KR20180015924A - Bone graft and the Dental implanting base manufacturing method - Google Patents

Abstract

The present invention relates to a method for manufacturing a bone graft material and a dental implant material (column). More specifically, the method for manufacturing a bone graft material and a dental implant material comprises: a heating step of removing microproteins contained in animal bones by heating animal bones in which fat and protein are removed; a bone powder forming step of forming bone powder by pulverizing the heat-treated animal bones; a neutralization step of putting the bone powder into neutralizing water, which is obtained by sodium phosphate monoanhydrate, sodium phosphate dianhydrate and purified water, and stirring the mixture; and a coating step of coating the neutralized bone powder or a dental implant material with octacalcium phosphate. According to the present invention, the bone graft material is porous and has an excellent effect of forming new bones since the surface alkalinity is adjusted to pH 7.5, and octacalcium phosphate (OCP), which is a substance promoting new bone formation, is attached to the surface of the bone graft material or the implant material, such that the effect of forming new bones is more excellent.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for manufacturing a bone graft material and a dental implant material,

The present invention relates to a method of manufacturing a bone graft material and a dental implant material (column).

Bone grafts are divided into human bone (autograft, allograft), animal bone (xenograft), and synthetic bone (alloplastic and synthetic bone).

The human bone is used to separate the bones from other parts of the body or to use the bones of other people. The body parts and quality problems are naturally accompanied by the problems of the human bone. Therefore, as a substitute for the bones, xenograft, especially bovine bone, Is the mainstream of the stable supply of quantity and quality of materials.

In particular, the present invention relates to a method for manufacturing a bone graft material comprising a bone member such as animal bone or synthetic bone (artificial bone). In order to eliminate the immune response caused by the animal protein, it is preferable to completely remove the protein from the animal bone in the manufacturing process to form the animal bone into a pure calcium structure. In addition, the bone graft material has many pores (macroporosity and microporosity) and should have excellent new bone formation effect.

As a method of removing lipid and protein from animal bone to form a pure calcium structure, Japanese Patent No. 10-1272958 entitled " Bone graft material and manufacturing method thereof "has been disclosed. This discloses "a method for sterilizing a pig bone, separating the cancellous bone from the sterilized bone tissue, applying a mixed solution of chloroform and ethanol, hydrogen peroxide solution and ethanol sequentially to remove lipid and immunizing antigen ". However, such a method of removing lipids and proteins with a drug has drawbacks in that the removal of lipids and proteins is not perfect and the drug remains in the bone tissue. That is, even if an organic part such as protein or oil is removed from the bone, a very fine structure of collagen fiber exists in the bone, so that the animal bone is heated to a high temperature to burn and remove the protein It is commonly used. That is, a high temperature treatment method of heating the animal bone at a high temperature of 1,100-1,300 ° C for 2-3 hours and a low temperature treatment method of heating the animal bone at a temperature of 400-800 ° C for 2-3 hours are often performed. When treated at a high temperature, the protein can be easily treated and the bone graft material can be formed into a pure calcium structure, so that it is easy to manufacture, and the surface pH is 7 to 8, so that a stable new bone formation effect can be obtained. However, when heated at such a high temperature, there is a serious drawback that the surface of the bone graft material is melted and the effect of forming microporosity is lacking.

On the other hand, when the animal bone is treated at a low temperature of 400-800 ° C., the bone graft material with a multimicro-porosity can be obtained without causing the molten state. However, since the CaO and CaCO 3 fine powder exist, Alkali appearance is shown and tissue reaction is deteriorated. It is not easy to neutralize this strong alkalinity and thus only a small number of producers are producing low temperature treated bone grafts.

Clinical successes of bone grafts formed at low temperatures of 400 to 800 DEG C as bone grafts based on xenografts include Bio Oss (trade name, product of Geistlich Pharma AG: Bahnhofstrasse 40 CH-6110 Wolhusen) and high-temperature treatment (1100-1300). Cerabone (trade name: Botiss, Germany) is a bone graft material.

Bio Oss is a bone graft material made of animal bone (xenograft), which is formed at a low temperature of 400 to 800 ° C. It provides porous (multimacro and microporosity) bone grafts and adjusts the surface pH to 7.5, And provides excellent bone graft material. However, even these Bio Oss do not provide a satisfactory new bone formation effect.

Patent No. 10-1272958 "Bone graft material and method for manufacturing the same"

Accordingly, the present invention provides a bone graft material which is formed at a low temperature of 400 to 800 ° C, has excellent lipid and protein removal, has a large number of pores, exhibits a neutral pH value on the surface thereof, And to provide a graft material having an osteogenesis inducing factor and thus having an excellent new bone formation effect.

In order to solve the above problems,

A heating treatment process for removing lipids and proteins contained in animal bones by heating the animal bones from which fat and protein have been removed at a temperature of 400 to 800 ° C. for 2 to 3 hours,

A bone forming process for forming a macroporosity bone powder by pulverizing the heat treated animal bone to a size of 0.2 to 1.7 mm in diameter,

The neutralized water obtained by mixing sodium phosphate monoanhydrate with sodium phosphate di anhydrate and purified water is mixed with the above crushed bone powder and then subjected to a neutralization process in which the mixture is stirred in an agitator and,

And a step of applying octacalcium phosphate to the neutralized bone fragments. The present invention also provides a method for manufacturing a dental implant material by adding octacalcium phosphate to a dental implant material.

As described above, the bone graft material of the present invention is porous and has an excellent effect of forming a new bone. The alkalinity of the bone graft is adjusted to Ph 7.5 so that the new bone formation effect is excellent. Particularly, It is possible to provide a bone graft material and a dental implant that are superior in the effect of forming new bone by attaching phosphate (Octacalcium phosphate: OCP).

According to the present invention,

One. A heating treatment step of heating the animal bone from which fat and protein have been removed at a temperature of 400 to 800 ° C for 2 to 3 hours to remove micro-proteins contained in animal bone,

2. A bone forming process for forming a macroporosity bone powder by pulverizing the heat treated animal bone to a size of 0.2 to 1.7 mm in diameter,

3. A neutralization step in which bone meal is mixed with neutralized water obtained by mixing sodium phosphate monoanhydrate, sodium phosphate monoanhydrate and purified water,

4. And a step of applying an octacalcium phosphate to the bone fractions neutralized by the neutralization step.

However, in the case where the bone fragments are made of a synthetic bone other than the animal bone of the bone member, or a dental implants, it is not necessary to perform the neutralization process described above.

The octacalcium phosphate application process can be carried out,

 A bone meal washing step in which the neutralized bone meal is added to calcium acetate and sodium phosphate mono anhydrate and the aqueous solution of calcium acetate and sodium phosphate which is purified water,

The washed bone meal was mixed with the above-mentioned "aqueous solution of calcium acetate and sodium phosphate ", which became calcium acetate and sodium phosphate di anhydrate, and purified water, and the mixture was placed in a tray in which" calcium acetate and sodium phosphate Aqueous solution "to a thickness of 8 to 12 mm so as to fill the bone fragments, followed by drying with hot air.

 In the case of mixing with the "calcium acetate and sodium phosphate aqueous solution" to mix the bone fractions and drying with hot air, the mixture may be dried and dried with hot air. In this case, the thickness of the mixture on the tray may exceed 12 mm.

The neutralized water is preferably prepared by mixing 12 to 16 g of sodium phosphate monoanhydrate with 12 to 16 g of sodium phosphate monoanhydrate and 2700 to 3300 g of purified water. 180 to 220 g of bone meal per 3000 g of neutralized water is added, To neutralize the bone fragments.

"Calcium acetate and sodium phosphate aqueous solution" for the osseous cleansing process in the octacalcium phosphate application process is prepared by mixing 9 to 13 g of calcium acetate per 7.2 g of sodium phosphate mono anhydrate and 2700 to 3300 g of purified water do.

It is preferable that the amount of bone meal put in the "aqueous solution of calcium acetate and sodium phosphate" for washing is 180 to 220 g per 3,000 g of the aqueous solution of calcium acetate and sodium phosphate.

In mixing the washed bone meal with the above-mentioned "aqueous solution of calcium acetate and sodium phosphate ", a mixture of bone meal and" aqueous solution of calcium acetate and sodium phosphate "is added to a tray, and the bone meal is mixed with calcium acetate and sodium phosphate The mixing ratio should be adjusted so that the mixture can be spread to a thickness of 1 to 12 mm. The mixing ratio is preferably 1 to 0.7 to 0.9 (volume ratio) of an aqueous solution of calcium acetate and sodium phosphate.

The present invention further provides a method of manufacturing a bone graft material as described above, wherein the bone fragments are dental implant graft materials. That is, the dental implant material is placed in the above-mentioned "aqueous solution of calcium acetate and sodium phosphate ", which is made of calcium acetate, sodium phosphate di anhydrate and purified water, and stirred for 10 to 20 minutes, The process of cleaning the substrate material to remove foreign substances and air present on the surface

The dressing material washed in the washing step is mixed with calcium acetate, sodium phosphate di anhydrate and the above-mentioned "aqueous solution of calcium acetate and sodium phosphate ", and this mixture is placed in a tray," calcium acetate And an aqueous solution of sodium phosphate "to a thickness of 8 to 12 mm so as to lock the molding material, followed by drying with hot air. The present invention also provides a method for manufacturing a dental implant material.

When the above ingredients are mixed so as to be mixed with the "aqueous solution of calcium acetate and sodium phosphate ", and the mixture is dried by hot air, the mixture may be dried and dried by hot air. In this case, the thickness of the mixture on the tray may exceed 12 mm.

To dry the foodstuffs immersed in the "aqueous solution of calcium acetate and sodium phosphate", it is necessary to dry for 2-3 hours with hot air at 60-100 ° C.

Hereinafter, the present invention will be described in more detail.

1. Heat Treatment and Bone Shaping Process

Above figure (a) is a representative form of human and animal cancellous bone after protein, oil, and vascular tissue are removed and after heat treatment process is completed. This picture shows multimacroporosity and porosity is the first condition of the implant material that promotes the growth of blood vessels into the graft material, a prerequisite for tissue regeneration. The regeneration of blood vessels is completed within two weeks in the graft site, so the porous structure of the graft material that allows maximum vessel placement is very important

On the other hand, as shown in the above two figures (b), the low magnification structure of about 40 times of the other bone grafts has no structure of multimacroporosity, and there is no porous structure, restricting the regeneration of the blood vessels. The limited formation of blood vessels is a fundamental element that reduces oxygen, nutrients, and osteoblast supply into the regenerated tissue, thereby reducing the rate of new bone regeneration

The above two figures (c) can clearly observe the structure of the porosity with good bone graft material (left; Cerabone, right; Bio Oss).

2. Low Temperature Treatment Process

 Removal of proteins, oils, and other organic parts from the bone results in the presence of very fine structures of collagen fibers that are removed through heat treatment.

The above figure (d) shows a multimicroporosity pattern of natural osteoblast formed by collagen fiber after removal by low-temperature heat treatment at 400-800 ° C (3000x magnification) Bio Oss or the bone graft material of the present invention show the same shape.

The figure above shows a 2500x magnification image of a bone graft material made by high temperature heat treatment at 1,100 ~ 1300 ℃. The surface is dissolved by high temperature treatment to form a glass-like surface, dissolving, cooling and cracking, . This is a typical image of a bone graft material subjected to high temperature treatment.

In order to increase the bone regeneration, blood adhesion is required and the natural rough surface of the low temperature facilitates this, whereas the surface of the glass treated with high temperature is not attached to the surface of the blood. Therefore, the low-temperature-treated bone graft material is superior in terms of bone cell formation

The above two figures (bar) are the results of the experiment showing the difference of the osteogenesis according to the blood adhesion difference between the glass surface of the high temperature treatment and the rough surface of the low temperature treatment.

3. pH adjustment process of bone surface

The choice between high temperature heat treatment and low temperature heat treatment depends on whether there is a surface pH adjustment technique. If pH adjustment technology is used, low-temperature heat treatment can be performed. Without this technique, high-temperature heat treatment can not be performed even if the result of bone formation is decreased.

CaCO 3, which can dissolve on the surface, is present at a low temperature, and it shows a high alkalinity between pH 10 and 12. When using this strong alkaline bone graft, the tissue reaction becomes very bad until it becomes neutral And the advantage of the coarse structure of the natural form is lost. Therefore, it is an indispensable condition to treat the surface to be neutral (pH 7 ~ 8).

The Bio Oss is the only product with low temperature heat treatment technology and pH adjustment technology, and it has the technology of micro world which has not let anyone see it for more than 20 years. However, it has not been disclosed how the Bio Oss was neutralized by any method.

The present inventor has determined that a pH adjustment technique is necessary to obtain the advantage of the low temperature treatment. After a long period of experiment, the powdered bone meal is mixed with sodium phosphate monoanhydrate and sodium phosphatidianhydrate, sodium phosphate di anhydrate were added to the mixture, and the resultant mixture was stirred to produce a bone meal having neutral pH of 7.5.

The figure above shows the photograph of the bone graft material of the present invention. The right side shows a 10,000-fold magnification image before the pH adjustment and the right side shows a treatment technique of pH 7.5 as shown in Bio Oss, Show the completion of. However, the bone graft material of the present invention can identify the petiole structure not found in the Bio Oss, indicating that Octacalcium phosphate is attached to the surface. The octacalcium phosphate formed during the pH neutralization process appears to be partially formed by the reaction of calcium present on the surface of the bone meal and sodium phosphate used as a neutralizing agent in the low-speed drying process. Although octacalcium phosphate is known to promote new bone formation, there is no known technology for attaching such a bone graft promoter to a bone graft material.

4. Octacalcium phosphate application process

The application of octacalcium phosphate is a very important future technology for osteogenesis, and it is evaluated as a precursor of calcium phosphate that can dramatically shorten bone formation time.

The present invention is based on the finding that Octacalcium phosphate is attached to the bone graft in the pH adjusting step and furthermore it is considered to be more effective if a thick Octacalcium phosphate layer is formed on the bone graft material and a thick octacalcium phosphate layer is formed on the bone graft material To develop technology for

The present inventors have found that when calcium acetate and sodium phosphate di anhydrate are dissolved (dispersed) in water, calcium acetate and sodium Aqueous solution of phosphate "was produced.

Thus, the inventors of the present invention found that, after putting the bone meal into the aqueous solution of calcium acetate and sodium phosphate, stirring the mixture for 15 minutes to reduce the fine air on the surface to improve the contact efficiency,

A mixture of an aqueous solution of gastric calcium acetate and sodium phosphate and stomach bone fragments was mixed and spread on a tray to a thickness of 10 mm. The bone fragments were spread so as to be immersed in an aqueous solution of calcium acetate and sodium phosphate. As described above, the bone grafts were mixed with calcium acetate and sodium phosphate , And dried at a low speed for 2 to 3 hours with hot air at 80 DEG C to obtain the bone graft material of the present invention. In drying the bone fragments by hot air, it is possible to cause the fragments of the bone fragments to come into contact with the bone fractions evenly and to shorten the drying time.

In washing the bone meal, the bone meal is mixed with an aqueous solution of calcium acetate and sodium phosphate obtained by dissolving (dispersing) calcium acetate and sodium phosphate dianhydrate in water at 60 ° C and stirring desirable.

The above photograph (a) shows an enlarged image of the omentum of the bone graft material of the present invention, which shows that octacalcium phosphate is formed on the surface in a petal shape.

The present inventors used a trephine bur in the head of a rat to remove the skull in the same size circle, and then the bone graft material (Tioss) of the present invention and the Bio Oss were respectively transplanted and biopsy was performed 8 weeks later.

In the above two figures, the left side is a state in which the bone graft material (Ti oss) of the present invention is applied, and the right side is a state in which Bio oss is applied.

In the above picture, the blue part is the newly formed cancellous bone and the red part is the newly formed cortical bone.

The left circular shape shows almost the formation of the metaplasia in the bone graft material, but the right side shows a lot of new bone around the Bio oss, but the formation of the bone graft material is 30-40% less than that of the bone graft material of the present invention.

5. A preferred embodiment of the present invention as described above will be described below.

 Example:

The present inventors have found that,

A heating treatment step of heating the molten bone from which fat and protein have been removed at a temperature of 600 DEG C for 2 hours and 30 minutes to remove fine proteins contained in the molten metal,

A bean bone forming step of pulverizing the heat treated bean bone to a size of 0.2 to 1.7 mm in diameter to form macroporosity bone fragments,

 The bone meal was neutralized by adding 14.2 g of sodium phosphate monoanhydrate to 12 g of sodium phosphate monoanhydrate and 3000 g of purified water and stirring for 60 minutes,

00g of the neutralized bone fractions were added to 10.57g of calcium acetate, 7.2g of sodium phosphate mono anhydrate and 3000g of purified water, and the mixture was stirred for 15 minutes to remove impurities present on the surface of the bone meal And a neutralized osseous cleaning process for removing air,

The washed bone fragments were mixed in the above-mentioned "aqueous solution of calcium acetate and sodium phosphate" obtained by mixing calcium acetate, sodium phosphate di anhydrate and purified water at 60 degrees Celsius, Acetate and sodium phosphate solution "at a thickness of 10 mm to the extent that the bone fractions are submerged, followed by drying for 3 hours with hot air at 80 [deg.] C to prepare a bone graft material of the present invention.

6. Process of bone-inducing substance treatment on dental implant material

The present inventors have found that,

The dental implant material was placed in the calcium acetate and sodium phosphate di anhydrate and the aqueous solution of calcium acetate and sodium phosphate as the purified water and stirred for 15 minutes to be present on the surface of the molding material The process of removing the foreign substances and the air, and

The filling material washed in the washing step was placed in the above-mentioned "aqueous solution of calcium acetate and sodium phosphate" at 60 DEG C, and the above-mentioned filling material put in the "aqueous solution of calcium acetate and sodium phosphate" was placed in a tray, The dental implant material was prepared by a coating process in which the material was spread to a thickness of 10 mm so that the material was immersed in the aqueous solution, and then dried for 2 hours and 30 minutes with hot air of 80 degrees Celsius.

In washing the dental implant material, the washing liquid is preferably an aqueous solution of calcium acetate and sodium phosphate, which is made up of calcium acetate, sodium phosphate di anhydrate and purified water. Thus, in the process of washing, the effect of "adhering calcium acetate and sodium phosphate aqueous solution" to the filling material can be obtained.

Octa calcium phosphate, which is a bone formation inducing substance adhering to the surface of the food material, can reduce the healing period by half, and contributes greatly to the reduction of failure due to bone formation

Claims (4)

A method for producing a bone graft material, which comprises preparing bone graft by applying octacalcium phosphate coating step
The process of claim 1, wherein the octacalcium phosphate application step
A bone meal washing step of washing the bone meal by adding the bone meal to calcium acetate and sodium phosphate mono anhydrate and an aqueous solution of calcium acetate and sodium phosphate which is purified water,
Mixing the washed bone fragments with the above-mentioned "aqueous solution of calcium acetate and sodium phosphate ", mixing the bone fractions so that the bone fractions are submerged in the" aqueous solution of calcium acetate and sodium phosphate " A method for producing a graft material.
The method of claim 1 or 2, wherein the bone fragments are bone fragments of animal bone, and the bone fragments are obtained by heating the animal bone from which fat and protein have been removed at a temperature of 400 to 800 DEG C for 2 to 3 hours, A heat treatment process for removing proteins, and a bone particle formation process in which heat-treated animal bones are ground to a size of 0.2 to 1.7 mm to form macroporosity bone fragments. Further, the bone fragments are prepared by sodium phosphate monoanal Wherein the neutralization step is performed by adding neutralizing water mixed with sodium phosphate monoanhydrate, sodium phosphate monoanhydrate, and purified water, and stirring the mixture.
3. The method according to claim 1 or 2, wherein the bone fragments are implant materials for dental implants.