KR100519199B1 - A process of preparing for delayed absorbable bone fixation device - Google Patents

Abstract

The present invention relates to a method for producing an absorption delayed fracture fixation for use in the treatment of fractures in humans and animals, comprising: [i] removing soft tissue from fresh dense bone, and [ii] forming dense bone using electrolyte coolant. Step, [iii] immersing the dense bone in a mixed solution of chloroform and methanol for 5 days to 10 days, [iii] lyophilizing the immersed dense bone and [iii] sterilizing the lyophilized molded dense bone with ethylene oxide gas It consists of the steps of packaging. Absorption delayed fracture fixation prepared by the present invention is excellent in the fixation force until the union is absorbed and decomposed slowly in the human body or animal body and at the same time can be eliminated reoperation to remove the fracture fixation after cure, osteogenic proteins ( BMP) is also excellent in inducing and promoting the formation of new bone.

Description

A process of preparing for delayed absorbable bone fixation device

The present invention relates to a method for producing a fracture fixation for use in fixing broken bones in vivo in the treatment of fractures in humans and animals.

More specifically, the present invention induces the formation of new bones so that the union of fractures is accelerated using dense bones collected from animals, and is gradually absorbed and decomposed in vivo (hereinafter referred to as "absorption delay"). The present invention relates to a method for preparing a fracture fixation which does not need to remove the fixation after the fracture is treated while fixing the broken bone firmly until it is completely coalesced.

Fracture fixtures are broadly classified into external fracture fixtures installed outside the living body and internal fracture fixtures inserted and installed inside the living body, and the present invention relates to the internal fracture fixtures among them.

The method of internal fixation of fractures is known to be the most robust and reliable method as defined by Arbeitsgemeinschaft fur Osteosynthesefragen / Association for the Study of Internal Fixation (AO / ASIF).

Until now, internal fractured bones (hereinafter abbreviated as "fracture fixtures") made of metallic titanium or stainless steel have been the most widely used. Fracture fixtures may be manufactured in various forms such as plates, pins, screws, and the like.

However, since the metallic fracture fixation is present as a foreign body after the fracture is treated, there is a problem that requires a reoperation to remove it. During reoperation, the patient suffered a lot of pain, suffered the cost of surgery and the risk of reoperation. In addition, the fixture does not have a function of inducing the formation of new bones so that the fusion of fractures within the raw material proceeds quickly.

In order to solve the above problems, fracture fixtures made of biodegradable polymers such as polyglycolic acid, polygelatin, polydioxanone, polylactide and the like are also used.

However, the fracture fixture is decomposed in vivo and reoperation for removal thereof can be omitted, but the strength of the fracture fixture is difficult to use in treating fractures of long bones (long bones) such as arms or legs, and the union of fractures in live vegetables is difficult. There was also a problem that there is no function to induce the formation of new bone to proceed quickly.

Fracture fixtures of the biodegradable polymers are weak in strength and are mainly used only for fracture treatments or sutures such as facial bones, jaw bones, finger bones, toe bones, and the like.

On the other hand, U.S. Patent No. 5,968,047 proposes a fracture fixation made of human or animal dense bone (Cortical Bone).

However, the U.S. Patent only refers to the term Biological Activity Material, which collectively represents all the biological components in bone, and refers to bone morphogenic proteins that promote the formation of new bone. Although not specifically stated, no treatment method for preserving the osteogenic protein (BMP) without damaging and a method for suppressing or removing an immunorejective substance component have not been described.

In addition, the fracture fixation of the dense bone insists on the shape of the bone plate, screws and pins as a fracture fixture without mention of absorption or absorption process, and in particular in terms of functional superiority in the form of a screw formed of dense bone. Doing.

According to the literature, when dense bone is implanted in vivo, even if there are few immunorejection reactants in the dense bone, it is known that an inflammatory reaction occurs as a heterologous protein or foreign substance and absorption of the graft bone is caused by the action of macrophages and osteoclasts.

On the other hand, if all organic substances, proteins, and immunorejection reaction substances, except osteoarthritis, are removed from the dense bone, they remain intact and remain as foreign bodies, so they can be reoperated or permanently removed to remove them just like iron fixtures after fracture treatment. I can only do it.

In addition, the literature related to the bone plate has been reported the application of delayed fixation using dense bone, but these materials are absorbed or vulnerable early, so there is no fixed and supportive force, so they do not require large fixation force and have low momentum of jaw, facial bone or finger bone. There is a drawback that is used only limited to the fixing of the toe bone.

An object of the present invention is to solve the conventional problems described above can be securely fixed to the fracture site until the fracture is completely fused in vivo, and after the fracture is completely biodegradable to eliminate the reoperation It is to provide a method for producing an absorption delayed fracture fixation that can be.

It is also an object of the present invention to provide an absorption delaying fracture fixation having a function of inducing and promoting the formation of new bone so as to accelerate the union of the bone containing osteogenic proteins (hereinafter referred to as "BMP") of human or animal It is to provide a method for manufacturing using dense bone.

The present invention, using the dense bone collected from the animal [ⅰ] fixed bones and supportive strength of the broken bones, [ii] there is no foreign body action on the living body and biodegradation after fracture treatment, there is no need for reoperation to remove the fixation, [ Ⅲ] It is intended to provide a method for producing a delayed-release fracture fixture containing BMP that can induce and promote new bone formation. To this end, the present invention is to provide a method for treating the fracture fixture of the dense bone to delay absorption in vivo, a method for suppressing the immune rejection reaction, and a method for treating the fracture fixture in order not to damage the BMP.

Method for producing an absorption delayed fracture fixation of the present invention for achieving such a problem,

[Iii] manually or mechanically removing the soft tissues having an immune rejection mechanism from the dense bone obtained from animals within 24 hours after death;

[Ii] shaping the dense bone using electrolyte cooling water,

[Iii] inhibiting and degreasing immune rejection by immersing the compacted bone in a mixture of chloroform and methanol for at least 5 days;

[8] lyophilizing the degreased dense bone at a temperature of -40 ° C. or lower so that the moisture content is 5% or less; and

[8] The lyophilized molded dense bone is characterized in that it comprises a step of packaging after sterilization with ethylene oxide gas.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

First, soft tissues having an immune rejection mechanism are removed by manual or mechanical methods from dense bones (Cortical Bone) collected from animals within 24 hours after death.

In this case, the dense bone may be used immediately after being collected from animals within 24 hours after death, or may be used after being refrigerated or frozen after collection. Soft tissue of dense bone is muscle, periosteum, blood or spongy bone attached to the dense bone.

The reason for harvesting fresh dense bone from animals within 24 hours is to avoid damaging the BMP in the dense bone.

In addition, the reason why the soft tissue is removed from the dense bone is to remove the immune rejection substance in the fracture fixator to the maximum so that the dense bone is not absorbed and degraded too quickly (that is, delayed absorption) in vivo.

BMP is a bone morphogenic protein contained in dense bone and has the function of inducing new bone formation. BMP has recently been commercialized in 1965, when Urist first discovered BMP from the dead bones of dead bovine bone and transplanted it into rabbit muscle to form new bone. Such BMP is mainly obtained by adding BMP to the bone graft to form new bone, thereby obtaining a graft effect.

Next, the dense bone from which the soft tissue has been removed is cut and molded while using electrolyte cooling water to prepare a fracture fixture.

Fracture fixtures produced by the method of the present invention include all of the form (plate), pin (pin) or screw (Screw).

In the present invention, the reason for using the electrolyte coolant during cutting and molding is to prevent the damage and denaturation of the BMP by heat generated during cutting and molding the dense bone. It is more preferable to manage so that the heat generated during cutting and shaping of the dense bone does not exceed 70 ° C.

As electrolyte coolant, it is more preferable to use lactic ringer liquid cooling water or Hartmann liquid cooling water composed of an electrolyte component similar to a living body. Lactic acid added electrolyte coolants are more effective in improving local acidosis due to foreign body inflammation.

Next, the compacted dense bone is immersed in a mixed solution of chloroform and methanol for 5 days or longer to suppress the immune rejection reaction.

The present invention by immersing the dense bone in the mixed solution for 5 days to 10 days to extract the fat in the dense bone and inhibit the rejection of the immune rejection reaction substances remaining in the dense bone to the maximum fixation of the fracture fixation in vivo.

In addition, the present invention is characterized by using a mixture of chloroform and methanol so as not to damage the BMP in the dense bone. At this time, chloroform and methanol may be mixed in a ratio of 1: 1.

In order to more effectively remove the immune rejection substance in the immersion process, it is more preferable to install and use a suction device and / or an ultrasonic cleaner in the immersion tank. The ultrasonic cleaner has a function of generating hundreds of thousands of bubbles per second by a negative pressure phenomenon and a vibration effect to separate and remove foreign substances attached to a substrate and to destroy cells.

Therefore, in the dipping process, it is more effective to separate the immune rejection material in the fine pores of the dense bone with an ultrasonic cleaner and then extract it with a suction device.

Osteoblasts and blood cells are not observed in a circular or oval Habersian cannal in FIG. 13 sonicated in the immersion process, but osteoblasts and blood cells are observed in FIG. 12 without ultrasonication.

Next, the freeze-dried fracture fixture (dense bone), which was immersed in a mixed solution of chloroform and methanol, was lyophilized to a moisture content of 0 to 5% at a temperature of -40 ° C or lower, and then sterilized and packaged with ethylene oxide gas. To produce a final fracture fixture.

The reason for the rapid freeze treatment at a temperature below -40 ° C is to suppress the damage of residual BMP and to pre-cool the freeze-drying treatment, and the reason for the freeze-drying treatment so that the water content is 0-5% To stop the metabolism of all organic substances to prevent damage and degeneration of BMP in the dense bone and to promote the absorption of ethylene oxide gas. In addition, ethylene oxide gas that does not affect BMP is used in sterilization treatment to prevent invasion and contamination of microorganisms.

Alternatively, the dense bone treated with chloroform and methanol may be rapidly frozen and stored at a temperature below -20 ° C. For quick freezing, it is most effective to use liquid nitrogen at -196 ° C.

To further improve the absorption delay effect of the fracture fixation, the absorbent material or the biodegradable polymer may be applied to the whole surface of the dense bone after the immersion and degreasing treatment and the lyophilization treatment or the surface of the dense bone where the dense bone and the host bone are not adhered to each other. It is more preferable to coat selectively. The reason why the biodegradable polymer is coated on the entire surface of the dense bone is to allow the fixation to begin absorption after the fracture is completely self-healing.

The reason why the absorbent material or biodegradable polymer is coated on the surface where the dense bone and the host bone are not adhered to each other is because at the contact surface of the dense bone and the fractured bone, it stimulates the formation of new bone on the fracture surface and promotes the healing of the fracture. This is because absorption and decomposition reactions do not occur in vivo.

Collagen may be used as the absorption delaying material, and the biodegradable polymer may include polyglycolic acid, polygelatin, polydioxanone, polylactide, or the like. Can be used.

When inserting and using fracture-fixing material of dense bone coated with absorption delaying material or biodegradable polymer in vivo, coated absorption delaying material is hydrolyzed by macrophages and biodegradable polymer is completely absorbed in vivo first. Decomposition and absorption of dense bone occurs, so the delaying effect of fracture fixation can be maximized. By controlling the coating thickness of the absorbent material or biodegradable polymer, the absorption period of the dense bone can be effectively managed.

As described above, in order to suppress immune rejection and delay absorption of dense bone, the present invention removes the soft tissue of dense bone by a mechanical method or the like, and [ii] is immunized by immersion in a mixture of chloroform and methanol for a long time. To suppress (degrease) the rejection reaction, [iv] selectively install and use a suction device or an ultrasonic cleaner during the immersion, [v] lyophilize dense bone to -40 ° C or lower, and [v] selectively It is characterized in that the dense bone is coated with an absorbing delay material or a biodegradable polymer.

In addition, the present invention is to collect and use fresh bone dense to induce the formation of new bone, [ii] using a solution that does not affect the BMP when removing the immune rejection material from the dense bone, Use electrolyte coolant to suppress heat generation. [Iii] Freeze-drying treatment to bring moisture content below 5%, [iii] sterilization with ethylene oxide gas which does not affect BMP, and [iii] dense bone optionally treated with chloroform and methanol below -20 ℃ It is characterized by cryopreservation by rapid freezing at the temperature of.

Fracture fixture prepared by the present invention can be shortened the fracture treatment time by inducing, promoting the formation of new bone is contained BMP as it is. In addition, it is gradually absorbed and decomposed (absorption delay) in vivo, eliminating the need for reoperation to remove the fixture, and firmly fixing the broken bone until the fracture is completely coalesced.

In order to further enhance the strength of the fracture fixation produced by the present invention, it is more preferable to supplement the moisture content by immersing the sterilized, packaged product in the electrolyte solution before use in fixing the fracture.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples. However, the present invention is not limited only to the following examples.

Example 1

The soft tissue was manually removed from the dense bone collected from the dog after 20 hours after death, and then formed into a plate using electrolyte coolant, which was immersed in a mixed solution of chloroform and methanol (1: 1) for 5 days, and then Freeze-drying treatment was carried out so that the moisture content is 5% at -90 ° C, sterilized with ethylene oxide gas, and then packaged to prepare a fracture fixture of dense bone. The fracture fixation was performed to fix the ulnar intervertebral portion of the dog's ulnar bone, which caused a transverse fracture with a gap of 3 mm. The radiographs immediately after the operation were as shown in FIG. 1, the radiographs after 8 weeks after the operation were as shown in FIG. 2, and the radiographs after 22 weeks after the operation were as shown in FIG. 3. As shown in FIG. 2, after 8 weeks after the operation, new bone formation was induced from the bone fragment side of the defect, and the defect began to be filled, and the defect was being filled. About half of the thickness of the bone was absorbed in vivo. . In addition, as shown in FIG. 3, after 22 weeks after the operation, the defects were completely filled and coalesced, and about 3/4 of the bone plates were absorbed in the part not contacted with the host bone in vivo.

Example 2

The soft tissue was manually removed from the dense bone collected from the dog after 20 hours, and then formed into a plate using electrolyte cooling water, and then the formed product was immersed in a mixed solution of chloroform and methanol (1: 1) for 6 days. It was. At this time, the suction device and the ultrasonic cleaning device were installed in the immersion tank to perform the suction treatment and the ultrasonic treatment simultaneously with the immersion. Subsequently, the immersed molded product was lyophilized to have a water content of 4% at -80 ° C, sterilized with ethylene oxide gas, and packaged to prepare a fracture fixation of dense bone. Using the fracture fixator, surgery was performed to fix the intervertebral fracture of the dog's ulnar bone, which caused a transverse fracture with a defect interval of 4 mm. The radiographs immediately after the operation were as shown in FIG. 4, the radiographs after 12 weeks after the operation were as shown in FIG. 5, and the radiographs after 22 weeks after the operation were as shown in FIG. 6. As shown in FIG. 5, after 12 weeks after the operation, new bone formation was induced from the bone fragment side of the defect and the defect began to fill, and the defect was almost fused, and the thickness of the bone was gradually absorbed in vivo. Also, as shown in FIG. 6, after 22 weeks after surgery, the defects were slowly filled and coalesced, and almost all of the bone plates were absorbed in vivo.

Example 3

Twenty hours later, the soft tissue was manually removed from the dense bone collected from the dog, and then formed into a plate using electrolyte cooling water, which was immersed in a mixed solution of chloroform and methanol (1: 1) for 5 days. The freeze-drying treatment was then performed at -90 ° C. to 5% water content, and the polyglycolic acid (biodegradable polymer) was coated with a thickness of 1 mm on the surface where the dense bone and the host bone were not adhered to each other. Next, sterilized by ethylene oxide gas and then packaged to prepare a fracture fixation of dense bone. The fracture fixation was performed to fix the ulnar intervertebral portion of the dog's ulnar bone, which caused a transverse fracture with a gap of 3 mm. The radiographs immediately after the operation were as shown in FIG. 7, the radiographs after 6 weeks after the operation were as shown in FIG. 8, and the radiographs after 22 weeks after the operation were as shown in FIG. 9. As shown in FIG. 8, after 6 weeks after the operation, new bone formation was induced from the bone fragment side of the defect and the defect was filled, and the thickness of the bone plate was maintained as it is. In addition, as shown in FIG. 9, 22 weeks after the operation, the defect was completely filled and coalesced, and the outside of the dense bone plate began to be absorbed.

Comparative Example 1

Using a plate- and screw-type conventional fracture fixator made of titanium, surgery was performed to fix the intervertebral fracture of the dog's ulnar bone, which caused a transverse fracture with a gap of 2 mm. The radiograph immediately after the operation was as shown in FIG. 10, and the radiograph after 22 weeks after the operation was as shown in FIG. 11. As shown in FIG. 11, even after 22 weeks after surgery, no new bones were formed in the defects, no defects were coalesced at all, and the bone plates were not absorbed at all in vivo.

The fracture fixation produced by the method of the present invention can induce new bone formation and shorten the treatment period. Also, since it is absorbed and degraded slowly in vivo, it can fix the fracture area firmly until the fracture is completely fused, so it is also useful for treating long bones such as arms and legs. Costs and patient pain can also be reduced.

1 is a radiograph immediately after surgery as in Example 1

Figure 2 is a radiograph after 8 weeks after surgery as in Example 1

3 is a radiograph after 22 weeks after surgery as in Example 1

4 is a radiograph immediately after surgery as in Example 2

5 is a radiograph after 12 weeks after surgery as in Example 2

6 is a radiograph after 22 weeks after surgery as in Example 2

7 is a radiograph immediately after surgery as in Example 3

8 is a radiograph after 6 weeks after surgery as in Example 3

9 is a radiograph after 22 weeks after surgery as in Example 3

10 is a radiograph immediately after surgery using a titanium bone plate and a screw as in Comparative Example 1

11 is a radiograph after 22 weeks after the operation as in Comparative Example 1

12 is a photograph of the dense bone not sonicated in the dipping step

Figure 13 is a photograph of the dense bone sonicated during the dipping step

Claims (13)

[Iii] manually or mechanically removing the soft tissues having an immune rejection mechanism from the dense bone obtained from animals within 24 hours after death; [Ii] shaping the dense bone using electrolyte cooling water, [8] inhibiting and degreasing immune rejection by immersing the compacted bone in a mixed solution of chloroform and methanol for 5 days to 10 days; [9] a step of lyophilizing the degreased dense bone at a temperature of -40 ° C to -200 ° C such that the moisture content is 0 to 5%; [8] A method for producing an absorbent delayed fracture fixation product comprising the step of packaging the lyophilized molded dense bone with ethylene oxide gas and then packaging. The method of claim 1, wherein the dense bone is collected from an animal within 24 hours after death and refrigerated or frozen. The method of claim 1, wherein the soft tissue is muscle, periosteum, blood vessels or sponges attached to the dense bone. The method according to claim 1, wherein the mixed solution of chloroform and methanol is a 1: 1 mixture of chloroform and methanol. The method of claim 1, wherein the dense bone is suctioned, sonicated, or simultaneously treated with suction and sonication when the dense bone is immersed in a mixture of chloroform and methanol. The method of claim 1, wherein collagen or polyglycolic acid, polygelatin, polydioxanone, and polylactide in dense bone immersed in a mixture of chloroform and methanol and lyophilized Polylactide) method for producing an absorption delayed fracture fixation, characterized in that the coating of one polymer selected from the group consisting of. The method of claim 6, wherein one polymer selected from the group consisting of collagen or polyglycolic acid, polygelatin, polydioxanone and polylactide is selected from the group consisting of dense bone and A method for producing a delayed-absorption fracture fixable, characterized in that the host bone is coated on a surface that is not bonded to each other. delete delete The method of claim 1, wherein the fracture fixative is used after being immersed in an electrolyte solution. The method of claim 1, wherein the fracture fixation is in the form of a plate, a pin or a screw. The method of claim 1, wherein the electrolyte cooling water is lactic ringer liquid cooling water or Hartman liquid cooling water. delete