KR102106312B1 - Bone alternative synthetic bone having paste form, and method for producing the same - Google Patents

Abstract

The present invention relates to a new method for manufacturing a composite material for a bone substitute, more specifically, to form a porosity while effectively controlling the polymerization rate through a two-paste system through a mixing process of the first paste and the second paste, while forming a porosity. It is a technology related to a method for manufacturing a synthetic bone for bone substitute having an antibacterial effect against various strains while increasing strength and promoting blood circulation.
The composite material produced according to the present invention can maximize the advantages of organic and inorganic materials. Specifically, cyanoacrylate maintains shape and has adhesion, and calcium phosphate has bone conduction to new bone ( osteo-conductivity), sodium chloride promotes the rate of new bone replacement through the formation of pores and increased influx of body fluids, and sorbitol makes the powder-like material into a paste form, mixing organic and inorganic materials. Facilitate. In addition, tetracycline is a broad-spectrum antibiotic, and is a technology that can be applied to have antibacterial properties against various bacteria.
Therefore, the composite material for bone substitute according to the present invention is expected to be useful as a bone substitute for filling bone defects.

Description

Bone alternative synthetic bone having paste form, and method for producing the same}

The present invention relates to a new method for manufacturing a composite material for bone replacement, and more specifically, a first paste containing osteoconductive inorganic materials as an inorganic material and cyanoacrylate as an organic material. This is a technique for manufacturing a composite material for bone substitute using a 2-paste system for mixing a second paste.

When the technical idea of the present application is applied, it provides an effect of increasing the strength of synthetic bone for bone replacement and promoting blood circulation smoothly through mixing of the first paste and the second paste.

In addition to the mechanical functions of supporting and supporting the human body, bones act as a reservoir of calcium while regulating the concentration of calcium ions in the body, and have important physiological functions to produce red blood cells and white blood cells necessary for the human body from bone marrow.

Bone can be damaged due to aging and other physiological reasons or damaged by various accidents.The transplantation of damaged bones involves the transplantation of the patient's own tissues (autologous bone grafts), bones of others (allogeneic bones) or animals (heterologous bones) And transplantation.

However, by implanting the tissue of another person, an immunological rejection reaction occurs, or when there is insufficient material available in the patient's body due to a large damage site, an artificial bone graft material (bone substitute material) is used.

The bone substitute should be highly compatible with living tissue, the amount of use should not be limited, the form should be easy to be given, the given form should not be changed for a long time, and it should be replaced by living tissue or there should be no obstacle to tissue growth. There is no material yet to satisfy the requirements of.

As research into synthetic bones (alloplastic bones, synthetic bones) is underway, research is underway covering all material fields, such as metals, organics, and ceramics. Brown is an absorbent porous hydroxy-apatite (hydroxy-) among inorganic materials. apatite (hereinafter referred to as HA), and Wolfe announced that beta-tricalcium phosphate (β-TCP) is slowly decomposed and replaced with new bone because it has a structure similar to that of natural bone, Chow, etc. Reported on the bone conduction of β-TCP. In addition, Posset et al. Reported tetracalcium phosphate, and Frankenburg et al. Reported studies on calcium phosphate cement.

However, the techniques presented so far still have limitations in various areas, and currently used synthetic bones are mostly calcium sulfate-based and calcium phosphate-based, and calcium phosphate is similar to natural bone composition and Due to its excellent osteoconductivity, it has received considerable attention as a bone substitute.

In addition, some studies have been made in the form of bone cement in which various inorganic materials are mixed, rather than solely of inorganic materials. This is a material having a viscosity rather than a powder form, which prevents initial fluidity and prevents some form. It is considered to be a good idea in terms of retention, but it is difficult to expect satisfactory results due to the problem that most of these materials are supplied as powders, or when giving shape, the strength is weak and the shape is difficult to maintain for a long time.

Since these bio-ceramic materials for bone regeneration are bone-inducing materials, not bone-inducing materials, it is desirable to use a porous body having a suitable size of connected pores that allow bone tissue to grow and enter into the material. It is a property that requires physical properties to have a similar biodegradation rate.

Cyanoacrylate is a liquid material that is frequently used as an instant adhesive, and is a decomposable polymer that undergoes polymerization through rapid ion reactions by weakly basic substances such as water or amide groups and cures even in the presence of moisture. , Its application has been expanded to medical adhesives, and soft tissue adhesives based on Cyanoacrylate are various, such as Histoacryl (n-butyl-2-cyanoacrylate), Dermabond (octyl-cyanoacrylate), Traumaseal, GluStitch, etc. As it has been approved by the FDA and its use is gradually increasing, butyl-, octyl cyanoacrylate, which has a slow biodegradation rate, is currently used for medical purposes.

The advantage of Cyanoacrylate is that it is polymerized under room temperature conditions, and polymerization is performed without applying heat, catalyst, or pressure. Polymerization is possible even in moist conditions. In the past, however, when Cyanoacrylate is in contact with general inorganic materials, polymerization is instantaneous. There has been a problem that the curing reaction cannot be controlled, and the polymerization reaction occurs rapidly due to the surface properties of the inorganic material, which is a weak base.

In addition, since the viscosity of pure cyanoacrylate is very low, a polymer is added to solve the problem of adhesion with intimate tissue such as bone, but this reduces the physical properties such as adhesion, and in the case of pure cyanoacrylate, the cell may be destroyed by high reaction heat. Also had problems that cannot be excluded.

Therefore, the study of composite materials in which cyanoacrylate and inorganic materials are mixed is known as a situation without any exception except the present inventors due to the difficulty of mixing. Filed in Korea, registered as a registered patent No. 10-0650453, registered as a patent overseas (USA), and the technology for producing paste-like composite materials is also registered as a domestic registered patent No. 10-1019741. This is a technology for controlling the polymerization rate of Cyanoacrylate in a water environment by preparing a porous material of.

The present inventors have tried to overcome the problems of the prior art and problems newly emerging in the process of carrying out their own patented technology, and as a result, a first paste containing cyanoacrylate and a bone conducting inorganic material (osteoconductive inorganic materials) It is possible to effectively control the polymerization rate of cyanoacrylate in a moisture environment by using a 2-paste system that mixes a second paste containing), as well as a composite for a paste-like bone substitute having porosity. It has been confirmed that the material can be produced and this has led to the completion of the invention.

The present inventors have attempted to synthesize a new bone replacement inorganic material with high strength and new bone conduction ability while maintaining bioactive properties through a two-paste system to overcome the problems of low strength and low new bone displacement, which are problems of the prior art. It is an invention started with a problem.

The object of the present invention is a process of mixing the first paste and the second paste to effectively control the polymerization rate through a two-paste system while forming porosity while increasing the strength of synthetic bones for bone substitutes and promoting blood circulation to various strains. It is to provide a synthetic bone for bone substitute having antimicrobial action and a method for manufacturing the same.

As a means for solving the above problems, the inventors of the present invention can effectively control the polymerization rate when preparing a composite material for bone substitutes using a 2-paste system, as well as for bone substitutes in a paste form having porosity. Density of material using materials such as β-Tricalcium Phosphate, Cyanoacrylate, Sodium chloride, Calcium sulfate hemihydrate to synthesize composite materials It is a completed invention by confirming that it is possible to obtain an inorganic material for high-strength bone replacement in the form of a paste that increases strength and induces phase equilibrium to increase the ability to conduct new bone.

In addition, in order to overcome the problem of Cyanoacrylate, which is hardly cured in a moisture environment, a composite material capable of controlling the polymerization rate can be prepared using Monocalcium phosphate, and also tetracycline-based antibiotics are used. It is a completed invention by confirming that it is possible to obtain synthetic bones for bone substitutes having antibacterial action against various strains.

The present technology may be composed of an invention related to a method for manufacturing a composite material for bone substitute including the following steps.

A) 40 ± 10 parts by weight of β-tricalcium phosphate (β-TCP), which is an osteoconductive inorganic material, and 40 ± 10 parts by weight of liquid biocompatible material provided as polysaccharides or monosaccharides, and calcium sulfate hemihydrate 20 A first step process in which ± 5 parts by weight is mixed to obtain 100 parts by weight of the first paste,

B) 40 ± 10 parts by weight of liquid cyanoacrylate and 30 ± 10 parts by weight of monocalcium phosphate, 20 ± 5 parts by weight of sodium chloride, and 10 ± 5 parts by weight of barium sulfate as a solid filler in a moisture environment. A second step of obtaining 100 parts by weight of the second paste for promoting the polymerization reaction of the

C) The first paste and the second paste are mixed at a weight ratio of 50 ± 10: 50 ± 10, and a third step of obtaining a composite material for bone substitute is disclosed. do.

It is possible to secure the antimicrobial properties of the paste by using a wide range of antibiotics in the first step process of the present application, for example, a tetracycline (Tetracycline) -based antibiotic is added at a rate of 1 ± 0.5 parts by weight. It also includes technical ideas to secure antibacterial properties.

In addition, the bone conduction inorganic materials used in the first step (osteoconductive inorganic materials) in addition to β-tricalcium phosphate (β-TCP), hydroxyapatite (HA), β-tricalcium phosphate and BCP plus hydroxyapatite, heterogeneous Bone, allogeneic bone, autologous bone can be applied by being replaced with a bone material selected, and the first and second pastes may be used with contrast agents that exhibit impermeability, for example, zirconium oxide (Zrconium) as a material that exhibits impermeability. oxide), bismuth oxide (Bismuth Oxide), a molding material selected from 1 ± 0.5 parts by weight may be added and used.

Synthetic bones for bone substitutes produced by the method for preparing a composite material for bone substitutes of the present application are provided as synthetic bones for bone substitutes having characteristics of fast, new bone conduction ability and securing high strength while maintaining bioactive properties.

According to the present invention, by using a two-paste system (2-paste system), as well as effectively controlling the polymerization rate when the cyanoacrylate and the inorganic material are mixed, it is possible to manufacture a composite material for bone substitute having porosity. It provides an effect.

In addition, the composite material manufactured according to the present invention can maximize the advantages of organic and inorganic materials, and cyanoacrylate maintains shape and has adhesion, and calcium phosphate is bone conductive to new bone. (osteo-conductivity) and sodium chloride can accelerate the rate of new bone replacement by increasing the pore formation of the material and the influx of body fluids, and sorbitol makes the mixing of organic and inorganic materials into a paste in powder form. Provides a facilitating effect.

According to the present invention, the synthetic bone for high-strength bone replacement has an increased ease of material shaping and high compressive strength prior to the procedure during implantation of a bone substitute material for filling bone defects in paste form. While maintaining the original condition, it is widely used as an excellent material to replace the existing synthetic bone for bone replacement as the blood circulation in the pore is improved by inducing a phase equilibrium reaction by changing the concentration of body fluid in the pore of the inorganic material due to the dissolution of NaCl. Is expected.

In addition, in order to achieve successful replacement of new bone, tetracycline (Tetracycline) -based antibiotics having antimicrobial activity against various strains are developed to develop new synthetic bones for antimicrobial activity to have antimicrobial activity against various types of inflammation. It provides an effect.

1: Compressive strength of synthetic bone for bone replacement using a 2-paste system
Figure 2: When the compressive strength of a block-type material is measured using a universal tester, the appearance of the specimen
Figure 3: Compressive strength of materials by week after SBF solution immersion test
Figure 4: USB microscope surface observation before and after solubility test

Hereinafter, embodiments in which the technical idea of the present invention is specifically implemented will be described in more detail through the following examples, but these examples are merely examples for illustrating the practical applicability of the present invention, and thus the rights of the present invention. It will be understood that the scope is not to be construed as being limited by these examples.

In order to reveal the origin of various used raw materials used in the examples of the present application, manufacturers and raw material names of raw materials used are identified as follows.

-2-octyl cyanoacrylate (2-OCA): Glustitch INC. (CAS NO .: 133978-15-1)

-Beta-Tricalcium Phosphate: HIMED (CAS NO .: 7758-87-4)

-Monocalcium phosphte: Samjeon Chemical (CAS NO .: 7758-23-8)

-Sodium chloride: Acros Oranics (CAS NO .: 7647-14-5)

Calcium Sulfate Hemihydrate: Acros Organics (CAS NO .: 10034-76-1)

Sorbitol F Solution: Sigma Aldrich (CAS NO .: 50-70-4)

Tetracycline hydrochloride: Sigma Aldrich (CAS NO .: 64-75-5)

Barium Sulfate: Sigma Aldrich (CAS NO .: 7727-43-7)

The best embodiment of the best mode for obtaining the composite material for bone replacement by applying the technical idea of the present application can be applied as follows, which shows an optimized embodiment after undergoing numerous trial errors as in the manufacturing embodiment of Table 1 below. .

Example 1: Preparation of composite

First paste production

39.7 parts by weight of β-Tricalcium Phosphate

19.9 parts by weight of calcium sulfate hemihydrate

Sorbitol F Solution 39.7 parts by weight

Tetracycline hydrochloride (TC) 0.7 parts by weight

It was composed of 100% by weight by mixing in proportions,

Second paste production

2-octyl cyanoacrylate (2-OCA) 31.8 parts by weight

Monocalcium phosphte 31.8 parts by weight

Sodium chloride 23.8 parts by weight

12.6 parts by weight with barium sulfate

It was composed of 100% by weight by mixing in proportions.

Composite production

The first paste 50 parts by weight, the second paste 50 parts by weight can be mixed to obtain a composite material for bone replacement.

When obtaining the composite material for bone replacement in a similar form to Example 1, various amounts of the first paste and the second paste are used as raw materials, and the raw material composition changes of the synthetic bone for bone substitute are shown as the results in Table 1. Compressive strength was measured and the results are shown in Table 2 in order to determine what changes the composition change result in Table 1 gives to the compressive strength.

Β-TCP beta-tricalcium phosphate (β-Tricalcium Phosphate) from the raw material of paste 1 shown in Table 2

Composition ratio table of synthetic bone for bone replacement using 2-paste system (unit: g) Sample Paste 1 Paste 2 β-TCP CSH TC Sorbitol 2-OCA NaCl MCPA BaSO ₄ One 0.40 0.20 0.01 0.40 0.30 0.20 0.25 0.11 2 0.40 0.20 0.01 0.40 0.30 0.23 0.30 0.12 3 0.40 0.20 0.01 0.40 0.30 0.24 0.31 0.13 4 0.30 0.20 0.01 0.50 0.30 0.21 0.32 0.14 5 0.40 0.20 0.01 0.40 0.30 0.19 0.29 0.15 6 0.39 0.30 0.01 0.41 0.30 0.18 0.28 0.16 7 0.38 0.10 0.01 0.42 0.30 0.17 0.27 0.17

Example 2: Compressive strength test

1) Each paste is prepared by weighing according to the weight of each material, and mixed using a powder mixer (KM Tech, LS-300).

2) Mix the first paste and the second paste according to each weight part,

3) Put into a mold made of Teflon material to produce 0.5cm diameter / 1cm height material.

4) Teflon material mold after curing for about 2 hours in a thermo-hygrostat (TH-PE-065) that maintains a temperature of 37.5 ° C with a relative humidity of 95% and a material filled in the mold of Teflon material. Separate from.

5) The material separated from the mold has a curing time of about 22 hours in a thermo-hygrostat maintaining a temperature of 37.5 ℃.

6) After the curing time is over, after removing the moisture on the surface of the material, the results of measuring the compressive strength using a universal testing machine (Taewon Co., Ltd., TW-D102) are shown in Table 2, and compressing samples 1 to 7 Contents in which the strength measurement results are graphically presented are shown in FIG. 1, and FIG. 2 shows photographs of each compression piece.

Compression strength measurement result of synthetic bone for bone replacement using 2-paste system Sample Paste 1 Paste 2 Compressive strength β-TCP CSH TC Sorbitol 2-OCA NaCl MCPA BaSO ₄ One 0.40 0.20 0.01 0.40 0.30 0.20 0.25 0.11 2.41 2 0.40 0.20 0.01 0.40 0.30 0.23 0.30 0.12 3.26 3 0.40 0.20 0.01 0.40 0.30 0.24 0.31 0.13 3.80 4 0.30 0.20 0.01 0.50 0.30 0.21 0.32 0.14 1.82 5 0.40 0.20 0.01 0.40 0.30 0.19 0.29 0.15 2.43 6 0.39 0.30 0.01 0.41 0.30 0.18 0.28 0.16 3.90 7 0.38 0.10 0.01 0.42 0.30 0.17 0.27 0.17 3.25

Example 3: Compressive strength test after immersion in SBF solution

From the results of Table 2, from the results of Sample 3, the experimental results expected by the present inventors were confirmed, and the compressive strength after immersion of the SBF solution was measured based on the sample 3 product.

  The SBF solution means an analog solution, and an example of manufacturing SBF solution applied herein was made and used with reference to Patent No. 10-0650453.

1) Each paste is prepared by weighing according to the weight of each material, and mixed using a powder mixer (KM Tech, LS-300).

2) Mix the first paste and the second paste according to each weight part,

3) Put into a mold made of Teflon material to produce 0.5cm diameter / 1cm height material.

4) Teflon material mold after curing for about 2 hours in a thermo-hygrostat (TH-PE-065) that maintains a temperature of 37.5 ° C with a relative humidity of 95% and a material filled in the mold of Teflon material. Separate from.

5) The material separated from the mold has a curing time of about 22 hours in a thermo-hygrostat maintaining a temperature of 37.5 ℃.

6) After the curing time is over, remove moisture from the surface of the material, and measure the compressive strength using a universal testing machine (Taewon Co., Ltd., TW-D102).

7) After immersing in SBF solution for each sample, maintain the temperature of 37.5 ℃.

8) After SBF immersion, the compressive strength of the samples was measured weekly and the results are shown in Table 3.

After SBF solution immersion test, compressive strength measurement result of each material Sample Before immersion
Compressive strength (MPa) Compressive strength at 1st week of immersion
(MPa) Compressive strength at 2 weeks of immersion
(MPa) Compressive strength at 4 weeks of immersion
(MPa) 3 3.80 2.62 2.12 1.65

Example 4: Dissolution rate test

As an experiment to evaluate the solubility of the sample and confirm that the material melts to form pores, the solubility test was conducted with the most excellent compressive strength material during the compressive strength test.

Dissolution rate test method

1) Example 1: Prepare a sample according to the method of manufacturing a composite

2) Measure the weight of the Erlenmeyer flask without a lid (M1)

3) After measuring (M2) the weight of the Erlenmeyer flask and the sample, calculate and record the mass (M2-M1) of the sample (M3)

4) Add (100 ± 1) ml of distilled water to the Erlenmeyer flask to make full contact with the sample

5) Stir the Erlenmeyer flask containing the sample for 120 hours in a shaking incubator at 20 ° C, 2 Hz (120 rpm) (JOTECH, ISF-7100R).

6) After washing the filtered residue three times with distilled water, dry it in an oven at 60 ℃ for 24 hours.

7) The weight (M4) of the dissolved sample was measured to calculate the dissolution rate compared to the weight before immersion, and the results are shown in Table 4.The test result values graphically showing the compressive strength before and after the SBF solution immersion test are shown in FIG. Did.

Solubility test using shaking incubator Paste 1 Paste 2 M3 (g) M4 (g) M3-M4 (g) Dissolution rate (%) β-TCP CSH TC Sorbitol 2-OCA NaCl MCPA BaSO ₄ Dissolution rate (%) 0.40 0.20 0.01 0.40 0.30 0.24 0.31 0.13 0.216 0.160 0.056 26

In the results of Table 4, M3 represents the weight of the composite material before immersion in the SBF solution, M4 represents the weight of the composite material after immersion in the SBF solution, and M3-M4 is the weight of the changed material before and after immersion in the SBF solution. It shows the meaning, and the dissolution rate is calculated by a method referring to the solubility test during the evaluation of the chemical properties of the dental bone graft material, and can be explained as having a meaning that it is composed of a porous material rapidly when inserted into the body.

8) Surface observation was observed with a USB microscope (Isworks, K89) at a magnification of 1000 times, and the result is as shown in FIG. 4, which means that after immersion in SBF solution, the composite material constitutes a porous material. It can be described as having.

Fig. 1 of the present application shows the compression strength test result data of the synthetic bone for bone replacement using the two-paste system by applying the technical idea of the present application, and Fig. 2 shows the compressive strength of a block-type material using a universal testing machine. Figure 3 is a photograph of the appearance of the specimen, Figure 3 is a graph showing the compressive strength of each material after the SBF solution immersion test, Figure 4 is before and after the solubility test, USB microscope surface observation photograph, It will be said that there is no need for a separate code explanation.

Claims (5)

Method for manufacturing a composite material for bone substitute comprising the following steps:
A) 40 ± 10 parts by weight of β-tricalcium phosphate (β-TCP), an osteoconductive inorganic material, 40 ± 10 parts by weight of sorbitol (Sorbitol F Solution), and 20 ± 5 parts by weight of calcium sulfate hemihydrate A first step of becoming 100 parts by weight of the first paste;
B) 40 ± 10 parts by weight of liquid cyanoacrylate and 30 ± 10 parts by weight of monocalcium phosphate, 20 ± 5 parts by weight of sodium chloride, and 10 ± 5 parts by weight of barium sulfate as a solid filler in a moisture environment. A second step of obtaining 100 parts by weight of a second paste for promoting the polymerization reaction of the;
C) a third step in which the first paste and the second paste are mixed at a weight ratio of 50 ± 10: 50 ± 10 to obtain a composite material for bone replacement;
Method for producing a composite material for bone substitute characterized in that it comprises a process. According to claim 1,
Method for manufacturing a composite material for bone substitute, characterized in that a wide range of antibiotics are added at a rate of 1 ± 0.5 parts by weight to secure the antimicrobial properties of the paste in the first step. According to claim 1,
The bone conduction inorganic materials used in the first step are BCP, heterologous bone in which hydroxyapatite (HA), β-tricalcium phosphate and hydroxyapatite are added in addition to β-tricalcium phosphate (β-TCP). , Allogeneic bone, autologous bone, a method for manufacturing a composite material for bone replacement, characterized in that it is applied by being replaced by a selected bone material. According to claim 1,
For adjusting the impermeability in the first and second pastes, a contrast agent selected from zirconium oxide and bismuth oxide is added at a rate of 1 ± 0.5 parts by weight and used for bone replacement. Method of manufacturing a composite material. delete

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