KR20160028731A - Chemical composition for manufacturing bio-glue for hard tissue and kit of manufacturing bio-glue for hard tissue - Google Patents

Abstract

The present invention relates to a composition and a kit for producing a bioadhesive for hard tissues. To this end, the composition of the present invention contains modified cyanoacrylate and diacrylate.

Description

Technical Field [0001] The present invention relates to a composition for preparing a bio-adhesive for hard tissue and a kit for manufacturing bio-

TECHNICAL FIELD [0001] The present invention relates to a composition for preparing a hard tissue bio-adhesive and a kit for manufacturing a bio-adhesive for hard tissue.

Our skeleton consists of 206 bones. These bones support our bodies, protect important organs such as the brain and internal organs, as well as allowing them to move independently, enabling various exercises.

In recent years, there has been an increase in cases of bone tissue damage due to diseases such as osteoporosis and automobile accidents due to the progress of the aging society. Materials for repairing these damaged bone tissues have been studied for a long time. Alumina (Al ₂ O ₃ ), stainless steel, or titanium (Ti), which are materials that exhibit hydrophilicity without releasing harmful components in the body, have been used for this purpose.

However, since these materials do not chemically bond directly to the bone, the surface of the material is made porous or uneven to enhance the binding ability with the bone, . However, bone cement is used to fix the implant to the surrounding bone tissue, which requires a long period of time of 2 to 3 months or longer before such a bond is achieved. In the case of preserving a bone defect having a complicated shape or fixing a metal artificial joint to a natural bone, it is preferable to use a substance that can be hardened after maintaining fluidity for a certain period of time. For this purpose, a cement material which has a fluidity for a few minutes after mixing the powder and the liquid, and then exhibits mechanical properties close to the bone in combination with the surrounding bone while curing. Since such a material can be injected into the affected part by a syringe, it can be used in various forms such as a case where the damaged part is very complicated or a part where the access is not easy. In order to accomplish this, a method in which methyl methacrylate (MMA) monomer is cured by polymerization or a method in which various ceramic powders are cured by mixing with water, an aqueous sodium phosphate solution, an organic acid or a polymer aqueous solution Has been studied.

Recently, polymer based on poly (methyl methacrylate) PMMA has been mainly used, and it is widely used as bone cement in clinical practice. In addition, bone cement containing PMMA is advantageous in that it has a somewhat lower toxicity than other polymers.

The bone cement using PMMA of the prior art has a problem of low bonding strength because polymerization shrinkage and reaction with the adherend surface do not proceed.

That is, when the polymerization shrinkage ratio is high, small cracks or cracks are generated after polymerization with the adherend surface such as hard tissue, and the surrounding tissues grow and enter between these gaps. As a result, the cement is detached from the bone. In addition, since the bonding strength between the bone cement and the adherend surface is weak, there is a problem that the aforementioned side effects are accelerated.

Accordingly, it is an object of the present invention to provide a composition for producing a hard-tissue adhesive composition comprising a modified cyanoacrylate and a diacrylate.

In particular, it is an object of the present invention to provide a composition for producing a low toxic bioadhesive agent capable of remarkably alleviating polymerization shrinkage and improving strength.

It is another object of the present invention to provide a composition for the production of a hard tissue biodegradable adhesive capable of improving fixation and strength.

It is an object of the present invention to provide the composition for preparing a hard tissue-containing bio-adhesive and the kit for manufacturing a hard-tissue-like bio-adhesive.

To achieve the above object, there is provided a composition for the production of a hard tissue biodegradable composition comprising a modified cyanoacrylate and a diacrylate.

 According to a preferred embodiment of the present invention, the composition for preparing a hard tissue biocide may further comprise a bone component.

The present invention provides a kit for the production of a hard tissue-containing bioadhesive containing a composition for preparing a hard tissue bioadhesive comprising a modified cyanoacrylate and a diacrylate and an initiator separately.

Another aspect of the present invention provides a hard tissue bioadhesive comprising a random copolymer containing modified cyanoacrylate and diacrylate as monomers.

The present invention can provide a composition for preparing a hard tissue bioadhesive comprising a modified cyanoacrylate and a diacrylate.

This can provide a bioadhesive composition having a strong binding force with an adherend and having a low toxicity. In addition, it is possible to provide a novel composition for a hard tissue biodegradable adhesive which is improved in strength, lowered polymerization shrinkage and alleviated toxicity.

INDUSTRIAL APPLICABILITY The present invention can provide a kit for manufacturing a low toxicity bioadhesive which significantly reduces the polymerization shrinkage and can improve the strength.

Fig. 1 is a graph showing the results of bonding strength tests of Examples 1 to 4 and Comparative Example 1. Fig.
2 is a graph showing the results of polymerization shrinkage of Examples 1 to 4 and Comparative Example 1. Fig.
3 is a graph showing the toxicity test results of Examples 1 to 4 and Comparative Example 1. Fig.

Hereinafter, the present invention will be described in detail. The following detailed description is an explanation of one embodiment of the present invention, and therefore, even if there is a definite expression, the scope of the right defined by the claims is not limited.

As used herein, the term " bioadhesive for hard tissue " refers to a substance that induces adhesion to hard tissue in vivo. The bioadhesive of the present invention can be used, for example, as a dental or medical bioadhesive, and can be used particularly as bone cement for repairing damaged bone tissue or for fixing an artificial joint to a bone.

In the bone cement using PMMA of the prior art, a low adhesion strength due to the non-reaction between the polymerization shrinkage and the adherend surface is a crucial problem.

That is, when the polymerization shrinkage ratio is high, small gaps and cracks are formed after polymerization with the adherend surface such as the hard tissue, and the fiber structure grows and flows into and creeps through the gaps, so that the fixation between the cement and the bone is weakened . In addition, such a situation may cause a problem that the above-described side effect is further accelerated by weakening the bonding strength between the bone cement and the adherend surface.

Accordingly, the present inventors have found that the above problems can be solved by including modified cyanoacrylates and diacrylates, and the present invention has been completed.

That is, the present invention provides a composition for preparing a hard tissue bioadhesive comprising a modified cyanoacrylate and a diacrylate.

Thus, the bio-adhesive for hard tissue of the present invention can provide a composition for producing a bio-adhesive which forms a strong binding force with an adherend and has low toxicity. In addition, it is possible to provide a novel composition for a hard tissue biodegradable adhesive by lowering the polymerization shrinkage ratio as well as improving the strength.

Hereinafter, each component constituting the composition for preparing a bioadhesive of the present invention will be described.

First, the modified cyanoacrylate will be described.

The modified cyanoacrylate of the present invention is a monomer which forms a random copolymer with an initiator together with diacrylate in a hard tissue in vivo. At this time, the modified cyanoacrylate reacts with water present on the surface of the hard-adhered adherend to form a strong bond with the adherend surface.

According to a preferred embodiment of the present invention, the modified cyanoacrylate is a compound represented by the following formula (1).

[Chemical Formula 1]

N in Formula 1 may be an integer of 10 to 1000, preferably an integer of 10 to 100. And m may be an integer of 1 to 20, preferably an integer of 1 to 5.

The weight average molecular weight of the compound represented by Formula 1 may be 1,000 to 1,000,000, and the viscosity of the compound represented by Formula 1 may be 80 to 400 mPa · s.

The modified cyanoacrylate of the present invention is prepared by heating allyl 2-cyanoacrylate to obtain a modified cyanoacrylate which is a polymer compound represented by the formula (1).

Conventional polymerization of 2-cyanoacrylate for a bioadhesive is a method for polymerizing 2-cyanoacrylate for bioadhesive in which a polymerization reaction occurs at a double bond portion adjacent to a cyano group by anionic polymerization and all of the intramolecular double bonds are eliminated To obtain a polymer compound.

For example, in the case of the polymerization of 2-cyanoacrylates having two or more intramolecular double bonds such as allyl 2-cyanoacrylate, partial polymerization occurs in the double bond portion of the allyl group through heating. A 2-cyanoacrylate polymer compound, which is a bioadhesive for soft tissues in which all of the intramolecular double bonds have been eliminated, is obtained by repeating the polymerization reaction at the double bond portion adjacent to the cyano group by anionic polymerization.

However, the present invention relates to a bioadhesive compound represented by the general formula (1) wherein one double bond in the molecule remains at a position adjacent to the cyano group by heating at a temperature sufficient to cause a prepolymerization reaction in the double bond portion of the allyl group Can be manufactured.

 The compound of this type can obtain a high bonding strength with the adherend surface due to the rapid polymerization effect and a polymerization shrinkage inhibiting effect through the double bond adjacent to the cyano group remaining after being applied to the hard tissue for bioadhesive use.

Further, the prepolymerization at the double bond position of the allyl group results in an increase in the alkyl chain of 2-cyanoacrylate and an effect of reducing toxicity. In addition, the viscosity of the modified cyanoacrylate, which is a compound for a bioadhesive compound represented by Formula 1, prepared by controlling the heating temperature and the heating time during preliminary polymerization, can be easily controlled.

However, the above-mentioned modified cyanoacrylate alone is insufficient in obtaining the required physical properties for the improvement of strength and polymerization shrinkage. That is, conventionally, a bioadhesive containing a modified cyanoacrylate has a high polymerization shrinkage ratio and a low strength, and has been used only as a bioadhesive for soft tissues such as skin.

However, the present invention provides a bioadhesive composition for hard tissue comprising a modified cyanoacrylate and diacrylate, whereby the polymerization shrinkage ratio in vivo can be greatly reduced and the strength can be improved.

Next, the diacrylate will be described.

The diacrylate of the present invention is a monomer which becomes a random copolymer with an initiator together with the modified cyanoacrylate in a hard tissue in vivo. At this time, the diacrylate greatly reduces polymerization shrinkage and improves strength.

According to a preferred embodiment of the present invention, the diacrylate is selected from the group consisting of bisphenol A glycol dimethacrylate (Bis-GMA), triethylene glycol dimethacrylate (TEGDMA), urethane And polymer materials including urethane dimethacrylate (UDMA), ethoxylated bisphenol A glycol dimethacrylate (Bis-EMA), and the like. And most preferably may be Bis-GMA.

The bis-GMA is an aromatic organic compound having a benzene ring structure having a large molecular weight, which is a compound having the structural formula (2). In such Bis-GMA, a bond is generated between the double bonds at both ends and also reacts with the modified cyanoacrylate. This greatly reduces the polymerization shrinkage and plays an important role in improving the strength.

(2)

Meanwhile, according to a preferred embodiment of the present invention, the diacrylate may be contained in an amount of 0.01 to 70 parts by weight, preferably 10 to 50 parts by weight, based on 100 parts by weight of the modified cyanoacrylate.

If the amount of diacrylate is less than 0.01 part by weight, it is difficult to expect polymerization volume shrinkage and strength enhancement effect by diacrylate. When the amount of diacrylate exceeds 70 parts by weight, there is a problem in use because the viscosity is rapidly increased without dissolving The weight ratio of the above range is most preferable.

According to a preferred embodiment of the present invention, the composition for preparing a hard tissue biocide can be prepared by heating allyl 2-cyanoacrylate, followed by mixing with diacrylate. According to another preferred embodiment of the present invention, the composition for hard tissue biodegradable adhesive composition may be prepared by mixing and heating allyl 2-cyanoacrylate and diacrylate.

That is, the modified cyanoacrylate is prepared by preliminarily polymerizing allyl 2-cyanoacrylate, and since the chemical structure of the diacrylate is not changed by heating, the allyl 2- Can be mixed regardless of the order of the heating reaction denatured with the non-acrylate.

In the present invention, the heating is preferably performed at 50 to 200 ° C, and if the heating temperature is outside the above range, the prepolymerization may not be completed or a side reaction may occur. The heating time is preferably 3 seconds to 2 hours, and if the heating time is out of the above range, the preliminary polymerization is not completed or a side reaction occurs.

Accordingly, the composition for preparing a hard tissue biodegradable adhesive of the present invention is a novel biodegradable adhesive for a hard tissue that can strongly bond to a hard surface of adherent anchor acrylate, enhance strength by diacrylate such as Bis-GMA, and alleviate polymerization shrinkage .

According to a preferred embodiment of the present invention, the composition for preparing a hard tissue-containing bioadhesive may further comprise a bone component.

By further including a bone component in the composition for the production of a hard tissue biodegradable adhesive of the present invention, it is possible to further improve the affinity with the hard tissue and the strength, and the polymerization shrinkage rate can also be advantageously reduced.

According to a preferred embodiment of the present invention, the bone component includes bivalve, hydroxyapatite, an inorganic component of animal-derived bone, and calcium phosphate (calcium phosphate including calcium phosphate and various trace elements mainly composed of phosphoric acid tricalcium phosphate, and the like. Preferably, it may be hydroxyapatite and / or tricalcium phosphate.

And the bone component may include 0.05 to 30 parts by weight based on 100 parts by weight of the sum of modified cyanoacrylate and diacrylate. If the amount of the bone component is less than 0.05 part by weight, there may be a problem of no improvement in strength, reduction in polymerization shrinkage and improvement in bone affinity, and if the amount is more than 30 parts by weight, the polymerization is inhibited and the strength is weakened, There may be a problem that this becomes impossible.

Another aspect of the present invention provides a composition for preparing a hard tissue bioadhesive comprising a modified cyanoacrylate and a diacrylate and a kit for manufacturing a hard tissue biodegradable adhesive containing an initiator separately.

The description of the modified cyanoacrylate and diacrylate is the same as described above, and the modified cyanoacrylate may serve as a liquid phase and a solvent for the diacrylate in powder form. And the initiator serves to make polymerization of the composition for preparing a hard tissue bioadhesive possible at room temperature without heating.

According to a preferred embodiment of the present invention, the initiator may include at least one selected from the group consisting of benzoyl peroxide, ammonium persulfate, hydrogen peroxide, and AIBN (azobisisobutyronitrile) , Preferably benzoyl peroxide.

The initiator may be included in an amount of 0.01 to 10 parts by weight, preferably 0.01 to 3 parts by weight, based on 100 parts by weight of the composition for preparing a hard tissue biodegradable adhesive. If the amount is less than 0.01 parts by weight, the reaction rate may be slow, unreacted materials may increase, toxicity may increase or the strength may be weak. If the amount is more than 10 parts by weight, There may be a problem that the strength is weakened.

According to a preferred embodiment of the present invention, the kit for manufacturing a hard tissue biocide may further comprise a reaction catalyst.

The reaction catalyst serves not only to decompose the initiator but also to enable the polymerization of the composition for the production of a hard-tissue biodegradable adhesive, such as the initiator, to be possible at room temperature without heating. The reaction catalyst may be tertiary amines or sulfunic acids. Specifically, the reaction catalyst is mainly used in tertiary amines, and the tertiary amines include N, N-dimethyl-para-toluidine , N-dihydroxyethyl-para-toluidine, and dimethylaniline. In the present invention, The reaction catalyst may be contained in an amount of 0.01 to 50 parts by weight based on 100 parts by weight of the composition for preparing a hard tissue bio-adhesive.

In conclusion, the present invention provides a composition for preparing a hard tissue-containing bioadhesive comprising a modified cyanoacrylate and a diacrylate, and a kit for manufacturing a bio-adhesive for hard tissue.

In particular, the present invention can provide a composition for preparing a bioadhesive having a binding force with a strong adherend and a low toxicity, by providing a composition for preparing a hard tissue bioadhesive containing no solvent at all. In addition, it is possible to provide a composition for the production of a bioadhesive for a hard tissue which has not only an improved strength but also a reduced polymerization shrinkage.

That is, the bio-adhesive kit for hard tissue of the present invention comprises a composition for preparing a tissue adhesive for biological tissue, which is a transparent liquid substance, and an initiator which is a solid powder. Therefore, when the two components are mixed at an appropriate ratio before use, the cyanoacrylate of the bioadhesive reacts with moisture of the hard tissue surface to cause the adhesion reaction. And at the same time, it is possible to provide a hard-tissue adhesive for a hard tissue which is capable of securing the fixation and strength improvement by a crosslinking reaction by an initiator.

On the other hand, in the case of PMMA-based bone cement, the compressive strength is generally known to be about 60 MPa.

The hard tissue biodegradable adhesive prepared by the hard tissue biodeactor kit provided in the present invention can produce a hard tissue adhesive of 30 MPa or more and is capable of producing a biodegradable adhesive having a compressibility of not less than 60 MPa or preferably not less than 80 MPa depending on the content of diacrylate Strength can also be provided. That is, the bio-adhesive for hard tissue of the present invention can be used as a preferred use depending on the compressive strength. If the compressive strength of the hard tissue biodegradable adhesive of the present invention is about 30 MPa, it can be used for cartilage in the hard tissue, and the compressive strength of 60 MPa or higher can be used as bone cement in the hard tissue.

In the case of conventional bone cement, the polymerization shrinkage ratio is high, and there is a problem that a gap is formed after the polymerization with the adherend surface such as hard tissue.

On the other hand, the hard tissue biodegradable adhesive provided by the present invention has a polymerization shrinkage of less than about 20%, preferably less than 10%. In particular, when the modified cyanoacrylate and diacrylate form a random copolymer at a specific polymerization ratio, the polymerization shrinkage ratio may be little.

Therefore, the present invention provides a hard tissue bio-adhesive comprising a random copolymer containing modified cyanoacrylate and diacrylate as a monomer, wherein the hard tissue bio-adhesive may have a compressive strength of 30 MPa or more, May be less than 20%.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the embodiments of the present invention described below are illustrative only and the scope of the present invention is not limited to these embodiments. The scope of the present invention is indicated in the claims, and moreover, includes all changes within the meaning and range of equivalency of the claims. In the following Examples and Comparative Examples, "%" and "part" representing the content are based on weight unless otherwise specified.

Example  One

A solution of bis-GMA powder 0.1 in 500 l of this viscous solution obtained after allyl 2-cyanoacrylate was heated at 150 캜 for 40 minutes to prepare modified cyanoacrylate and then cooled to room temperature. g. The mixture was stirred at 60 ° C for 3 hours to obtain a transparent mixed solution in which Bis-GMA was dissolved.

To this solution, benzoyl peroxide of 0.1% by weight of the total content of modified cyanoacrylate and Bis-GMA powder as polymer was added and reacted at 60 캜 for 1 hour to prepare a bioadhesive.

Example  2

Except that 0.15 g of Bis-GMA powder was used.

Example  3

Was prepared in the same manner as in Example 1, except that 0.3 g of Bis-GMA powder was used.

Example  4

Was prepared in the same manner as in Example 1, except that 0.5 g of Bis-GMA powder was used.

Example  5

Bis-GMA-modified cyanoacrylate was prepared by mixing 500 μl of allyl 2-cyanoacrylate and 0.3 g of Bis-GMA and heating at 150 ° C. for 40 minutes, and the mixture was cooled to room temperature A transparent mixed solution was obtained. To this solution, benzoyl peroxide (0.1% by weight of the total content of modified cyanoacrylate and Bis-GMA powder as polymer) was added and reacted at 60 ° C for 1 hour to prepare a bioadhesive.

Example  6

Allyl 2-cyanoacrylate was heated at 150 占 폚 for 40 minutes to prepare modified cyanoacrylate, followed by cooling to room temperature, and 0.5 g of UDMA (urethanedimethacrylate) was mixed into 500 l of this solution . The mixture was stirred at 60 DEG C for 3 hours to obtain a transparent mixed solution. To this solution, benzoyl peroxide (0.1% by weight of the total content of modified cyanoacrylate and UDMA as a polymer) was added and reacted at 60 ° C for 1 hour to prepare a bioadhesive.

Example  7

UDMA-modified cyanoacrylate was prepared by mixing 500 μl of allyl 2-cyanoacrylate and 0.3 g of UDMA at 150 ° C. for 40 minutes and heating. The resulting viscous, transparent mixed solution cooled at room temperature . To this solution, 0.1% benzoyl peroxide (weight ratio of modified cyanoacrylate and UDMA as a polymer) was added and reacted at 60 ° C for 1 hour to prepare a bioadhesive.

Example  8

Modified cyanoacrylate was prepared by heating allyl 2-cyanoacrylate at 150 ° C for 40 minutes. To 500 g of this viscous solution cooled to room temperature, 0.1 g of Bis-GMA powder, And 0.03 g of hydroxyapatite powder were mixed. Then, the mixed solution was obtained by dissolving Bis-GMA while stirring at 60 ° C for 3 hours.

To this solution was added 0.1% benzoyl peroxide by weight of the total content of modified cyanoacrylate and Bis-GMA powder, and the mixture was reacted at 40 ° C for 20 minutes to prepare a bioadhesive.

Comparative Example  One

Allyl 2-cyanoacrylate was heated at 150 ° C. for 40 minutes to prepare modified cyanoacrylate. To 500 μl of the viscous solution cooled to room temperature, allyl 2-cyanoacrylate (" allyl 2-cyanoacrylate) 0.1% by weight of benzoyl peroxide was added and reacted at 60 ° C for 1 hour to prepare a bioadhesive.

Experimental Example  One

The compression strength, polymerization shrinkage and cytotoxicity of Examples 1 to 4 and Comparative Example 1 were measured.

One. Bis - GMA Measurement of compressive strength according to amount

The hard tissue adhesives prepared in Examples 1 to 4 and Comparative Example 1 were filled into an accurate sized Teflon mold (cylindrical shape having a diameter of 12 mm and a height of 30 mm) to be polymerized. Then, the manufactured adhesive was set in the longitudinal direction, and the breaking strength was measured by setting a crosshead speed at 1 mm / min in a universal testing machine (Instron model 4467, Canton, MA, USA) .

It can be seen from the measurement results shown in Fig. 1 that the compressive strength of Comparative Example 1 is remarkably low, about 20 MPa. In Examples 1 and 2, it is 30 to 40 MPa, and in Examples 3 and 4, it is 80 MPa or more. That is, it can be seen from the present invention that bone cement having excellent compressive strength can be produced.

2. Bis - GMA Change in polymerization shrinkage rate according to the amount

The biocompatible adhesives prepared in Examples 1 to 4 and Comparative Example 1 were filled in a Teflon mold (cylindrical shape having a diameter of 12 mm and a height of 30 mm), and the filled positions were marked and then polymerized. And the shrunk volume after polymerization was measured as the volume of water required to fill the water to the location indicated in the mold.

The measurement results of the polymerization shrinkage ratio are shown in Fig. In the case of Comparative Example 1, it can be seen that the polymerization shrinkage ratio is relatively large, about 28%. On the contrary, in the case of Examples 1 and 2, the polymerization shrinkage rate was decreased, and in Examples 3 and 4, shrinkage due to polymerization hardly occurs.

3. Cells ( NIH  3 T3 ) Was used for cytotoxicity test

To analyze the cytotoxicity of the biomaterials prepared, NIH 3T3 cell line cells were seeded at a concentration of 50,000 cells / well in a 24-well plate well and cultured for 24 hours. Then, the medium was removed. Then, 100 μl of the adhesives of Examples 1 to 4 and Comparative Example 1 were added to the center of each well and polymerized. Then, the medium was added again, and the WST assay was performed at the time of day to measure the degree of color development by living cells. Respectively.

The control CTRL was obtained by culturing the cell culture dishes in the same manner without any adhesive.

As a result of the measurement, referring to FIG. 3, the cell viability of Comparative Example 1 was markedly lowered, whereas the results of Examples 1 to 4 were almost similar to those of the control group. Therefore, Comparative Example 1 showed high cytotoxicity, and Examples 1 to 4 can be judged to have little cytotoxicity.

Claims (18)

Modified cyanoacrylate and diacrylate. ≪ RTI ID = 0.0 > 21. < / RTI > The method according to claim 1,
Wherein the modified cyanoacrylate is a compound represented by the following formula (1): " (1) "
[Chemical Formula 1]

N in Formula 1 is an integer of 10 to 1000,
m is an integer of 1 to 20; The method according to claim 1,
The diacrylate may be selected from the group consisting of bisphenol A glycol dimethacrylate (Bis-GMA), triethylene glycol dimethacrylate (TEGDMA), urethane dimethacrylate (UDMA) And ethoxylated bisphenol A glycol dimethacrylate (Bis-EMA). 2. The composition for hard tissue biodegradation according to claim 1, The method according to claim 1,
Wherein the diacrylate is 0.01 to 70 parts by weight based on 100 parts by weight of the modified cyanoacrylate. The method of claim 4,
Wherein the diacrylate is 10 to 50 parts by weight based on 100 parts by weight of the modified cyanoacrylate. The method according to claim 1,
The composition for preparing a hard tissue biodegradable adhesive includes
Wherein the allyl 2-cyanoacrylate is heated and then mixed with diacrylate. The method according to claim 1,
The composition for preparing a hard tissue biodegradable adhesive includes
A mixture of allyl 2-cyanoacrylate and diacrylate is mixed and heated to prepare a composition for hard tissue bioadhesive preparation. The method according to claim 1,
The composition for the preparation of a hard tissue biodegradable adhesive according to claim 1, further comprising a bone component. The method of claim 8,
Wherein the bone component comprises at least one selected from the group consisting of bovine bone, hydroxyapatite, and tricalcium phosphate. The method of claim 8,
Wherein the bone component comprises 0.05 to 30 parts by weight based on 100 parts by weight of the sum of modified cyanoacrylate and diacrylate. A kit for manufacturing a hard tissue biodegradable adhesive comprising the composition for preparing a hard tissue biocide of claim 1 and an initiator separately. Claim 11
Wherein the initiator comprises at least one selected from the group consisting of benzoyl peroxide, ammonium persulfate, hydrogen peroxide, and azobisisobutyronitrile (AIBN). Claim 11
Wherein the initiator is contained in an amount of 0.01 to 10 parts by weight based on 100 parts by weight of the composition for preparing a hard tissue biodegradable adhesive. Claim 11
Further comprising a reaction catalyst,
The reaction catalyst is tertiary amines or sulfunic acids,
The tertiary amine is preferably selected from the group consisting of N, N-dimethyl-para-toluidine, N-dihydroxyethyl-para-toluidine and dimethylaniline ). ≪ / RTI > The kit for manufacturing a hard tissue bio-adhesive according to claim 1, Claim 14
Wherein the kit further comprises 0.01 to 50 parts by weight of a reaction catalyst based on 100 parts by weight of the composition for preparing a hard tissue biodegradable adhesive. Modified cyanoacrylate, and diacrylate as monomers. 18. The method of claim 16,
Wherein the compressive strength of said hard tissue bio-adhesive is 30 MPa or more. 18. The method of claim 16,
Wherein the polymer shrinkage ratio of the hard tissue biotherapeutic agent is less than 20%.

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