KR20180054378A - Method for preparation of bone filler having coiled ceramic structure and bone filler prepared thereby - Google Patents

Abstract

The present invention relates to a method for producing a bone filler containing coiled ceramics, and to a bone filler produced by the method. The method for producing the bone filler according to the present invention can produce a bead-shaped bone filler including the coiled ceramic through an extrusion container having a double nozzle, and as a sintering process is not performed to make the implantation in a bone graft site easy. In addition, since the bone filler according to the present invention can form pores by coiling of ceramic fibers, an excellent effect can be shown on the induction of bone formation, and bone adhesion can be improved due to a hydrogel surrounding the coiled ceramic.

Description

TECHNICAL FIELD The present invention relates to a method of manufacturing a bone filler including a coil structure ceramic and a bone filler prepared by the method.

The present invention relates to a method for manufacturing a bone filler made of beads containing coil structure ceramics and a bone filler prepared thereby.

Generally, when a part of the bone tissue is deficient or needs reinforcement in a specific part of a living body, the bone is implanted into the part. Thus, when bone grafts are transplanted into a living body, the grafted bone induces the formation of new bone at the graft site, and the graft itself is gradually degraded, partly or wholly. When a certain period of time elapses, most of the graft site becomes filled with newly generated bone.

Here, it is common that a bone graft to be implanted in a living body is a mixture of an extracted portion of a bone tissue in a living body and an artificial bone artificially made of a material such as ceramics. At this time, the artificial bone is often referred to as a bone filler or a bone substitute.

The form of bone filler is simple granule type and granular type with surface irregularities and pores.

Simple granulation methods are representative of simple sintering methods, which are described in U.S. Patent No. 4,218,255, U.S. Patent No. 4,693,986, U.S. Patent No. 5,030,611, and U.S. Patent No. 5,064,436. The foregoing prior art discloses a simple sintering method for producing a bone filler by preparing granules using fine powder and then sintering the granules and introducing fine pores into the surface of the granules by controlling the degree of sintering in the sintering process It is described that the pore is hardly introduced. However, since the bone filler produced by the simple sintering method has a very high strength of the granule itself, but has a smaller specific surface area than that of the concavo-convex shape having irregularities formed on its surface, the area of attachment of the bone is relatively small. As a result, Is lowered.

On the other hand, the granular form into which surface irregularities and pores are introduced is classified into a porous form, a semi-porous form or a porous form by a porous formed body used in the manufacturing process. The most representative method for producing the granules of the present invention is a replica method using a porous polymer sponge, which is described in U.S. Patent No. 4,889,833. In the prior art, the porous sponge is impregnated into the bioactive ceramic slurry by the replica method to apply the slurry on the sponge skeleton, and then the porous body is formed by burning the sponge in the process of drying, degreasing and sintering the slurry, Followed by pulverization and sieving, thereby producing an intact granule having an appropriate size. The microporous granules prepared by this method have an advantage of controlling the size of pores generated according to the pore size of the porous sponge skeleton. However, due to the extremely low strength of the corpuscle filler in the form of a granule, the granule is not suitable for mass production due to the inconvenience of repeatedly impregnating and degreasing the slurry several times in order to obtain granules of desired strength So that the manufacturing cost is increased. In addition, the surface of the granules produced after grinding is very sharp, which is also inappropriate for adhesion of bone cells.

Prior Art 1. United States Patent No. 4,218,255 (registered on August 19, 1980) Prior art document 2. United States Patent No. 4,693,986 (registered on September 15, 1987) Prior art document 3. US Patent No. 5,030,611 (Registered on July 9, 1991) Prior Art Document 4. US Patent No. 5,064,436 (Registered on November 12, 1991) Prior Art Document 5. US Patent No. 4,889,833 (Registered on December 26, 1989)

SUMMARY OF THE INVENTION The present invention has been made in order to solve the above-mentioned problems, and it is an object of the present invention to provide a method of manufacturing a bead type bone filler including a coil structure ceramic.

It is another object of the present invention to provide a bead type bone filler including a coil structure ceramic.

According to a preferred embodiment of the present invention, a method of manufacturing a bone filler comprises the steps of: preparing a first paste containing calcium phosphate-based ceramics; Preparing a second paste comprising a hydrogel; Placing the first paste in a container connected to an inner pipe of an extrusion container having a double nozzle and extruding the second paste into a container connected to an outer pipe of an extrusion container having a double nozzle to form a droplet; And immersing the droplet in a crosslinking liquid to obtain beads containing a coil structure ceramic.

Further, the present invention is characterized by further comprising the step of immersing the beads containing the coil-structured ceramic immersed in the cross-linking solution in a hardening liquid.

Here, the nozzle size of the inner pipe for extruding the first paste is 100 to 1000 mu m.

Also, the hydrogel may be selected from the group consisting of alginate, gelatin, collagen, fibrinogen, chitosan, agar, Matrigel, starch, pectin, Hydroxyethyl ethyl cellulose, polyvinyl alcohol, polyurethane, poly (ethylene glycol), poly (propylene glycol), polypropylene glycol, And at least one polymer selected from the group consisting of methyl cellulose, carboxymethylcellulose, hyaluronan, and poly (vinylpyrrolidone).

Here, the polymer is contained in a concentration of 0.1 to 10% by weight in the second paste.

The calcium phosphate-based ceramics may be selected from the group consisting of hydroxyapatite, dicalcium phosphate dihydrate (DCPD), monocalcium phosphate monohydrate (MCPM), dicalcium phosphate anhydrous (DCPA), biphasic calcium phosphate (BCP) phosphate, and β-TCP (β-Tricalcium phosphate). However, the present invention is not limited thereto, and a bioceramic raw material capable of inducing a self-curing reaction may be used.

In addition, the first paste may contain at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), alginate, gelatin, collagen Fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, polyurethane, polyvinylpyrrolidone, A thickening agent of at least one of poly (ethylene glycol), poly (propylene glycol), hyaluronan and poly (vinylpyrrolidone) .

Also, it is characterized in that 10 to 100 parts by weight of the solution containing the thickening agent is added to 100 parts by weight of the calcium phosphate-based ceramic.

In addition, the cross-linking solution of calcium chloride (CaCl _2), magnesium chloride (MgCl _2), at least one, and the hardening solution of calcium phosphate (CaP) and calcium carbonate (CaCO ₃₎ is H ₂ O, PBS (phosphate buffer saline, MCPM (monocalcium phosphate monohydrate), DAHP (diammonium hydrogen phosphate), NH ₄ H ₂ PO ₄ , KH ₂ PO ₄ , K ₂ HPO ₄ and NaH ₂ PO ₄ .

According to another preferred embodiment of the present invention, a bead-shaped bracing material comprises: an inner structure in which a single ceramic fiber is formed into a coil; And organic particles forming a surface surrounding the internal structure and containing a hydrogel.

Here, the internal structure includes calcium-deficient hydroxyapatite (CDHA).

In addition, the internal structure may be formed of a material such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), alginate, gelatin, collagen, Fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, polyurethane, polyethylene, polyvinylpyrrolidone, A thickening agent of at least one of poly (ethylene glycol), poly (propylene glycol), hyaluronan and poly (vinylpyrrolidone) .

The hydrogel may be selected from the group consisting of alginate, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), gelatin, collagen, Fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, polyurethane, polyethylene, polyvinylpyrrolidone, (Poly (ethylene glycol)), poly (propylene glycol), hyaluronan and poly (vinylpyrrolidone). .

The method of manufacturing a bone filler according to the present invention can produce a bead-shaped bone filler including a coil structure ceramic through an extrusion vessel having a double nozzle and can easily inject the bone graft site without sintering .

In addition, since the bone filler according to the present invention can form pores by the coiling of ceramic fibers, it exhibits an excellent effect in inducing bone formation, and bone adhesiveness can be improved due to the hydrogel surrounding the coil structure ceramic.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view showing a method of manufacturing a bone filler material in the form of a bead including the coil structure ceramic of the present invention. FIG.
2 is a photograph showing that the extrusion pressure of the first paste is too large to form beads in the production method of the present invention.
3 is a schematic view showing that a first paste to be extruded from an inner tube is formed in a coil shape and a second paste is extruded from an outer tube to form a droplet while surrounding the coil in the manufacturing method of the present invention .
4 is a photograph showing the beads produced in Examples 1 and 2 according to the present invention.
5 is a photograph showing the beads manufactured according to Example 3 of the present invention.
6 is a photograph showing droplets formed by Experimental Example 2 according to the present invention.
FIG. 7 is a graph showing changes in size of beads according to the extrusion pressure and the inner tube nozzle size in the manufacturing method of the present invention.
8 is an XRD analysis result of confirming the phase change of? -TCP due to self-curing upon immersion in PBS according to Example 1 of the present invention.
9 is an XRD analysis result of confirming the phase change of? -TCP due to autocuring upon immersion in MCPM according to Example 5 of the present invention.

Hereinafter, the present invention will be described in detail. Prior to this, terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms, and the inventor should appropriately interpret the concepts of the terms appropriately It should be interpreted in accordance with the meaning and concept consistent with the technical idea of the present invention based on the principle that it can be defined. Therefore, the constitutions described in the embodiments described herein are merely the most preferred embodiments of the present invention, and are not intended to represent all of the technical ideas of the present invention. Therefore, various equivalents which can be substituted at the time of application It should be understood that variations can be made.

In the present invention, the term " bone filler " is also referred to as a " bone substitute ", " bone graft material ", and is defined as implantation when a part of bone tissue in a living body is deficient or needs reinforcement.

The term " beads " used in the present invention is also referred to as " beads ", and is defined as spherical particles.

A method for producing a bone filler according to the present invention comprises:

Preparing a first paste containing calcium phosphate-based ceramics;

Preparing a second paste comprising a hydrogel;

Placing the first paste in a container connected to an inner pipe of an extrusion container having a double nozzle and extruding the second paste into a container connected to an outer pipe of an extrusion container having a double nozzle to form a droplet; And

And immersing the droplet in a crosslinking liquid to obtain beads containing a coil structure ceramic (see Fig. 1).

Hereinafter, the method for producing a bone filler of the present invention will be described in more detail.

First, a first paste containing calcium phosphate-based ceramics is prepared.

In the first paste preparing step, it is preferable that the step of preparing a paste usable in the extrusion step is made of calcium phosphate-based ceramics.

The calcium phosphate-based ceramics are not particularly limited in their kind but may be selected from the group consisting of hydroxyapatite, dicalcium phosphate dihydrate (DCPD), monocalcium phosphate monohydrate (MCPM), dicalcium phosphate anhydrous (DCPA), biphasic calcium phosphate , α-TCP (α-Tricalcium phosphate), and β-TCP (β-Tricalcium phosphate), and more preferably α-TCP (α-Tricalcium phosphate).

For example, when α-TCP (α-Tricalcium phosphate) is used as the calcium phosphate-based ceramic, it reacts with water to form a calcium-deficient hydroxyapatite (CDHA) It is possible to improve the mechanical strength and maintain the stable shape of the structure. In addition, it is more advantageous in introducing cells and other functional materials than β-TCP (β-Tricalcium phosphate) which requires acidic conditions in the curing process.

[Reaction Scheme 1]

_{3αCa 3 (PO 4) 2 +} H 2 O → Ca 9 (HPO 4) (PO 4) 5 (OH)

In addition, the first paste may further include an additive which is an organic material having excellent biocompatibility in order to impart fluidity and moldability in an extrusion process. The type of the thickening agent is not particularly limited, and examples thereof include hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), alginate, gelatin Gelatin, collagen, fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, Polyurethane, poly (ethylene glycol), poly (propylene glycol), hyaluronan, and poly (vinylpyrrolidone). But it is preferably at least one, and more preferably, it may contain hydroxypropylmethylcellulose (HPMC).

In addition, the thickener may include a solvent, and the type of the solvent is not particularly limited, but is preferably distilled water, tetrahydrofuran, dioxane, ethyl ether, 1,2-dimethoxyethane, dimethylformamide, dimethyl Sulfoxides, dichloromethane, dichloroethane and C ₁ to C ₄ alcohols, and more preferably ethanol. Here, the viscosity can be controlled so that the first paste can be easily extruded and the coils can be formed well by using the coagulant containing the solvent. The viscosity of the first paste may be adjusted to a range of preferably 10,000 to 1,000,000 cP, preferably 50,000 to 500,000 cP, more preferably 100,000 to 300,000 cP.

As a preferred example, the first paste may be prepared by using a ball mill apparatus using the gradual solution containing the calcium phosphate-based ceramic and the solvent. The first paste may contain 10 to 100 parts by weight, more preferably 30 to 80 parts by weight, of the incrementing agent solution based on 100 parts by weight of the calcium phosphate-based ceramic, Preferably 50 to 70 parts by weight. If the content of the thickening agent is less than the above range, the viscosity may become high and the fluidity may be insufficient, so that formation of the coil may be difficult. If the content of the thickening agent exceeds the above range, the mechanical properties may be greatly deteriorated.

Next, a second paste containing a hydrogel is prepared.

In the second paste preparation step, a paste usable in an extrusion process is prepared including a hydrogel made of a polymer.

Here, the type of the polymer is not particularly limited, but may be selected from the group consisting of alginate, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC) Such as gelatin, collagen, fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, Polyurethane, poly (ethylene glycol), poly (propylene glycol), hyaluronan, and poly (vinylpyrrolidone) , And more preferably includes at least one of Alginate and Alginate.

The second paste may preferably contain the polymer in a concentration of 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, and most preferably 1 to 2% % ≪ / RTI > by weight. Here, when the polymer is contained below the defined concentration, it is difficult to form droplets in the extrusion process, and the surface tension of the formed droplets may flow into the hydrogel because the weight of the calcium phosphate-based ceramics formed in the droplets can not be maintained. The viscosity of the second paste is increased and it becomes difficult to control the shape of the filler.

Further, the second paste may further include a gelling agent having a biostability. When the gelling agent is included, there is an advantage that the paste can easily control the physical properties so as to have fluidity suitable for extrusion and molding. The type of the gelling agent is not limited, but preferably includes at least one of H ₂ O, PBS, tris (hydroxymethyl) aminomethane, and N- [tris (hydroxymethyl) methyl] glycine And more preferably, PBS.

In addition, the hydrogel may induce crosslinking by physical (ionic, stereocomplex, thermal, and / or chemical) (UV, depending on the physical properties thereof) and physical crosslinking is advantageous.

Next, the first paste and the second paste are put into an extrusion container having a double nozzle and extruded to form droplets.

Here, the first paste is placed in a container connected to the inner tube of the extrusion container, and the second paste is put into a container connected to the outer tube of the extrusion container and extruded.

The extrusion container may be composed of two containers connected to the inner pipe and the outer pipe. The first paste material for forming the coil structure ceramic is inserted into the container connected to the inner pipe and is extruded. A second paste material for forming the outer surface is put in the container and extruded to form an organic-inorganic composite body.

In addition, the nozzle size of the inner tube of the extrusion container is preferably 100 to 1000 占 퐉, more preferably 200 to 700 占 퐉, and most preferably 300 to 500 占 퐉. If the size of the inner pipe nozzle is less than the above defined range, the size of the beads becomes large to control the shape, the content of the ceramic in the beads is relatively small and the bony filling effect is not sufficient. The size of the beads is shortened, the coils are not formed well, the internal pores are not formed sufficiently, and the ceramic is protruded to the outside of the hydrogel. It is possible.

In the extrusion process, pressure can be applied by various methods. However, in the case of extruding a first paste containing a ceramic paste, a screw pressure is preferably used because a high pressure is required, and a second paste containing a hydrogel In the case of extrusion, pneumatic pressure is preferably used because it requires fine pressure control, but it is not limited thereto.

It is preferable that the first paste has an extrusion pressure of 100 to 1000 U and the second paste has an extrusion pressure of 1 to 300 U. The extrusion pressure is a pressure for moving a distance of 1 mm per minute. The higher the extrusion pressure, the more the amount of the paste to be discharged increases. If the extrusion pressure of the first paste is too low, the content of the ceramic in the beads is relatively small and the filling effect of the trowel is not sufficient. If the extrusion pressure of the first paste is too high, the ceramic in the first paste is contained in the second paste (See FIG. 2). In this case, it is impossible to manufacture beads in the form of beads.

Here, when extrusion is performed by the pressure according to the present invention, a first paste to be extruded from the inner tube is formed in the form of a coil, and a second paste is extruded from the outer tube to form a droplet while surrounding the coil. At this time, when the surface tension of the extruded droplet is smaller than the weight of the droplet due to gravity, the droplet shape is maintained. As the time for maintaining the shape of the droplet is lengthened, the extrusion amount of the first and second pastes increases, The size of the beads to be formed becomes large (see Fig. 3)

Next, the liquid droplets prepared above are immersed in a crosslinking liquid to obtain beads containing coil structure ceramics.

As the weight of the droplet due to the gravity increases, the surface tension of the extruded second paste becomes larger than the surface tension of the second paste while the extrusion of the previous step continues, and the droplet is dripped by the gravity into the crosslinking solution located below .

Here, when the droplet is dropped into the crosslinking liquid, it is preferable to maintain the crosslinking reaction for 30 minutes to 3 hours, more preferably 30 to 2 hours for maintaining the crosslinking reaction.

The crosslinking solution is not limited in its kind but may contain at least one of calcium chloride (CaCl ₂ ), magnesium chloride (MgCl ₂ ), calcium phosphate (CaP) and calcium carbonate (CaCO ₃ ) And more preferably calcium chloride (CaCl ₂ ).

When the dropwise droplet crosslinking reaction of the polymer is performed by the cross-linking solution, a bead containing a coil-structured ceramic inside and an organic substance located outside is formed.

The beads after completion of the crosslinking reaction are not subjected to a sintering process separately. The beads of the present invention, which have not undergone the sintering process, have the advantages of being easily injected regardless of the shape of the bone graft site, having excellent bone adhesion and bone induction.

Next, a step of immersing the beads immersed in the cross-linking solution in the hardening liquid and curing may be further roughened.

The curing liquid is not limited in its kind but may be selected from the group consisting of H ₂ O, phosphate buffer saline (PBS), monocalcium phosphate monohydrate (MCPM), diammonium hydrogen phosphate (DAHP), NH ₄ H ₂ PO ₄ , KH ₂ PO ₄ , K ₂ HPO _4, and NaH ₂ PO ₄ , and most preferably may include PBS (phosphate buffer saline).

The concentration of the curing liquid is preferably 0.1 to 5.0 M. If the concentration of the curing liquid is less than 0.1 M, there is a problem that the curing reaction takes a long time. If the concentration exceeds 5.0 M, the curing reaction occurs too quickly, causing a nonuniform reaction.

Further, in the curing step, the beads may preferably be immersed in a curing solution for 6 to 24 hours to induce a self-curing reaction, more preferably to immerse in a curing solution for 6 to 12 hours to induce a self-curing reaction , The immersing time may be suitably adjusted in consideration of the size and reactivity of the beads.

Here, in order to further crosslink the hydrogel in the curing liquid, the curing liquid and the above-mentioned crosslinking liquid may be further included. It is preferable that the added amount of the crosslinking liquid is so low that it reacts with the curing liquid and does not cause precipitation and does not cause pH change of the curing liquid.

As a preferred example, a first paste containing calcium phosphate-based ceramics, a second paste formed of a hydrogel containing alginate, a calcium chloride (CaCl ₂ ) crosslinking solution, and a hardening solution containing calcium chloride (CaCl ₂ ) and PBS A bone filler can be produced. The first paste and the second when the paste is respectively injected into the inner tube and outer tube of the extrusion container droplets formed by the extrusion step the crosslinking liquid immersion, a divalent cation of the alginate in the hydrogel (Ca ^{2 +,} Ba ^{2 +,} Sr ^{2 +,} Etc.) are substituted with Na ⁺ ions to form a crosslinked network of Alg-Ca. Among them, Ca ^{2 +} can be expected to have the highest crosslinking effect. Then, the bead-shaped bone filler is taken out from the cross-linking solution and immersed in a curing solution containing PBS and calcium chloride (CaCl ₂ ) (step 2), whereby the cross-linking of the alginate can be additionally induced. Therefore, in step 1, alginate is mixed with calcium chloride (CaCl ₂ ) at a low concentration to induce primary crosslinking. After molding, secondary crosslinking is performed by further immersing the alginate in a curing solution containing calcium chloride (CaCl ₂ ) .

Next, the method may further include washing and drying the beads after the curing step. Here, distilled water, saline, PBS and the like may be used for the washing.

The bone filler according to the present invention can be prepared at room temperature and can be stored in distilled water after being washed or freeze dried.

In the bead type bone filler according to the present invention,

An inner structure in which a single ceramic fiber is formed as a coil; And organic particles forming a surface surrounding the internal structure and containing a hydrogel.

Hereinafter, the bead type bone filler of the present invention will be described in more detail.

It is preferable that the internal structure includes phase-changed calcium-deficient hydroxyapatite (CDHA) through hydration reaction of? -TCP.

In addition, the internal structure may be formed of at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), alginate, gelatin, collagen Fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, polyurethane, polyvinylpyrrolidone, At least one of at least one of poly (ethylene glycol), poly (propylene glycol), hyaluronan, and poly (vinylpyrrolidone) It is preferable to include an increasing agent.

The hydrogel may be selected from the group consisting of alginate, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), gelatin, collagen, Fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, polyurethane, polyethylene, polyvinylpyrrolidone, A polymer which is at least one of poly (ethylene glycol), poly (propylene glycol), Hyaluronan, and poly (vinylpyrrolidone) .

In addition, the organic particles may further include a gelling agent having a biostability. When the gelling agent is included, there is an advantage that the paste can easily control the physical properties so as to have fluidity suitable for extrusion and molding. The type of the gelling agent is not limited, but preferably includes at least one of H ₂ O, PBS, tris (hydroxymethyl) aminomethane, and N- [tris (hydroxymethyl) methyl] glycine And more preferably, PBS.

Here, the content of the composition of the internal structure and the organic particles is the same as that described above.

The bead-shaped bony filler preferably has a diameter of 1 to 10 mm, more preferably a diameter of 2 to 5 mm.

The foregoing description is merely illustrative of the technical idea of the present invention, and various changes and modifications may be made by those skilled in the art without departing from the essential characteristics of the present invention. Therefore, the embodiments disclosed in the present invention are intended to illustrate rather than limit the scope of the present invention, and the scope of the technical idea of the present invention is not limited by these embodiments. The scope of protection of the present invention should be construed according to the following claims, and all technical ideas within the scope of equivalents should be construed as falling within the scope of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example  One.

Step 1. A first paste was prepared by mixing a? -TCP powder and a 30% by weight aqueous ethanol solution (thickener) containing 1% by weight of hydroxypropylmethylcellulose (HPMC) at a weight ratio of 1: 0.5.

Step 2. The alginate powder was dissolved in a PBS solution to prepare a second paste containing a hydrogel having an alginate concentration of 1 wt%.

Step 3. The first paste prepared in Step 1 was placed in a container containing an inner tube having a diameter of 400 mu m in the extrusion container of the double nozzle and the second paste prepared in Step 2 was placed in a container containing an outer tube and extruded, An enemy was prepared. Here, the extrusion pressure of the first paste was adjusted to 600 U and the extrusion pressure of the second paste was adjusted to 100 U.

Step 4. The droplets prepared in the above step 3 were immersed in calcium chloride (CaCl2) of 2.5 M, and crosslinking was induced for 1 hour to prepare a bead type filler.

Step 5. The bead type bone filler prepared in step 4 was washed and immersed in PBS for 12 hours to induce a curing reaction. The bead type bone filler was finally washed with distilled water and dried to prepare a bead type bone filler containing a coil structure ceramic Respectively.

Example  2.

A bead type bone filler including a coil structure ceramic was produced in the same manner as in Example 1 except that a second paste containing a hydrated gel having an alginate concentration of 2 wt% was produced.

Example  3.

A bead-shaped bone filler including a coil structure ceramic was produced in the same manner as in Example 1, except that BCP (Biphasic Calcium Phosphate) was used instead of the α-TCP powder.

Experimental Example  One. Biz  Form Bone filler  Observation of coil shape microscope

In order to confirm the shape of the bead type bone filler of Examples 1 and 2, a stereoscopic microscope was observed, and the results are shown in Fig.

4 (a) is a bone filler according to Example 1 prepared using a hydrogel having a concentration of alginate of 1 wt%, and FIG. 4 (b) shows a bone filler prepared by using a hydrated gel having an alginate concentration of 2 wt% 2 < / RTI >

As shown in FIG. 4, in the case of a bone filler prepared using alginate having a concentration of 1 wt% and a concentration of 2 wt%, the coil shape of the ceramics in the beads is maintained, and the shape in which the coils I could confirm that it did not appear.

FIG. 5 shows the shape of the bead type filler of Example 3, and it was confirmed that the beads can be manufactured using various ceramic components that cause a self-curing reaction through the method of the present invention.

Example  4.

A bead type bone filler including coil structure ceramics was prepared in the same manner as in Example 1 except that the diameter of the inner tube was 500 mu m.

Experimental Example  2. Inner tube In diameter  Following Biz  Size observation

In order to confirm the bead size according to the diameter of the inner tube when manufacturing the bead type bone filler, the shape of the beads prepared by adjusting the inner diameter of the inner tube to 400 탆 and 500 탆 as in Examples 1 and 4 was observed with a stereoscopic microscope The results are shown in FIG.

6 (a) is a bone filler according to Example 1 manufactured using a double nozzle having an internal pipe diameter of 400 탆, and FIG. 6 (b) is a bore filler according to the embodiment prepared using a double nozzle having an internal pipe diameter of 500 탆 3, and the diameter of the manufactured beads was measured. As a result, the bone filling material of Example 1 was 3.0 mm and the bone filling material of Example 4 was 2.6 mm.

When the diameter of the inner pipe nozzle is 500 mu m, the amount of the first paste to be extruded per unit time is larger than that of 400 mu m, so that the time for maintaining the surface tension of the droplet is shortened, .

Experimental Example  3. Inner tube  Depending on the extrusion pressure Biz  Size observation

The diameter of the beads was measured by varying the extrusion pressure in the range of 400 to 800 U by controlling the inner tube extrusion pressure in order to confirm the bead size according to the extrusion pressure in manufacturing the bead type bone filler. FIG. 7 shows changes in the size of the beads according to the extrusion pressure.

As a result of the experiment, the beads prepared with the extrusion pressure of 600 U according to Example 1 using a double nozzle having a diameter of 400 탆 were measured to have a diameter of 3.0 mm and an extrusion pressure of 400 U The beads were measured at a diameter of 2.7 mm and the diameter of the beads produced at an extrusion pressure of 800 U was measured to be 3.3 mm.

Therefore, as the extrusion pressure of the first paste is adjusted to be smaller, the diameter of the beads becomes smaller, and the diameter of the beads becomes larger as the extrusion pressure of the first paste is adjusted more greatly.

Example  5.

Except that the beads were immersed in PBS for 12 hours to immerse in MCPM for 5 minutes to induce a curing reaction and were washed with distilled water and then dried to obtain beads including a coil structure ceramic Were prepared.

Experimental Example  4. Coil structure of ceramic Self-curing  Reaction observation

XRD analysis was performed to investigate the autocuring reaction of the coil structure ceramic of the bead type bone filler of Examples 1 and 5, and the results are shown in FIGS. 8 and 9, respectively.

8, when the droplet prepared according to Example 1 is immersed in PBS, the α-TCP contained in the beads is phase-transformed into a calcium-deficient hydroxyapatite (CDHA) through a hydration reaction I can confirm that this is happening.

Therefore, it was found that the mechanical strength of the ceramic was improved through the phase change, so that the beads-like structure could be stably maintained to serve as a bone filler.

On the other hand, when the droplet prepared according to Example 5 was immersed in MCPM, it was confirmed that phase deformation to CDHA was similarly caused. However, even if the immersion time was 5 minutes, it was confirmed that the phase deformation was completed within 5 minutes because there was no large difference in structure from the case of immersion for 15 to 60 minutes. This is because the MCPM exhibits acidity and hardening through the acid-base reaction of calcium phosphate progresses partly because the acid-base reaction proceeds relatively fast.

Claims (14)

Preparing a first paste containing calcium phosphate-based ceramics;
Preparing a second paste comprising a hydrogel;
Placing the first paste in a container connected to an inner pipe of an extrusion container having a double nozzle and extruding the second paste into a container connected to an outer pipe of an extrusion container having a double nozzle to form a droplet; And
And immersing the droplets in a crosslinking liquid to obtain beads containing coil structure ceramics.
The method according to claim 1,
Further comprising the step of immersing the beads immersed in the crosslinking solution in a curing liquid.
The method according to claim 1,
Wherein a nozzle size of the inner pipe for extruding the first paste is 100 to 1000 占 퐉.
The method according to claim 1,
The hydrogel may be selected from the group consisting of alginate, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), gelatin, collagen, Fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, polyurethane, polyethylene glycol, And at least one polymer selected from the group consisting of poly (ethylene glycol), poly (propylene glycol), hyaluronan, and poly (vinylpyrrolidone) By weight.
5. The method of claim 4,
Wherein the polymer is contained in a concentration of 0.1 to 10 wt% in the second paste.
The method according to claim 1,
The calcium phosphate-based ceramics may be selected from the group consisting of hydroxyapatite, dicalcium phosphate dihydrate (DCPD), monocalcium phosphate monohydrate (MCPM), dicalcium phosphate anhydrous (DCPA), biphasic calcium phosphate, And β-TCP (β-Tricalcium phosphate).
The method according to claim 1,
The first paste may contain at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), alginate, gelatin, collagen, Fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, polyurethane, polyethylene wax, A thickening agent of at least one of poly (ethylene glycol), poly (propylene glycol), hyaluronan and poly (vinylpyrrolidone) ≪ / RTI >
8. The method of claim 7,
And 10 to 100 parts by weight of a solution containing the thickening agent, based on 100 parts by weight of the calcium phosphate-based ceramic.
The method according to claim 1,
Wherein the cross-linking liquid comprises at least one of calcium chloride (CaCl ₂ ), magnesium chloride (MgCl ₂ ), calcium phosphate (CaP) and calcium carbonate (CaCO ₃ ).
3. The method of claim 2,
The curing solution may be selected from the group consisting of H ₂ O, phosphate buffer saline (PBS), monocalcium phosphate monohydrate (MCPM), diammonium hydrogen phosphate (DAHP), NH ₄ H ₂ PO ₄ , KH ₂ PO ₄ , K ₂ HPO ₄ and NaH ₂ PO ₄ The method comprising the steps of:
An inner structure in which a single ceramic fiber is formed as a coil; And
Forming a surface surrounding the internal structure and containing organic particles
Wherein the bead-shaped bone filler is in the form of a bead.
12. The method of claim 11,
Wherein the internal structure comprises a calcium-deficient hydroxyapatite (CDHA).
12. The method of claim 11,
The internal structure may be formed of at least one selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), alginate, gelatin, collagen, Fibrinogen, chitosan, agar, matrigel, starch, pectin, polyvinyl alcohol, polyurethane, polyethylene wax, A thickening agent of at least one of poly (ethylene glycol), poly (propylene glycol), hyaluronan and poly (vinylpyrrolidone) Wherein the bone filler is a bone filler.
12. The method of claim 11,
The hydrogel may be selected from the group consisting of alginate, gelatin, collagen, fibrinogen, chitosan, agar, Matrigel, starch, pectin, Polyvinyl alcohol, polyurethane, poly (ethylene glycol), poly (propylene glycol), methyl cellulose (hydroxyethyl ethyl cellulose), polyvinyl alcohol, Wherein the filler comprises at least one polymer selected from the group consisting of methyl cellulose, carboxymethylcellulose, hyaluronan and poly (vinylpyrrolidone).

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