention relates to a bone graft material that can have excellent bone formation activation, biocompatibility, and ease of use by including a bone graft material and Hydroxypropyl methylcellulose (Hydroxypropyl methylcellulose) combination.

However, for a clearer and more concise description, the description of this embodiment will omit parts that overlap with other embodiments. The omission of the description does not mean that this part is excluded from the present invention. The scope of rights shall be the same as that of other embodiments. The form is also recognized.

In describing the present invention, the detailed description will be omitted when it is judged that the specific description of the well-known technology related to the present invention may cause unnecessary confusion to the gist of the present invention. In addition, the terms described later are terms defined in consideration of the functions in the present invention, and they may be different according to the user, the user's intention or convention. Therefore, its definition should be determined based on the entire content throughout this specification.

The technical idea of the present invention is determined by the claims, and the following embodiments are only a means for effectively explaining the technical idea of the present invention to those with ordinary knowledge in the technical field of the present invention.

In the present invention, in the case where the repeating unit, compound or resin represented by the chemical formula has isomers, the corresponding chemical formula representing the repeating unit, compound or resin represents a representative chemical formula including the isomer.

Specific embodiments of the present invention will be described below. However, it is only an example, and the present invention is not limited to this.

The bone graft material composition of the present invention includes a porous bone graft material and Hydroxypropyl methylcellulose. The bone graft material composition can be transplanted to and filled in a bone defect part and used for the repair of the bone defect part.

Here, "filling" includes both the case where it is applied to the bone defect part in a state without rigidity and the case where it is applied to the bone defect part in a state with rigidity. Adding rigidity to the bone graft material composition and applying it to the bone defect can mean that it is applied to the bone defect after being manufactured into a shape corresponding to the bone defect by a shape forming device (for example, a three-dimensional printer, etc.) .

The bone graft material composition can provide the bone graft material composition with adhesion to the bone defect by including hydroxypropyl methylcellulose. At the same time, the bone graft material composition can be given shape maintenance properties by HPMC. In the case of excellent shape maintenance, even if the bone graft material composition is applied to the upper jaw, it can be applied to match the bone defect without flowing down, and it can help the bone graft material combination even if there is an impact due to masticatory motion, etc. The object does not leave the bone defect.

In the bone graft material composition according to an embodiment of the present invention, in order to optimize the solubility of hydroxypropyl methylcellulose, the composition ratio of the composition is hydroxypropyl methylcellulose relative to the porous bone graft material. The weight part is 0.1 to 6 parts by weight, and more preferably, it can be formed to be 0.3 to 3 parts by weight.

In the case where the content of the hydroxypropyl methyl cellulose is less than 0.3 parts by weight relative to 1 part by weight of the porous bone graft material, although the content of hydroxypropyl methyl cellulose is small and dissolves quickly in a short time, However, since the amount combined with the bone graft material is too small, it is easy to be precipitated, and there may be a problem that it is difficult to function as a bone graft material. Moreover, when the content of the hydroxypropyl methylcellulose exceeds 3 parts by weight relative to 1 part by weight of the porous bone graft material, the bone graft material hydroxypropyl methylcellulose occurs due to the high content of the hydroxypropyl methylcellulose. Propyl methyl cellulose solidifies and therefore dissolves very slowly, which may not be suitable for the rate of osteogenesis. On the contrary, when the content of a part of the hydroxypropyl methyl cellulose exceeds 3 parts by weight relative to 1 part by weight of the porous bone graft material, the volume of the hydroxypropyl methyl cellulose increases, thereby forming hydroxypropyl methyl cellulose. The methyl cellulose wraps the shape of the bone graft material, so that water may be absorbed before the dissolution of hydroxypropyl methyl cellulose occurs in the humid environment in the oral cavity, so the volume of the bone graft material may increase over time. Therefore, in order to optimize the solubility of hydroxypropyl methyl cellulose, the content of hydroxypropyl methyl cellulose is set to be 0.1 to 6 parts by weight relative to 1 part by weight of the porous bone graft material. More preferably, The implementation is 0.3 to 3 parts by weight.

In the dissolution, as an example, water can be used as a solvent, and the dissolution rate formed with the dissolution time when the bone graft material composition is hydrated is expressed in %. Compared with the hydrated bone graft material composition, the water is used in 1 to 1.5 parts by weight, and more preferably, 1.2 to 1.5 parts by weight are used for hydration. It is an example of the optimal amount of hydration for the hydration of the bone graft material composition.

A bone graft material composition kit according to another embodiment of the present invention includes the aforementioned bone graft material composition and a syringe for installing it. By providing the syringe including the bone graft material composition, the convenience of use can be ensured, and the possibility of contamination during use can be effectively reduced.

However, for a clearer and more concise description, the description of this embodiment will omit parts that overlap with other embodiments. The omission of the description does not mean that this part is excluded from the present invention. The scope of rights shall be the same as that of other embodiments. The form is also recognized.

A method of manufacturing a bone graft material composition according to another embodiment of the present invention includes the following steps:

Adding bone-forming protein to the solvent or adding the solvent to the bone-forming protein, so that the bone-forming protein is dissolved in the solvent to produce a bone-forming protein solution;

Mixing and stirring the graft material powder and the hydroxypropyl methyl cellulose powder adsorbing the bone-forming protein to form a viscous gel with a hydroxypropyl methyl cellulose dissolution rate of 50% or more within 48 hours; as well as

The mixed and stirred mixture of the graft material powder and the hydroxypropyl methylcellulose powder is frozen and dried at a low temperature in a vacuum state to form a sponge shape including a structure containing a plurality of pores, and therefore can have an excellent The effect of bone formation activation, biocompatibility, and ease of use.

However, in order to make the description clearer and more concise, the description of this embodiment will omit the part that overlaps with the previous embodiment. The omission of the description does not mean that the part is excluded from the present invention. The scope of rights shall be the same as the aforementioned The same form of implementation is recognized.

Fig. 1 is a diagram schematically showing the sequence of a method for manufacturing a bone graft material composition according to an embodiment of the present invention.

2 is a graph showing the result data (Table 1) of Experimental Example 1 related to the present invention and showing the residual rate according to the weight ratio and time of hydroxypropyl methylcellulose (Hydroxypropyl methylcellulose).

First, the bone-forming protein is dissolved in a solvent to produce a bone-forming protein solution. The bone-forming protein may be added to the solvent or the solvent may be added to the bone-forming protein, and the bone-forming protein may be dissolved in the solvent to produce a bone-forming protein solution.

The bone morphogenetic protein may be at least one selected from the group consisting of: BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP -9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, its recombinant bone morphogenetic protein and its equivalent bone formation The protein may preferably be rhBMP-2 in terms of the bone formation effect of the present invention.

The bone morphogenetic protein concentration of the bone morphogenetic protein solution according to an embodiment of the present invention may be 0.05 to 0.15 mg/ml, and may preferably be 0.08 to 0.12 mg/ml. The bone formation of the bone morphogenetic protein can be activated by satisfying the concentration range. When the bone morphogenetic protein concentration is lower than 0.05, the ability to form new bone may decrease, and when it exceeds 0.15, it may cause side effects.

And, for example, the acidity of the bone-forming protein solution according to an embodiment of the present invention may be pH 4.6-5. By satisfying the acidity range, the bone formation of the bone morphogenetic protein can be activated. When the acidity of the bone morphogenetic protein solution is lower than pH 4.6, the new bone formation ability may decrease, and the new bone formation ability is expressed when the acidity exceeds 5 May fall. For example, acidity can be adjusted with phosphate buffer saline, and phosphate buffer saline may have the effect of new bone formation.

Next, the graft material powder is impregnated with the bone-forming protein solution to adsorb the bone-forming protein to the graft material powder. The bone formation protein solution can be added dropwise to the graft material powder prepared in advance or the bone formation protein solution is sprinkled into the graft material powder, so that the graft material powder is immersed in the bone formation protein solution to make bone formation. The protein is adsorbed to the graft material powder.

The graft material powder can be autologous bone, homologous bone, or xenogeneic bone. For example, the graft material powder can be manufactured by injecting a Snap tube.

The average particle size (D50) of the graft material powder may be 200 μm to 5,000 μm, and may preferably be 250 μm to 1,000 μm. In the case where the average particle size of the powder is less than 200 μm, the graft material may be rapidly absorbed, resulting in insufficient bone conduction required for bone formation. In the case of more than 5,000 μm, it may be difficult to perform precision processing when applied to the patient.

The step of adsorbing the bone-forming protein to the graft material powder according to an embodiment of the present invention may include a step of performing adsorption using a refrigerated centrifuge.

According to the situation, the bone-forming protein can be suspended in the solution. In the case of rotating and adsorbing by a centrifuge, the bone-forming protein can be prevented from being suspended in the solution, so that the bone-forming protein can be well adsorbed on the surface of the graft material powder or in the pores. . Fast rotation and adsorption can make the bone-forming protein not fall from the graft material powder and re-suspend. If the speed is slow, the bone-forming protein may be suspended and cannot be adsorbed well. The bone morphogenetic protein can quickly adsorb to the surface of the graft material powder or into the pores.

The rotation speed of the refrigerated centrifuge according to an embodiment of the present invention may be above 4000 rpm. In the case of using a centrifuge for adsorption, it is possible that the faster the rotation speed, the better the adsorption. For example, the rotation speed of the centrifuge can be above 4000 rpm. When the aforementioned range is met, the bone formation protein can be prevented from being in the solution. Within the suspension.

The step of performing adsorption using a refrigerated centrifuge according to an embodiment of the present invention may be performed at a refrigerating temperature below 5°C. By performing the adsorption step using a refrigerated centrifuge at a refrigerated temperature below 5°C, it is possible to prevent the temperature of the solution from rising due to rotation and to prevent the deformation of the heat-fragile bone-forming protein while maximizing the transplantation of the bone-forming protein by the rotation Adsorption effect on the surface of the material powder or in the pores. The refrigeration may be a temperature at which the solution is not frozen, for example, 5°C or less, and may preferably be 0.5°C to 1.5°C.

Next, the graft material powder to which the bone-forming protein is adsorbed and the hydroxypropyl methylcellulose powder are mixed and stirred to form a gel. Accordingly, a viscous gel can be formed, and the formed gel can improve the adhesion of the graft material powder. For example, the stirring can be performed with a blender. A product of uniform quality can be obtained by mixing the graft material powder and the powdered hydroxypropyl methylcellulose.

According to an embodiment of the present invention, the volume ratio of the graft material powder adsorbed with bone-forming protein to the hydroxypropyl methylcellulose powder may be 1:0.2 to 1:0.8. When the volume ratio of the hydroxypropyl methylcellulose powder is less than 0.2, it is difficult to form a gel, and when it exceeds 0.8, the volume of the gel becomes larger than that of the graft material powder, and it may be difficult to form a bone graft. Material composition. In terms of the effect of the invention, preferably, the volume ratio of the graft material powder that adsorbs the bone-forming protein and the hydroxypropyl methylcellulose powder may be 1:0.6 to 1:0.7.

Next, the mixed and stirred graft material powder and hydroxypropyl methylcellulose powder mixture are vacuum freeze-dried to form a sponge shape including a porous structure. The mixed and stirred mixture of the graft material powder and the hydroxypropyl methylcellulose powder may be frozen and dried at a low temperature in a vacuum state to form a sponge form having a structure including a plurality of pores.

By performing a vacuum freeze-drying process, a sponge shape including a porous structure can be formed. A sponge form including a porous structure can be formed by allowing the gel to be absorbed by the graft material powder, and the formation of the sponge form including a porous structure is judged to be a major contribution to the vacuum treatment.

The method for manufacturing the bone graft material composition of an embodiment of the present invention may further include a packaging step.

The method of manufacturing the bone graft material composition of an embodiment of the present invention may further include the step of installing the bone graft material composition including a sponge shape into a microtube of a size that can be inserted into a syringe, wherein the sponge shape includes The structure of the multiple pores manufactured. By further including the step of installing a microtube of a size that can be inserted into a syringe, it has a size that can be inserted into the syringe, so that the syringe can be directly inserted without a separate process, so that it can be used in the process of manufacturing the bone graft material composition. Easy to operate.

The method of manufacturing the bone graft material composition of an embodiment of the present invention may further include a step of putting the bone graft material composition including a sponge shape into a syringe and sealing it, wherein the sponge shape includes the The structure of multiple pores. By equipping the syringe with the bone graft material composition, the convenience of use can be ensured, and the possibility of contamination during use can be effectively reduced.

The method for manufacturing the bone graft material composition of an embodiment of the present invention may further include a step of sterilization.

In an embodiment of the present invention, the bone graft material composition in the form of a sponge including a structure including a plurality of pores can be sterilized by using Ethylene Oxide Gas. For example, the concentration of ethylene oxide gas (Ethylene Oxide Gas) may be 450 mg/l to 1200 mg/l.

When the concentration of ethylene oxide gas (Ethylene Oxide Gas) is lower than 450mg/l, the sterilization may be insufficient, and when it exceeds 1200mg/l, the bone-forming protein may be deformed.

According to an embodiment of the present invention, the bone graft material composition in the sponge form including a structure including a plurality of pores can be sterilized by irradiating gamma rays. For example, the irradiation amount of gamma rays may be 10kGy to 25kGy. In the case where the gamma ray irradiation amount is less than 10 kGy, sterilization may be insufficient, and when it exceeds 25 kGy, the bone morphogenetic protein may be deformed.

The bone graft material manufactured according to the method of manufacturing the bone graft material as described above has a predetermined dissolution rate under predetermined conditions for application to the human body, for example, application to teeth. This dissolution rate can be determined by the content of HPMC and the like included in the bone graft material.

Take the case of applying bone graft material to teeth as an example. When the operator applies the bone graft material to the tooth defect, the hydroxypropyl methylcellulose (HPMC: Hydroxypropyl methylcellulose) contained in the bone graft material needs to be within a predetermined period of time. Only with a predetermined dissolution rate or higher can it be applied to the teeth with adhesion, and can be treated in accordance with the shape of the defect of the tooth. During treatment, the bone graft material cannot flow around or detach when the bone graft material is applied to the tooth defect, and it cannot happen that the hydroxypropyl methylcellulose (HPMC: Hydroxypropyl methylcellulose) does not dissolve in the bone graft material to make it The phenomenon that bone graft material cannot be adhered to the bone defect and cannot be treated. Therefore, bone graft materials require critical dissolution conditions of HPMC, and their functions may vary according to the dissolution conditions of HPMC.

When using bone graft materials for treatment, HPMC as an additive needs to have a dissolution rate of more than 50% within 48 hours in order to function as bone graft materials. If there is no dissolution of more than 50% within 48 hours, the undissolved HPMC will solidify each other. The higher the solidification rate, the smaller the space where blood can flow into the bone graft material, making it difficult to function as the bone graft material. Function.

In addition, if the dissolution rate of HPMC reaches 89% or more (residual amount less than 11%) within 48 hours, because the HPMC content in the bone graft material is low, not only the bone graft material cannot maintain the shape, but also cannot aggregate, and in fact cannot be treated. . Furthermore, even after treatment, due to the patient's salivary gland activity, eating-induced chewing, breathing, and dialogue, the adhesion of the bone graft material decreases, and the shape of the object may be detached in a way that matches the shape of the defect. side effect.

In the bone graft material composition according to an embodiment of the present invention, in order to ensure shape maintenance, the content of hydroxypropyl methylcellulose relative to 1 part by weight of the porous bone graft material may be 0.3 to 3 parts by weight, More preferably, it may be formed to 0.4 to 2 parts by weight, in which case the shape maintenance property can be further strengthened. As can be seen from the experimental examples described later, the short axis change rate increases as the content of the hydroxypropyl methylcellulose increases, and the maximum breaking force shows a tendency to increase first and then decrease. As shown in Figure 4, this increase and decrease occur rapidly. Based on this, it can be confirmed that in order to produce a bone graft composition with shape maintenance properties, the content of hydroxypropyl methylcellulose can be achieved relative to that of bone. One part by weight of the graft material is 0.3 parts by weight or more and 3 parts by weight or less. In the case where the content of the hydroxypropyl methylcellulose is less than 0.3 parts by weight relative to 1 part by weight of the bone graft material, because the specific gravity of HPMC is too low, the addition effect of HPMC is weak, and it is easily removed under low pressure (force). It is squeezed and destroyed, and its shape maintenance is not suitable as a bone graft material. When the content of the hydroxypropyl methylcellulose exceeds 3 parts by weight relative to 1 part by weight of the porous bone graft material, due to HPMC’s If the content is too high, it is easy to be squeezed under a small force, and the rate of change of the short axis will increase, and its shape maintenance is not suitable as a bone graft material.

A bone graft material composition kit according to another embodiment of the present invention includes the aforementioned bone graft material composition and a syringe for installing it. By providing the syringe directly including the bone graft material composition, the convenience of use can be ensured, and the possibility of contamination during use can be effectively reduced.

However, for a clearer and more concise description, the description of this embodiment will omit parts that overlap with other embodiments. The omission of the description does not mean that this part is excluded from the present invention. The scope of rights shall be the same as that of other embodiments. The form is recognized the same.

A method of manufacturing a bone graft material composition according to another embodiment of the present invention includes the following steps:

Adding bone-forming protein to the solvent or adding the solvent to the bone-forming protein, so that the bone-forming protein is dissolved in the solvent to produce a bone-forming protein solution;

Mixing and stirring the graft material powder adsorbed with the bone-forming protein and the hydroxypropyl methylcellulose powder to form a viscous gel, thereby imparting shape maintenance to the bone graft material composition; and

The mixed and stirred mixture of the graft material powder and the hydroxypropyl methylcellulose powder is frozen and dried at a low temperature in a vacuum state to form a sponge shape including a structure containing a plurality of pores, and therefore can have an excellent The effect of bone formation activation, biocompatibility, and ease of use.

However, in order to make the description clearer and more concise, the description of this embodiment will omit the part that overlaps with the previous embodiment. The omission of the description does not mean that the part is excluded from the present invention. The scope of rights shall be the same as the aforementioned The form of implementation is equally recognized.

Fig. 1 is a diagram schematically showing the sequence of a method for manufacturing a bone graft material composition according to an embodiment of the present invention.

Figure 4 shows the "bone graft material composition sphere" maximum destructive force (N)/bone graft material composition sphere (short axis change) with respect to the weight ratio of hydroxypropyl methylcellulose (Hydroxypropyl methylcellulose) The graph of "rate" is a graph showing the weight ratio of hydroxypropyl methylcellulose (Hydroxypropyl methylcellulose) used in a bone graft composition with excellent shape maintenance.

First, the bone-forming protein is dissolved in a solvent to produce a bone-forming protein solution. The bone-forming protein may be added to the solvent or the solvent may be added to the bone-forming protein, and the bone-forming protein may be dissolved in the solvent to produce a bone-forming protein solution.

The bone morphogenetic protein may be at least one selected from the group consisting of: BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP -9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, its recombinant bone morphogenetic protein and its equivalent bone formation The protein may preferably be rhBMP-2 in terms of the bone formation effect of the present invention.

The bone morphogenetic protein concentration of the bone morphogenetic protein solution according to an embodiment of the present invention may be 0.05 to 0.15 mg/ml, and may preferably be 0.08 to 0.12 mg/ml. The bone formation of the bone morphogenetic protein can be activated by satisfying the concentration range. When the bone morphogenetic protein concentration is lower than 0.05, the ability to form new bone may decrease, and when it exceeds 0.15, it may cause side effects.

And, for example, the acidity of the bone-forming protein solution according to an embodiment of the present invention may be pH 4.6-5. By satisfying the acidity range, the bone formation of the bone morphogenetic protein can be activated. When the acidity of the bone morphogenetic protein solution is lower than pH 4.6, the new bone formation ability may decrease, and the new bone formation ability is expressed when the acidity exceeds 5 May fall. For example, acidity can be adjusted with phosphate buffer saline, and phosphate buffer saline may have the effect of bone formation.

Next, the graft material powder is impregnated with the bone-forming protein solution to adsorb the bone-forming protein to the graft material powder. The bone formation protein solution can be added dropwise to the graft material powder prepared in advance or the bone formation protein solution is sprinkled into the graft material powder, so that the graft material powder is immersed in the bone formation protein solution to make bone formation. The protein is adsorbed to the graft material powder.

The graft material powder can be autologous bone, homologous bone, or xenogeneic bone. For example, the graft material powder can be manufactured by injecting a Snap tube.

The average particle size (D50) of the graft material powder may be 200 μm to 5,000 μm, and may preferably be 250 μm to 1,000 μm. In the case where the average particle size of the powder is less than 200 μm, the graft material may be rapidly absorbed, resulting in insufficient bone conduction required for bone formation. In the case of more than 5,000 μm, it may be difficult to perform precision processing when applied to the patient.

The step of adsorbing the bone-forming protein to the graft material powder according to an embodiment of the present invention may include a step of performing adsorption using a refrigerated centrifuge.

Depending on the situation, the bone-forming protein can be suspended in the solution. In the case of rapid rotation and adsorption by a centrifuge, the bone-forming protein can be prevented from being suspended in the solution, so that the bone-forming protein can be well adsorbed on the surface or pores of the graft material powder Inside. Fast rotation and adsorption can make the bone-forming protein not fall from the graft material powder and re-suspend. If the speed is slow, the bone-forming protein may be suspended and cannot be adsorbed well. The bone morphogenetic protein can quickly adsorb to the surface of the graft material powder or into the pores.

The rotation speed of the refrigerated centrifuge according to an embodiment of the present invention may be above 4000 rpm. In the case of using a centrifuge for adsorption, it is possible that the faster the rotation speed, the better the adsorption. For example, the rotation speed of the centrifuge can be above 4000 rpm. When the aforementioned range is met, the bone formation protein can be prevented from being in the solution. Within the suspension.

The step of performing adsorption using a refrigerated centrifuge according to an embodiment of the present invention may be performed at a refrigerating temperature below 5°C. By performing the adsorption step using a refrigerated centrifuge at a refrigerated temperature below 5°C, it is possible to prevent the temperature of the solution from rising due to rotation and to prevent the deformation of the heat-fragile bone-forming protein while maximizing the transplantation of the bone-forming protein by the rotation Adsorption effect on the surface of the material powder or in the pores. The refrigeration may be a temperature at which the solution is not frozen, for example, 5°C or less, and may preferably be 0.5°C to 1.5°C.

Next, the graft material powder to which the bone-forming protein is adsorbed and the hydroxypropyl methylcellulose powder are mixed and stirred to form a gel. Accordingly, a viscous gel can be formed, and the formed gel can improve the adhesion of the graft material powder. For example, the stirring can be performed with a blender. A product of uniform quality can be obtained by mixing the graft material powder and the powdered hydroxypropyl methylcellulose.

According to an embodiment of the present invention, the volume ratio of the graft material powder adsorbed with bone-forming protein to the hydroxypropyl methylcellulose powder may be 1:0.2 to 1:0.6. When the volume ratio of the hydroxypropyl methylcellulose powder is less than 0.2, it is difficult to form a gel, and when it exceeds 0.6, the volume of the gel becomes larger than that of the graft material powder, and it may be difficult to form effectively Bone graft material composition. In terms of the effect of the invention, preferably, the volume ratio of the graft material powder that adsorbs the bone-forming protein and the hydroxypropyl methylcellulose powder may be 1:0.25 to 1:0.35.

Next, the mixed and stirred graft material powder and hydroxypropyl methylcellulose powder mixture are vacuum freeze-dried to form a sponge shape including a porous structure. The mixed and stirred mixture of the graft material powder and the hydroxypropyl methylcellulose powder may be frozen and dried at a low temperature in a vacuum state to form a sponge form having a structure including a plurality of pores.

By performing a vacuum freeze-drying process, a sponge shape including a porous structure can be formed. A sponge form including a porous structure can be formed by allowing the gel to be absorbed by the graft material powder, and the formation of the sponge form including a porous structure is judged to be a major contribution to the vacuum treatment.

The method for manufacturing the bone graft material composition of an embodiment of the present invention may further include a packaging step.

The method of manufacturing the bone graft material composition of an embodiment of the present invention may further include the step of installing the bone graft material composition including a sponge shape into a microtube of a size that can be inserted into a syringe, wherein the sponge shape includes The structure of the multiple pores manufactured. By further including the step of installing a microtube of a size that can be inserted into a syringe, it has a size that can be inserted into the syringe, so that the syringe can be directly inserted without a separate process, so that it can be used in the process of manufacturing the bone graft material composition. Easy to operate.

The method of manufacturing a bone graft material composition of an embodiment of the present invention may include a structure including the plurality of pores mounted to a microtube. As an example of the same structure, it may also include a step of putting a bone graft material composition including a sponge shape into a syringe and sealing it. By equipping the syringe with the bone graft material composition, the convenience of use can be ensured, and the possibility of contamination that may be generated during use can be effectively reduced.

The method for manufacturing the bone graft material composition of an embodiment of the present invention may further include a step of sterilization.

In an embodiment of the present invention, the bone graft material composition in the form of a sponge including a structure including a plurality of pores can be sterilized by using Ethylene Oxide Gas. For example, the concentration of ethylene oxide gas (Ethylene Oxide Gas) may be 450 mg/l to 1200 mg/l.

When the concentration of ethylene oxide gas (Ethylene Oxide Gas) is lower than 450mg/l, the sterilization may be insufficient, and when it exceeds 1200mg/l, the bone-forming protein may be deformed.

According to an embodiment of the present invention, the bone graft material composition in the sponge form including a structure including a plurality of pores can be sterilized by irradiating gamma rays. For example, the irradiation amount of gamma rays may be 10kGy to 25kGy. In the case where the gamma ray irradiation amount is less than 10 kGy, sterilization may be insufficient, and when it exceeds 25 kGy, the bone morphogenetic protein may be deformed.

The bone graft material according to the embodiment of the present invention, which can be manufactured according to the method for manufacturing the bone graft material as described above, may have shape maintainability in order to be applied to the human body, for example, to a tooth defect portion. Such shape maintenance can be determined by the content of HPMC and the like included in the bone graft material.

Take the case of applying bone graft material to the tooth as an example. When the operator applies the bone graft material to the tooth defect, the bone graft material needs to have more than a predetermined degree of plasticity, so that it can be applied to the tooth defect. It deforms to match the defect shape of the tooth. Not only that, it cannot flow around or detach when it is applied to a tooth defect. Therefore, the bone graft material needs to have a predetermined degree of plasticity or more, and further, it needs to have a predetermined degree of stiffness or more that can withstand gravity or the movement of the bone (teeth) defect.

The degree of rigidity and plasticity can be defined as shape maintenance. In order to quantify the objective degree of shape maintenance, shape maintenance is defined as the deformation of the spherical shape when a force of XXX N is applied to a XXX mm spherical test piece. The rate of change of the minor axis that is elliptical and can be quantified.

The shape maintainability for satisfying the previously described plasticity and rigidity should be 50 or more. In the case of less than 50, it is difficult to apply to the bone defect due to the strong elasticity. That is, when the operator injects the bone defect, the bone graft material needs to be deformed to match the shape of the bone defect. However, in the case of strong elastic properties, such deformation may be difficult to occur due to the high restorability. Moreover, when the shape maintenance is lower than 50, it has been confirmed that the actual treatment cannot be performed due to the flow to the surroundings during treatment such as hydration by the operator.

Therefore, in order to ensure the ease of actual treatment while ensuring the application possibilities of the bone graft material, the "maximum destructive force (N)/short axis change rate" can be set to be 50 or more to obtain excellent shape maintenance. The bone graft material A bone graft material composition that is easily deformed to match the shape of the bone defect and does not have the problem of flowing to the surroundings during treatment such as hydration. For this reason, when the content of hydroxypropyl methylcellulose is 0.3 parts by weight or more and 3 parts by weight or less with respect to 1 part by weight of the bone graft material, a bone graft composition having a shape maintainability of 50 or more can be formed.

In the bone graft material composition according to an embodiment of the present invention, the composition ratio of the composition for optimizing the bone graft material during treatment is relative to 1 part by weight of the hydroxypropyl methylcellulose of the bone graft material. 0.15 to 6 parts by weight, more preferably, may preferably be formed into 0.3 parts by weight to 3 parts by weight. In the case where the content of the hydroxypropyl methylcellulose is less than 0.3 parts by weight with respect to 1 part by weight of the bone graft material, the adhesion to the bone defect is insufficient, so it may fall from the bone defect during use. It has high performance and small content, so it has almost no effect on the osmotic pressure characteristics of bone graft materials. If it exceeds 3 parts by weight relative to 1 part by weight of the bone graft material, the hygroscopicity, wettability, etc. of the xenogeneic bone may be hindered, and bone formation may be hindered, and the curing of hydroxypropyl methylcellulose may occur. It dissolves well and flows out to the outside, which has a great influence on osmotic pressure, so its function may not be suitable as a bone graft material.

The bone graft material composition including the hydroxypropyl methylcellulose is dissolved in a solvent and used in the form of a solute. A solvent that can be used in this field can be appropriately selected and used as a solvent. As an example, water is used. Since the dissolution rate, concentration, osmotic pressure characteristics, shape maintenance and other physical properties of the bone graft material composition vary with solvent conditions, it is important to set appropriate solvent conditions and implement it.

The dissolution of bone graft material according to an embodiment of the present invention can be used to optimize the bone graft material during treatment, specifically, in order to form an optimal osmotic pressure with other solutions, it can be mixed with respect to the hydroxypropyl methyl group. The cellulose bone graft material composition is produced by 0.5 to 2 parts by weight of the solvent (water) 1 part by weight. As can be seen from the experimental examples described later, the solvent can be used as a bone graft material to form a proper penetration phenomenon with other solutions when the content of the solvent meets a predetermined range. As shown in FIG. 5, it can be confirmed that 0.5 to 2 parts by weight of mixed solvent (water) is required for 1 part by weight of the bone graft material composition including hydroxypropyl methylcellulose in order to form an appropriate penetration phenomenon.

In the case where the content of the solvent (water) is less than 0.5 part by weight relative to 1 part by weight of the bone graft composition including hydroxypropyl methylcellulose, the amount of the solvent (water) is too small to be well It dissolves, so the hydroxypropyl methyl cellulose cannot be combined with the bone graft material well, so that the hydroxypropyl methyl cellulose cannot function well. On the whole, the composition is too hard to be suitable for bone formation, and because it is formed to have a high osmotic pressure with other solutions, it is difficult to maintain the shape, which may cause obstacles in its function as a bone graft material.

In the case of more than 2 parts by weight relative to 1 part by weight of the bone graft material composition including hydroxypropyl methylcellulose, the amount of solvent (water) is too large and the dissolved matter does not have proper viscosity and fluidity, so it is difficult to With shape maintenance. In addition, due to the high content of the solvent (water), the dissolution of the hydroxypropyl methyl cellulose proceeds quickly, and therefore the hydroxypropyl methyl cellulose may dissolve and flow to the outside, thereby failing to perform its function. Also, in the same way, since it is formed to have a strong penetration phenomenon with other solutions, it is difficult to maintain the shape, which may cause obstacles in the function as a bone-maintaining material.

Therefore, in order for the bone graft composition including hydroxypropyl methylcellulose to function well as a hydroxypropyl methylcellulose and to have the shape maintenance of the bone graft material, the conditions are preferably relatively 0.5 to 2 parts by weight of the solvent (water) is mixed with 1 part by weight of a bone graft composition including hydroxypropyl methylcellulose to produce a bone graft solubilized material.

A bone graft material composition kit according to another embodiment of the present invention includes the aforementioned bone graft material composition and a syringe for installing it. By providing a syringe that directly includes the bone graft material, the convenience of use can be ensured, and the possibility of contamination during use can be effectively reduced.

However, for a clearer and more concise description, the description of this embodiment will omit parts that overlap with other embodiments. The omission of the description does not mean that this part is excluded from the present invention. The scope of rights shall be the same as that of other embodiments. The form is also recognized.

A method of manufacturing a bone graft material composition according to another embodiment of the present invention includes the following steps:

Adding bone-forming protein to the solvent or adding the solvent to the bone-forming protein, so that the bone-forming protein is dissolved in the solvent to produce a bone-forming protein solution;

Mixing and stirring the graft material powder and hydroxypropyl methylcellulose powder on which the bone-forming protein is adsorbed to form a viscous gel; and

The mixed and stirred mixture of the graft material powder and the hydroxypropyl methylcellulose powder is frozen and dried at a low temperature in a vacuum state to form a sponge shape including a structure containing a plurality of pores, and therefore can have an excellent The effect of bone formation activation, biocompatibility, and ease of use.

However, in order to make the description clearer and more concise, the description of this embodiment will omit the part that overlaps with the previous embodiment. The omission of the description does not mean that the part is excluded from the present invention. The scope of rights shall be the same as the aforementioned The same form of implementation is recognized.

Fig. 1 is a diagram schematically showing the sequence of a method for manufacturing a bone graft material composition according to an embodiment of the present invention.

FIG. 5 is the result data of the experimental example of the present invention, in order to show the ratio of the mixed salt water to pure salt water according to the time of the osmotic ratio after mixing the bone graft material solubilized by changing the weight of the solvent and the salt water Graph of osmotic pressure changes.

First, the bone-forming protein is dissolved in a solvent to produce a bone-forming protein solution. The bone-forming protein may be added to the solvent or the solvent may be added to the bone-forming protein, and the bone-forming protein may be dissolved in the solvent to produce a bone-forming protein solution.

The bone morphogenetic protein may be at least one selected from the group consisting of: BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP -9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, its recombinant bone morphogenetic protein and its equivalent bone formation The protein may preferably be rhBMP-2 in terms of the bone formation effect of the present invention.

The bone morphogenetic protein concentration of the bone morphogenetic protein solution according to an embodiment of the present invention may be 0.05 to 0.15 mg/ml, and may preferably be 0.08 to 0.12 mg/ml. The bone formation of the bone morphogenetic protein can be activated by satisfying the concentration range. When the bone morphogenetic protein concentration is lower than 0.05, the ability to form new bone may decrease, and when it exceeds 0.15, it may cause side effects.

And, for example, the acidity of the bone-forming protein solution according to an embodiment of the present invention may be pH 4.6-5. By satisfying the acidity range, the bone formation of the bone morphogenetic protein can be activated. When the acidity of the bone morphogenetic protein solution is lower than pH 4.6, the new bone formation ability may decrease, and the new bone formation ability is expressed when the acidity exceeds 5 May fall. For example, acidity can be adjusted with phosphate buffer saline, and phosphate buffer saline may have the effect of bone formation.

Next, the graft material powder is impregnated with the bone-forming protein solution to adsorb the bone-forming protein to the graft material powder. The bone formation protein solution can be added dropwise to the graft material powder prepared in advance or the bone formation protein solution is sprinkled into the graft material powder, so that the graft material powder is immersed in the bone formation protein solution to make bone formation. The protein is adsorbed to the graft material powder.

The graft material powder can be autologous bone, homologous bone, or xenogeneic bone. For example, the graft material powder can be manufactured by injecting a Snap tube.

The average particle size (D50) of the graft material powder may be 200 μm to 5,000 μm, and may preferably be 250 μm to 1,000 μm. In the case where the average particle size of the powder is less than 200 μm, the graft material may be rapidly absorbed, resulting in insufficient bone conduction required for bone formation. In the case of more than 5,000 μm, it may be difficult to perform precision processing when applied to the patient.

The step of adsorbing the bone-forming protein to the graft material powder according to an embodiment of the present invention may include a step of performing adsorption using a refrigerated centrifuge.

Depending on the situation, the bone-forming protein can be suspended in the solution. In the case of rapid rotation and adsorption by a centrifuge, the bone-forming protein can be prevented from being suspended in the solution, so that the bone-forming protein can be well adsorbed on the surface or pores of the graft material powder Inside. Fast rotation and adsorption can make the bone-forming protein not fall from the graft material powder and re-suspend. If the speed is slow, the bone-forming protein may be suspended and cannot be adsorbed well. The bone morphogenetic protein can quickly adsorb to the surface of the graft material powder or into the pores.

The rotation speed of the refrigerated centrifuge according to an embodiment of the present invention may be above 4000 rpm. In the case of using a centrifuge for adsorption, it is possible that the faster the rotation speed, the better the adsorption. For example, the rotation speed of the centrifuge can be above 4000 rpm. When the aforementioned range is met, the bone formation protein can be prevented from being in the solution. Within the suspension.

The step of performing adsorption using a refrigerated centrifuge according to an embodiment of the present invention may be performed at a refrigerating temperature below 5°C. By performing the adsorption step using a refrigerated centrifuge at a refrigerated temperature below 5°C, it is possible to prevent the temperature of the solution from rising due to rotation and to prevent the deformation of the heat-fragile bone-forming protein while maximizing the transplantation of the bone-forming protein by the rotation Adsorption effect on the surface of the material powder or in the pores. The refrigeration may be a temperature at which the solution is not frozen, for example, 5°C or less, and may preferably be 0.5°C to 1.5°C.

Next, the graft material powder to which the bone-forming protein is adsorbed and the hydroxypropyl methylcellulose powder are mixed and stirred to form a gel. Accordingly, a viscous gel can be formed, and the formed gel can improve the adhesion of the graft material powder. For example, the stirring can be performed with a blender. A product of uniform quality can be obtained by mixing the graft material powder and the powdered hydroxypropyl methylcellulose.

According to an embodiment of the present invention, the volume ratio of the graft material powder adsorbed with bone-forming protein to the hydroxypropyl methylcellulose powder may be 1:0.2 to 1:0.6. When the volume ratio of the hydroxypropyl methylcellulose powder is less than 0.2, it is difficult to form a gel, and when it exceeds 0.6, the volume of the gel becomes larger than that of the graft material powder, and it may be difficult to form effectively Bone graft material composition. In terms of the effect of the invention, preferably, the volume ratio of the graft material powder that adsorbs the bone-forming protein and the hydroxypropyl methylcellulose powder may be 1:0.25 to 1:0.35.

Next, the mixed and stirred graft material powder and hydroxypropyl methylcellulose powder mixture are vacuum freeze-dried to form a sponge shape including a porous structure. The mixed and stirred mixture of the graft material powder and the hydroxypropyl methylcellulose powder may be frozen and dried at a low temperature in a vacuum state to form a sponge form having a structure including a plurality of pores.

By performing a vacuum freeze-drying process, a sponge shape including a porous structure can be formed. A sponge form including a porous structure can be formed by allowing the gel to be absorbed by the graft material powder, and the formation of the sponge form including a porous structure is judged to be a major contribution to the vacuum treatment.

The method for manufacturing the bone graft material composition of an embodiment of the present invention may further include a packaging step.

The method of manufacturing the bone graft material composition of an embodiment of the present invention may further include the step of installing the bone graft material composition including a sponge shape into a microtube of a size that can be inserted into a syringe, wherein the sponge shape includes The structure of the multiple pores manufactured. By further including the step of installing a microtube of a size that can be inserted into a syringe, it has a size that can be inserted into the syringe, so that the syringe can be directly inserted without a separate process, so that it can be used in the process of manufacturing the bone graft material composition. Easy to operate.

The method of manufacturing the bone graft material composition according to an embodiment of the present invention may further include the step of putting the bone graft material composition including the sponge shape installed in the microtube into a syringe and sealing, wherein the sponge shape includes the The structure of multiple pores is described. By equipping the syringe with the bone graft material composition, the convenience of use can be ensured, and the possibility of contamination that may be generated during use can be effectively reduced.

The method for manufacturing the bone graft material composition of an embodiment of the present invention may further include a step of sterilization.

In an embodiment of the present invention, the bone graft material composition in the form of a sponge including a structure including a plurality of pores can be sterilized by using Ethylene Oxide Gas. For example, the concentration of ethylene oxide gas (Ethylene Oxide Gas) may be 450 mg/l to 1200 mg/l.

When the concentration of ethylene oxide gas (Ethylene Oxide Gas) is lower than 450mg/l, the sterilization may be insufficient, and when it exceeds 1200mg/l, the bone-forming protein may be deformed.

According to an embodiment of the present invention, the bone graft material composition in the sponge form including a structure including a plurality of pores can be sterilized by irradiating gamma rays. For example, the irradiation amount of gamma rays may be 10kGy to 25kGy. In the case where the gamma ray irradiation amount is less than 10 kGy, sterilization may be insufficient, and when it exceeds 25 kGy, the bone morphogenetic protein may be deformed.

The bone graft material manufactured according to the method of manufacturing the bone graft material as described above needs to ensure hydration properties in order to be applied to the human body, for example, to teeth. In other words, it needs to have critical osmotic pressure characteristics. The formation of a predetermined penetration ratio when mixed with other solutions (for example, saline) is an important factor for maintaining the predetermined concentration, thereby maintaining the predetermined shape, and maintaining the function of the bone graft material. These physical properties can be determined according to the content of HPMC and the like included in the bone graft material and the conditions of the solvent used to form the solute.

Taking the case of applying the bone graft material to the tooth as an example, when the operator applies the bone graft material to the tooth defect part, the bone graft material provided in the form of powder or the like is hydrated and applied to the bone defect part. In this hydration process, if the HPMC included in the bone graft material flows out in a large amount (the osmotic pressure of the hydrate rises), HPMC cannot be included in the bone graft material, not only cannot maintain the shape of the bone graft material, but also the bone graft material cannot cohere. Unable to treat. Therefore, the bone graft material composition needs to have osmotic pressure characteristics within a predetermined level to be able to maintain its shape without being affected by external conditions. Furthermore, when the external environment such as water, saliva, etc. is caused when the bone graft material is applied to the tooth defect, the bone graft material combination may flow to the surrounding or detach. Therefore, there is a problem that foreign matter may flow into the defect part. . Therefore, the bone graft material needs to have osmotic pressure characteristics within a predetermined level, and further, not only the internal physical properties, but also physical properties corresponding to external conditions.

In fact, when the osmotic pressure of saline is normalized to 100%, the saline needs to form an osmotic pressure of 104% to 112% within 12 to 48 hours after being added to the dissolution of the graft material. If the osmotic pressure exceeds 112%, the outflow of HPMC occurs during the hydration process, and the shape maintenance of the bone graft material and the adhesion with the bone defect are significantly reduced and cannot be applied to the bone graft material. Furthermore, if the osmotic pressure is lower than 104%, it will not be well hydrated, and it will be difficult to achieve corresponding plastic deformation with the bone defect, thus adversely affecting bone regeneration.

Hereinafter, although preferred embodiments are proposed to help the understanding of the present invention, the embodiments only illustrate the present invention and do not limit the scope of the claims. For those skilled in the art, it is within the scope of the present invention and the scope of technical ideas. It is obvious that various changes and modifications can be made to the embodiments, and it is also obvious that such changes and modifications fall within the scope of the claims.

Experimental example 1

1. Confirmation experiment of residual amount and solubility based on the ratio of hydroxypropyl methylcellulose (HPMC: Hydroxypropyl methylcellulose)

As shown in Table 1, HPMC was added to the bone graft material (0.25g) in different parts by weight (0.1-6). The mixture of bone graft material and HMPC was dissolved in a solvent (water), and the residual amount of HPMC over time was confirmed. The amount of HMPC added first is standardized to 100%, and the residual amount remaining after dissolution is compared with the standard value (100%) and shown as a percentage (%). The closer the ratio of the residual amount is to 100%, it means that it is almost not dissolved, and the closer to 0% it is that it is almost completely dissolved. As another meaning, the ratio of the residual amount of 100% can be interpreted as the dissolution rate of 0%, and the ratio of the residual amount of 0% can be interpreted as the dissolution rate of 100%.

The amount of the solvent (water) is the optimal hydration amount that the mixture can dissolve well, and is 1 to 1.5 times the weight of the entire mixture. As an example, it is 1.2 times the weight.

【Table 1】 0 hours 1 hour 3 hours 6 hours 12 hours 24 hours 48 hours 0.1 100% 0% 0% 0% 0% 0% 0% 0.2 100% 15% 3% 0% 0% 0% 0% 0.3 100% 62% 55% 50% 39% 29% 11% 0.4 100% 64% 60% 54% 43% 31% 14% 0.6 100% 80% 70% 58% 48% 33% 20% 0.8 100% 85% 78% 71% 58% 44% twenty two% 1.2 100% 93% 88% 82% 67% 57% 30% 1.5 100% 94% 89% 87% 73% 68% 35% 2 100% 95% 90% 88% 75% 73% 42% 3 100% 99% 94% 92% 81% 75% 50% 4 100% 99% 96% 93% 85% 78% 60% 5 100% 100% 98% 95% 88% 81% 70% 6 100% 100% 100% 100% 99% 99% 98%

As shown in Table 1 above, it was confirmed that as the dissolution time passed, the residual amount decreased and the dissolution rate increased. In addition, it can be confirmed that as the amount of HPMC increases, the residual amount in the same time period increases and the dissolution rate decreases.

Fig. 2 reflects the result data (Table 1) of the experimental example 1 and shows the residual rate according to the weight ratio of hydroxypropyl methylcellulose and time. The closer the Y-axis graph value is to 1, the closer the residual rate is to 100% (dissolution rate 0%), and the closer to 0, the closer to the residual rate 0% (dissolution rate 100%).

The dissolution rate of the hydroxypropyl methylcellulose of the bone graft material composition may require different conditions depending on its use, use environment, and use purpose. The composition ratio of the porous bone graft material and the hydroxypropyl methylcellulose can be implemented in consideration of the dissolution time and the dissolution rate according to the purpose.

Under the condition that more than 50% of the hydroxypropyl methylcellulose is dissolved within 48 hours, 0.1 to 3 parts by weight of hydroxypropyl methylcellulose can be mixed with 1 part by weight of the porous bone graft material to form a bone graft material The composition, as another example, under the condition that more than 60% of hydroxypropyl methylcellulose is dissolved within 48 hours, 0.1 to 2 parts of hydroxypropyl methylcellulose can be mixed with respect to 1 part by weight of the porous bone graft material. Parts by weight to form a bone graft material composition. As another example, the hydroxypropyl methylcellulose can be mixed with 1 part by weight of the porous bone graft material under the condition that more than 70% of the hydroxypropyl methylcellulose is dissolved within 48 hours. 0.1 to 1.2 parts by weight of methylcellulose to form a bone graft material composition. As another example, it can be compared to porous bone graft material under the condition that more than 80% of hydroxypropyl methylcellulose is dissolved within 48 hours. 1 part by weight is mixed with 0.1 to 0.6 parts by weight of hydroxypropyl methylcellulose to form a bone graft material composition. In consideration of the functionality of the bone graft material, it is preferable to configure the mixing ratio to be 0.3 parts by weight or more with respect to 1 part by weight of the hydroxypropyl methylcellulose of the porous bone graft material.

As another example, under the condition that 50% or more of hydroxypropyl methylcellulose is dissolved within 24 hours, 0.1 to 1 part by weight of hydroxypropyl methylcellulose can be mixed with respect to 1 part by weight of the porous bone graft material. The bone graft material composition is formed. In addition, in consideration of the functionality of the bone graft material, the mixing ratio may be configured to be 0.3 to 1.0 parts by weight to form the bone graft material composition.

As another example, under the condition that more than 50% of hydroxypropyl methylcellulose is dissolved within 12 hours, 0.1 to 0.6 parts by weight of hydroxypropyl methylcellulose can be mixed with respect to 1 part by weight of the porous bone graft material. The bone graft material composition is formed. In addition, in consideration of the functionality of the bone graft material, the mixing ratio may be configured to be 0.3 to 0.6 parts by weight to form the bone graft material composition.

Experimental example 2

2. The volume reduction rate and solubility confirmation experiment based on the HPMC ratio

As shown in Table 2, HPMC was added to the bone graft material (0.25g) in different parts by weight (0.1-6). The mixture of bone graft material and HPMC was dissolved (hydrated) in a solvent (water) to produce a test piece, and the residual amount of HPMC according to the passage of time was confirmed. Specifically, the hydrated test piece was put into a conical tube (conical tube) with a capacity of 15 ml without any gaps, and then washed for the first time, and then the portion of the conical tube that was not occupied by the test piece was truncated. Then, the open part of the remaining tapered tube after the cut was covered with a mash to allow only the dissolved test piece to pass through the open part.

After that, the conical tube is placed in an ultrasonic cleaner that maintains the temperature of the human body (for example, 37 degrees), and purified water is circulated at a predetermined speed to measure the volume of the test piece after 48 hours. The pure water remaining on the test piece can be removed before measuring the volume of the test piece.

Based on the amount of HPMC added, the volume reduction rate was measured in an environment similar to the human body. The larger the volume reduction rate, can be interpreted as the higher the solubility of the reagent, and the smaller the volume reduction rate, can be interpreted as the lower the solubility.

The amount of the solvent (water) is the optimal amount of hydration that can dissolve the mixture well, and is 1 to 1.5 times or 1.2 times to 1.5 times the weight of the entire mixture, as an example, 1.2 times.

【Table 2】 HPMC parts by weight Initial volume (cc) Volume after 48 hours (cc) Volume reduction rate (%) 0.1 0.270 0.101 62.58% 0.2 0.529 0.307 42.01% 0.3 0.652 0.544 16.54% 0.4 0.766 0.683 10.82% 0.6 1.131 1.010 10.70% 0.8 1.275 1.136 10.92% 1.2 1.987 1.791 9.85% 1.5 2.312 2.090 9.61% 2 2.768 2.554 7.73% 3 4.080 3.816 6.46% 4 4.378 4.728 -7.99% 5 5.426 5.954 -9.72% 6 5.672 6.322 -11.46%

【table 3】 HPMC parts by weight Initial weight (g) Weight after 48 hours (g) 0.1 1.630 0.610 0.2 3.190 1.850 0.3 3.930 3.280 0.4 4.620 4.120 0.6 6.820 6.090 0.8 7.690 6.850 1.2 11.980 10.800 1.5 13.940 12.600 2 16.690 15.400 3 24.600 23.010 4 26.400 28.510 5 32.720 35.900 6 34.200 38.120

As shown in Table 2 and Table 3, it can be confirmed that the volume and weight of the test piece change after 48 hours in a human environment based on the weight ratio of HPMC. In addition, it can be confirmed that as the amount of HPMC increases, the residual amount of HPMC increases and the dissolution rate decreases.

FIG. 3 reflects the result data regarding the experimental example 2 (Table 2), and shows the volume reduction rate according to the weight ratio of HPMC.

As shown in FIG. 3, it was confirmed that when the weight part of HPMC of the bone graft material composition was 0.2, the volume reduction rate was 40%, and when the weight part of HPMC was 0.3, the volume reduction rate dropped sharply to 16.54%. In addition, it can be confirmed that when the weight part of HPMC of the bone graft material composition is 3, the volume reduction rate is 6.46%, and when the weight part of HPMC is 4, the volume reduction rate has a negative value instead.

This means that when the weight part of HPMC relative to 1 part by weight of the bone graft material is less than 0.3, HPMC dissolves too quickly in the human environment and flows out, so that the volume of the test piece cannot be maintained, so HPMC cannot promote or help Bone formation. On the contrary, when the weight of HPMC exceeds 3 parts by weight relative to 1 part by weight of the bone graft material, the volume of HPMC will be greater than the volume of the bone graft material, thus forming a shape in which HPMC wraps the bone graft material, so that HPMC absorbs external The phenomenon of volume increase due to moisture. This phenomenon can be seen from Table 3, and it can be confirmed that when the weight of HPMC exceeds 3 parts by weight relative to 1 part by weight of the bone graft material, water is absorbed from the outside, and therefore the weight of the test piece increases after the experiment.

Therefore, in order to realize the functional side of the bone graft material, it is possible to mix 0.3 parts by weight or more and 3 parts by weight or less of HPMC with respect to 1 part by weight of the porous bone graft material.

Experimental example 3

3. Shape maintenance experiment based on HPMC ratio

As shown in Table 4, HPMC was added to the bone graft material (0.25g) in different parts by weight (0.1~6) and mixed and dissolved in a solvent (DBS) to form viscosity, and then to make it have a sphere shape Way of manufacturing. The size of the initial sphere is shown in Table 4 with the length of the major axis and the minor axis. A compressor (push-pull gage) was used to apply pressure to the ball, and the maximum destructive force (N) before the sphere was destroyed, that is, the short axis length at the maximum peak, was measured. Comparison of the initial minor axis length and the minor axis length at the maximum breaking force and the minor axis change rate is shown in Table 4.

Experimental example 4

4. Rigidity experiment based on HPMC ratio

The maximum destructive force (N) before the sphere of Experimental Example 3 was destroyed, that is, the maximum peak value, was measured and shown in Table 4. It can be explained that the higher the maximum destructive force, the greater the stiffness.

【Table 4】 Parts by weight Long axis (mm) Minor axis (mm) Maximum destructive power Short axis after change (mm) Short axis change rate (%) (Kgf) (N) 0.1 8.32 8.18 1.04 10.18 3.53 43.15 0.2 8.85 8.56 1.37 13.39 3.61 42.17 0.3 8.72 8.53 2.32 22.69 3.36 42.56 0.4 10.43 10.31 2.43 23.84 3.65 35.40 0.6 10.08 9.39 3.36 32.93 4.01 42.71 0.8 12.27 11.32 2.95 28.94 4.36 38.52 1.2 11.48 10.65 3.36 32.90 4.80 45.07 1.5 12.88 12.60 3.06 30.01 5.36 42.54 2 13.15 13.03 3.45 33.80 6.42 49.27 3 16.50 14.90 3.55 34.75 9.45 63.42 4 17.43 17.03 2.63 25.74 10.58 62.13 5 18.51 18.11 1.89 18.52 11.15 61.57 6 19.10 18.47 1.33 13.08 12.10 65.51

Experimental example 5

5. Confirmation of shape maintainability using the maximum destructive force (N) for the rate of change of the minor axis

In order to form a bone graft material composition excellent in shape maintenance, optimal rigidity and non-restorability are required. The following Table 5 shows the maximum destructive force with respect to the minor axis change rate according to the HPMC ratio. Figure 4 reflects the values in Table 5 and shows the "bone graft material composition ball (sphere) maximum destructive force (N)/bone graft material composition ball (sphere) with respect to the weight ratio of hydroxypropyl methylcellulose ) Rate of change of the short axis".

【table 5】 Parts by weight Maximum destructive force (N)/change rate of short axis 0.1 23.6 0.2 31.8 0.3 53.3 0.4 67.3 0.6 77.1 0.8 75.1 1.2 73.0 1.5 70.5 2 68.6 3 54.8 4 41.4 5 30.1 6 20.0

The HPMC has a high minor axis change rate of 0.1 to 0.2 parts by weight and a small maximum destructive force (N). The value of "maximum destructive force (N)/minor axis change rate" is low, so the shape maintenance is not excellent. This means that the shape is easily changed with a small amount of force, which has a very unfavorable effect on the treatment process of the bone graft material. This is understood as a phenomenon that occurs due to the lack of HPMC that can increase the rigidity of the bone graft material.

Moreover, in the case of a bone graft material containing 4 parts by weight or more of HPMC, the short axis change rate is high, the maximum destructive force (N) is low, and the value of "maximum destructive force (N)/short axis change rate" is low, Therefore, the shape maintainability is not excellent. That is, it can be seen that the inclusion of 4 parts by weight or more of HPMC in the bone graft material, that is, when the HPMC is included in an excessive amount, the rigidity of the bone graft material cannot be increased, but the shape maintainability is reduced.

If it is implemented in a manner that includes 0.3 parts by weight to 3 parts by weight of HPMC relative to 1 part by weight of the bone graft material, a "maximum destructive force (N)/short axis change rate" of 50 or more can be formed, and a bone with excellent shape maintainability can be obtained. Graft material composition. As another example, if it is implemented to include 0.4 to 2 parts by weight of HPMC with respect to 1 part by weight of the bone graft material, a "maximum destructive force (N)/minor axis change rate" of 60 or more can be formed and shape maintenance can be obtained. Excellent bone graft material composition. As another example, if it is implemented to include 0.6 parts by weight to 1.5 parts by weight of HPMC relative to 1 part by weight of the bone graft material, a "maximum destructive force (N)/short axis change rate" of 70 or more can be formed to obtain shape maintenance. Excellent bone graft material composition.

Experimental example 6

6. Determination of osmotic pressure of salt water

The osmotic pressure represents the pressure that the semipermeable membrane receives when the osmosis phenomenon occurs, and is formed in proportion to the concentration difference of the solution. The osmotic pressure of saline was measured by a control experiment, and as shown in Table 6 below, it was also measured whether the osmotic pressure changes with the passage of time. The value of osmotic pressure can be measured by introducing a solution and a pressure sensor connected to the outflow port. The osmotic pressure value of salt water measured in this experiment is 286, which is standardized to 100%.

Experimental example 7

7. Manufacturing of bone graft material hydrate including HPMC

Water was added to 1 part by weight of the bone graft material (0.5 g) and 0.6 part by weight of HPMC to produce a bone graft material hydrate including HPMC. The amount of the added water is 0.4 to 6 parts by weight relative to 1 part by weight of the bone graft material and HPMC mixture.

Experimental example 8

8. Measurement of osmotic pressure of saline added to hydrate of bone graft material including HPMC

Put the bone graft material hydrate produced in 7 into a 15ml conical tube and add 5ml of saline. At each time node in Table 6 below, 0.5 ml of saline was collected and the osmotic pressure was measured. As a numerical value relative to the control experiment value of 6 above, it is shown as "%".

【Table 6】 1 hour 3 hours 6 hours 12 hours 24 hours 48 hours Control 100% 100% 100% 100% 100% 100% 0.4 100% 108% 112% 113% 115% 117% 0.5 100% 104% 109% 110% 111% 112% 0.6 100% 103% 107% 109% 110% 111% 0.8 100% 103% 106% 107% 108% 109% 1.0 100% 102% 103% 106% 107% 108% 1.2 100% 103% 104% 105% 106% 108% 1.5 100% 101% 102% 105% 107% 108% 2.0 100% 102% 102% 104% 106% 107% 3.0 100% 109% 115% 116% 117% 117% 4.0 100% 109% 116% 117% 118% 118% 6.0 100% 110% 114% 116% 118% 118%

As shown in Table 6, the control experiment was set to 100% as the standard value. It is a value obtained by measuring and normalizing the osmotic pressure of pure salt water based on time.

As shown in Table 6, it can be confirmed that the osmotic pressure increases with the passage of time in the same part by weight. This is because as time goes by, the contact time and the amount of contact between saline and the HPMC-dissolved bone graft material hydrate increase, thereby increasing the osmotic pressure.

As shown in Table 6 above, it can be confirmed that the larger the weight part of water at the same time, the more the osmotic pressure increases. This is because the larger the amount of water, the faster the dissolution of HPMC in the hydrate of the bone graft material dissolved with HPMC, resulting in an increase in osmotic pressure.

As shown in Figure 5, it can be confirmed that when the weight part of the water is 0.4 or less, the osmotic pressure increases greatly in a short time and the osmotic ratio changes greatly. When the weight part of the water is 3 or more Under the circumstances, it can also be confirmed that the osmotic pressure has increased greatly in a short time and the osmotic ratio has changed greatly. A large increase in osmotic pressure in a short time means that HPMC does not fuse with the bone graft material and flows to the outside. As the concentration increases and the osmotic pressure increases, the shape maintenance decreases accordingly. Therefore, for optimal shape maintenance, it is suitable to set the weight part of water to 0.5 to 2 parts by weight relative to the weight part of the bone graft material composition including HPMC.

If the weight of the water is set to be 0.5 to 2 parts by weight compared to the weight of the bone graft material composition, the osmotic pressure of saline can form 104% to 112% or less of penetration within 12 hours to 48 hours. Pressure. The osmotic pressure value formed within 12 hours is not enough to grasp the performance of the functional maintenance of the bone graft material, and its direct application is slightly insufficient for the verification of the functionality and stability of the bone graft material. Therefore, the osmotic pressure formed within 12 hours to 48 hours can be confirmed to determine the functionality, osmotic pressure, shape maintenance, etc. as a bone graft material. If the osmotic pressure exceeds 115% compared to the osmotic pressure of pure saline within 48 hours, the hydration of the bone graft material composition including HPMC does not proceed well, and it does not fully function as an additive, so it is difficult to apply as a bone graft material The composition is no different from pure saline if it is approximately 100%. Therefore, it is difficult to consider that the bone graft material including HPMC has its physical properties and functions. Therefore, it is preferable to form a bone graft material composition in which the osmotic pressure of the saline solution is 104% to 112% or less compared to the control (control) within 12 hours to 48 hours after the addition.

without

Fig. 1 is a diagram schematically showing the sequence of a method for manufacturing a bone graft material composition according to an embodiment of the present invention. 2 is a graph showing the result data (Table 1) of Experimental Example 1 related to the present invention and showing the residual rate according to the weight ratio and time of hydroxypropyl methylcellulose (Hydroxypropyl methylcellulose). 3 is a graph showing the result data (Table 2) of Experimental Example 2 related to the present invention and showing the volume reduction rate according to the weight ratio of Hydroxypropyl methylcellulose. Figure 4 shows the "bone graft material composition sphere" maximum destructive force (N)/bone graft material composition sphere (short axis change) with respect to the weight ratio of hydroxypropyl methylcellulose (Hydroxypropyl methylcellulose) The graph of "rate" is a graph showing the weight ratio of hydroxypropyl methylcellulose (Hydroxypropyl methylcellulose) used in a bone graft composition with excellent shape maintenance. FIG. 5 is the result data of the experimental example of the present invention, in order to show the ratio of the mixed salt water to pure salt water according to the time of the osmotic ratio after mixing the bone graft material solubilized by changing the weight of the solvent and the salt water Graph of osmotic pressure changes.

Claims (4)

A bone graft material composition comprising: The porous bone graft material and hydroxypropyl methyl cellulose, wherein the content of the hydroxypropyl methyl cellulose is 0.15 to 6 parts by weight relative to 1 part by weight of the porous bone graft material. A bone graft material composition comprising: The porous bone graft material and hydroxypropyl methyl cellulose, wherein the content of the hydroxypropyl methyl cellulose is 0.2 to 5 parts by weight relative to 1 part by weight of the porous bone graft material. A bone graft material composition comprising: The porous bone graft material and hydroxypropyl methyl cellulose, wherein the content of the hydroxypropyl methyl cellulose is 0.25 to 4 parts by weight relative to 1 part by weight of the porous bone graft material. A bone graft material composition comprising: The porous bone graft material and hydroxypropyl methyl cellulose, wherein the content of the hydroxypropyl methyl cellulose is 0.3 to 3 parts by weight relative to 1 part by weight of the porous bone graft material.

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