Bone regeneration material comprising biodegradable fibers containing tricalcium phosphate particles

Abstract

Provided is a bone regeneration material comprising biodegradable fibers containing both β-TCP particles and m-CP particles. The bone regeneration material comprises biodegradable fibers entwined to form a cotton shape. The biodegradable fibers contain 35 to 85 wt% of tricalcium phosphate particles and 15 to 65 wt% of PLGA resin as the balance. The tricalcium phosphate contains, at a weight ratio of 5 to 50 : 95 to 50, β-TCP particles having a diameter of 0.5 to 5 μm and m-CP particles obtained by subjecting the β-TCP particles to bead milling so as thereby pulverize the β-TCP particles to a diameter of 0.1 to 0.5 μm and transform the β-TCP particles into an amorphous phase. The biodegradable fibers are spun from a spinning solution prepared using an anhydrous solvent and the m-CP particles are dispersed around the β-TCP particles within the fibers without aggregation.

Description

Bone regeneration material consisting of biodegradable fibers containing tricalcium phosphate particles

[0001] The present invention relates to a bone regeneration material comprising biodegradable fibers containing tricalcium phosphate particles.

[0002] β-phase tricalcium phosphate (β-TCP) is widely used as an osteogenic factor in bone regeneration materials. Existing bone regeneration materials using β-TCP particles include a granular type (OSFERION®) and a type in which β-TCP particles are incorporated into biodegradable fibers (REBOSSIS®). In the latter, the β-TCP particles contained in the biodegradable resin dissolve upon contact with body fluids as the resin decomposes, releasing calcium ions and phosphate ions to promote bone formation.

[0003] When the bone regeneration material is implanted in the affected area, the β-TCP particles dissolve in contact with body fluids, eluting calcium ions and phosphate ions. To promote early bone formation, it is desirable that the elution of calcium ions and phosphate ions from the β-TCP particles begin as soon as possible after implantation of the bone regeneration material in the affected area. However, because bone formation takes time, it is desirable that, after implantation of the bone regeneration material in the affected area, the necessary amounts of calcium ions and phosphate ions are gradually and continuously supplied in accordance with the progress of bone formation in the affected area.

[0004] Furthermore, it has been reported that bone formation in the affected area can be further promoted by supplying other biofunctional ions (silicon, boron, magnesium, etc.) in addition to calcium ions / phosphate ions.

[0005] Patent Document 1: Japanese Patent No. 6251462

[0006] Non-Patent Document 1: Creation of a metal ion sustained-release scaffold based on the activation mechanism of osteoblasts. Materia Vol. 59, No. 11 (2020) Akiko Obata, Toshihiro Kasuga

[0007] Under these circumstances, there is a need for a bone regeneration material that, after implantation at the affected area, initiates the elution of calcium ions, phosphate ions, and other ions effective in bone formation early, and that can realize effective bone formation by continuously and gradually releasing these ions throughout the progression of bone formation. However, it has been difficult to achieve all of these functions using crystalline β-TCP particles.

[0008] As a result of extensive research aimed at solving the above problems, the inventors of the present invention came up with the idea of ​​preparing particles (m-CP particles) in which the crystalline structure of β-TCP is modified to be amorphous by applying impact to β-TCP particles using a bead mill, and then incorporating the m-CP particles together with β-TCP particles into biodegradable fibers. β-TCP particles and m-CP particles have different dissolution rates, so by incorporating both, it is possible to quickly elute calcium ions / phosphate ions from the m-CP particles, followed by continuous, sustained release of calcium ions / phosphate ions from the β-TCP particles. Furthermore, when m-CP particles are subjected to impact, the crystalline bonds are broken and the particles are ionized to release phosphate ions (PO ４ ) ３－ Since the particles are negatively charged, they can be coordinated with positively charged metal or metalloid ions. However, when the particle size is reduced to an extremely small size by bead milling, they are prone to agglomeration in the fiber. When particles agglomerate, it takes a long time for the particles to come into contact with body fluids after implantation, making early bone formation difficult. The inventors of the present invention discovered that by using an anhydrous solvent in the preparation of the spinning solution, particles can be prevented from agglomerating and uniformly dispersed in the fiber.

[0009] Based on the above idea and discovery, the inventors of the present invention have developed a bone regeneration material comprising biodegradable fibers containing tricalcium phosphate particles, wherein the bone regeneration material is composed of biodegradable fibers having an outer diameter of 60 to 200 μm entangled with one another to form a cotton-like shape, the biodegradable fibers containing 35 to 85% by weight of tricalcium phosphate particles and the remainder being 15 to 65% by weight of polylactic acid-co-glycolic acid (PLGA resin), the tricalcium phosphate containing β-phase tricalcium phosphate particles (β-TCP particles) having a diameter of 0.5 to 5 μm and tricalcium phosphate particles (m-CP particles) obtained by bead milling the β-TCP particles to a diameter of 0.1 to 0.5 μm and modifying them to an amorphous phase, in a weight ratio of 5 to 50:95 to 50, and the biodegradable fibers are spun from a spinning solution prepared using an anhydrous solvent, and the m-CP particles are dispersed in the fibers surrounding the β-TCP particles without agglomeration. The inventors have arrived at the invention of a bone regeneration material comprising biodegradable fibers containing the tricalcium phosphate particles.

[0010] Preferably, the biodegradable fiber contains 50 to 75% by weight of tricalcium phosphate particles and 50 to 25% by weight of PLGA resin, and the tricalcium phosphate particles contain the β-TCP particles and the m-CP particles in a weight ratio of 10 to 25:90 to 75.

[0011] Preferably, the PLGA resin is a PDLLGA resin containing a D-form, and the anhydrous solvent is acetone.

[0012] Preferably, the m-CP particles are prepared by wet-milling β-TCP particles with acetone.

[0013] Preferably, the m-CP particles contain metal ions (eg, magnesium ions, silver ions) or semi-metal ions (eg, boron ions, silicon ions).

[0014] Preferably, the m-CP particles contain silver ions, and a bone regeneration material containing the m-CP particles containing silver ions exhibits antibacterial properties.

[0015] Preferably, the biodegradable fibers of the bone regeneration material of the present invention are spun using a wet spinning method.

[0016] Preferably, the outer diameter of the biodegradable fibers in the bone regeneration material of the present invention is 80 to 160 μm, more preferably 100 to 120 μm.

[0017] The inventors of the present invention have further disclosed a method for producing a bone regeneration material comprising biodegradable fibers containing tricalcium phosphate particles, comprising: pulverizing beta-phase tricalcium phosphate particles (β-TCP particles) to a diameter of 0.1 to 0.5 μm using a bead mill to prepare amorphous-phase modified tricalcium phosphate particles (m-CP particles); adding 30 to 80% by weight of β-TCP particles having a diameter of 0.5 to 5 μm, 5 to 35% by weight of the m-CP particles, and 15 to 65% by weight of PLGA resin to acetone and stirring them to prepare a spinning solution; spinning the spinning solution into biodegradable fibers using a wet spinning method, the biodegradable fibers having an outer diameter of 60 to 200 μm, the m-CP particles being dispersed surrounding the β-TCP particles without agglomeration within the fibers; and recovering a bone regeneration material in which the biodegradable fibers are entangled to form a cotton-like structure by washing the spun biodegradable fibers with ethanol and drying them at room temperature. The inventors have arrived at an invention of a method for producing a bone regenerating material comprising biodegradable fibers containing the above-mentioned tricalcium phosphate particles.

[0018] Preferably, the biodegradable fiber contains 40 to 70% by weight of the β-TCP particles, 5 to 15% by weight of the m-CP particles, and 15 to 65% by weight of the PLGA resin.

[0019] Preferably, the PLGA resin is a PDLLGA resin containing a D-form, and the anhydrous solvent is acetone.

[0020] Preferably, the m-CP particles are prepared by wet-milling β-TCP particles with acetone.

[0021] Preferably, the method includes the step of incorporating metal or metalloid ions into the m-CP particles.

[0022] In the bone regeneration material produced by the method of one embodiment of the present invention, the small-sized m-CP particles are dispersed within the fibers, surrounding the β-TCP particles, without agglomerating. Therefore, after the bone regeneration material is implanted into the affected area, the m-CP particles dissolve upon contact with body fluids, quickly releasing calcium ions and phosphate ions, followed by the β-TCP particles dissolving later, continuously and gradually releasing calcium ions and phosphate ions, thereby achieving effective bone formation.

[0023] The bone regeneration material produced by the method of one embodiment of the present invention uses PDLLGA resin, which has a fast decomposition rate, as a biodegradable fiber. Therefore, after the bone regeneration material is implanted into the affected area, the PDLLGA resin quickly decomposes upon contact with body fluids, resulting in the rapid elution of calcium ions and phosphate ions.

[0024] The biodegradable fibers constituting the bone regeneration material produced by the method of one embodiment of the present invention are spun using a spinning solution prepared by dissolving PDLLGA resin in anhydrous acetone, so that the tricalcium phosphate particles do not bond to each other and do not aggregate within the fibers.

[0025] The m-CP particles contained in the biodegradable fibers of the bone regeneration material of the present invention have a small particle size of 0.1 to 0.5 μm, a large specific surface area, and are amorphous and negatively charged, making it possible to coordinate metal ions or metalloid ions such as magnesium ions, boron ions, silver ions, and silicon ions. When a bone regeneration material carrying these metal ions or metalloid ions on its fibers is implanted in a living body, the biodegradable fibers dissolve in contact with body fluids, allowing these metal ions and metalloid ions to be eluted from the m-CP particles contained in the fibers along with calcium ions and phosphate ions.

[0026] The biodegradable fibers constituting the bone regeneration material produced by the method of one embodiment of the present invention are spun using a spinning solution prepared by dissolving PDLLGA resin in anhydrous acetone, and are therefore safer than those using chlorine-based solvents such as chloroform.

[0027] The biodegradable fibers that make up the bone regeneration material produced by the method of one embodiment of the present invention are spun using a wet spinning method, and therefore the production costs are lower than when electrospinning is used.

[0028] Figure 1 shows a cotton-shaped bone regeneration material made from the biodegradable fiber of the present invention. Figure 2 shows a conceptual diagram of the composition of the biodegradable fiber containing β-TCP particles and m-CP particles of the present invention. Figure 3 shows a cross-section of the biodegradable fiber containing β-TCP particles and m-CP particles of the present invention. Figure 4 shows a scanning electron microscope (SEM) photograph of the cross-section of the biodegradable fiber of the present invention cut using a cooled cross-section polisher (CCP; IB19520CCP manufactured by JEOL Ltd.). Figures 5(A) and (B) show the bead mill apparatus used in the present invention.

[0029] Preferred embodiments of the present invention will now be described with reference to the accompanying drawings.

[0030] <m-CP Particles> In the present invention, "m-CP particles" refers to tricalcium phosphate particles obtained by bead milling β-phase tricalcium phosphate particles to a diameter of 0.1 to 0.5 μm and modifying them to an amorphous phase. The m-CP particles break the crystalline structure of calcium phosphate, allowing negatively charged phosphate ions to coordinate with positive ions separated from metal or metalloid salts. The tricalcium phosphate contained in the biodegradable fiber according to an embodiment of the present invention contains β-TCP particles and m-CP particles in a weight ratio of 5 to 50:95 to 50. However, if the ratio of m-CP particles to β-TCP particles is less than 5:95, the high solubility of the m-CP particles is not fully realized. Conversely, if the ratio of m-CP particles to β-TCP particles is greater than 50:50, the m-CP particles will aggregate more severely, and the amount of ions eluted from the m-CP particles may temporarily become too high, potentially adversely affecting biological tissue.

[0031] <Bead Mill Apparatus> In the present invention, the term "bead mill apparatus" refers to a grinding machine used to subject particles to mechanochemical treatment, using beads with a diameter of 0.015 to 3 mm as grinding media (Figure 4). While the diameter of balls used as grinding media in a typical ball mill is 10 to 50 mm, the diameter of the beads used as grinding media in a bead mill apparatus is 0.015 to 3 mm. By using small-diameter beads as grinding media, it is possible to impart 100 to 500 times more energy to calcium phosphate particles than when using balls with a diameter of 10 to 50 mm. A planetary bead mill apparatus alternately rotates and revolves particles placed in a vessel, thereby applying stronger impact energy to the particles with the beads used as grinding media, resulting in higher grinding efficiency. There are various types and models of bead mill apparatuses, but any of them can be used as the bead mill apparatus of the present invention as long as they are capable of finely grinding calcium phosphate particles with beads.

[0032] <Bead mill treatment> In the present invention, "bead mill treatment" refers to a treatment in which beads are placed in a pot of a bead mill device, and a powder of particles is added and rotated at high speed to impart a large amount of energy to the particles constituting the powder through a violent mechanical impact. When calcium phosphate particles are subjected to a large amount of energy through a violent mechanical impact by the bead mill treatment, the particles are pulverized to reduce their diameter, and the bonds constituting the particles are broken and ionized.

[0033] <Wet milling> In the present invention, "wet milling" refers to a method in which beads are placed in a container and stirred to mill, as opposed to dry milling, in which milling is performed without mixing with a liquid (in air). When milling is performed in a dry bead mill, the milled particles are increasingly loaded against each other, causing clogging and making it easy for hard agglomerates to form during milling. In wet milling, H ＋If a polar liquid (e.g., water) is used, the crushed particles will form hydrogen bonds and aggregate. ＋ It is preferable to use a liquid that does not dissociate and has no polarity (e.g., acetone).

[0034] <Wet spinning method> "Wet spinning" generally refers to a method in which a polymer dissolved in a solvent is extruded from a nozzle into the liquid to form fibers. The wet spinning method used in the present invention is described in detail in WO2022 / 113888 (Method for producing a cotton-shaped bone regeneration material) and WO2023 / 228905 (Method for continuously producing a biodegradable fiber material containing inorganic filler particles using a wet spinning method, and a cotton-shaped bone regeneration material produced by the method).

[0035] Embodiment 1: Production of a bone regeneration material consisting of biodegradable fibers containing β-TCP particles and m-CP particles. 1. Preparation of m-CP particles: A powder of β-TCP particles with a diameter of 0.5 to 5 μm is placed in a zirconia pot (volume capacity 30 to 60 mL) of a planetary bead mill along with 35 to 50 g of beads with a diameter of 0.5 to 1.4 mm, in an amount such that the apparent volume ratio of the two is 1:2 to 4. 15 to 20 mL of acetone is added, and the planetary bead mill is rotated and revolved at a predetermined speed to perform wet milling. Impact from the beads pulverizes the β-TCP particles, reducing their particle diameter to 0.1 to 1.2 μm and increasing their specific surface area by 3 to 5 times. The crystalline structure of the β-TCP particles is partially amorphous, reducing the crystallinity to 50 to 10%.

[0036] 2. Spinning of Biodegradable Fibers Containing β-TCP and m-CP Particles 1) Preparation of Spinning Solution β-TCP particles, m-CP particles, and PDLLGA are mixed in a weight ratio of 30-55:5-35:15-65, the polymer is dissolved in acetone, and the mixture is mixed overnight to prepare a spinning solution with a polymer concentration of 17-23%. If the amount of PDLLGA resin is less than 15% by weight, the resin has difficulty binding the particles together, making spinning difficult. Conversely, if the amount of PDLLGA resin is more than 65% by weight, the biocompatibility of calcium phosphate cannot be fully realized. 2) Wet Spinning Biodegradable fibers are spun by wet spinning using the particle dispersion prepared above as the spinning solution. 3. Recovery of cotton-like bone regeneration material After wet spinning, the entangled aggregate of spun biodegradable fibers is roughly treated with an absorbent sheet to remove the poor solvent (water, etc.), and then dried overnight at room temperature to obtain cotton-like sample 1 (see Figure 1).

[0037] 4. Properties of the obtained biodegradable fiber / bone regeneration material: Biodegradable fibers with diameters of 60 to 200 μm are entangled to form a cotton-like structure. In the biodegradable fiber, m-CP particles do not aggregate but are dispersed around β-TCP particles (see Figures 2 and 3).

[0038] Embodiment 2: Manufacturing of a bone regeneration material comprising biodegradable fibers containing β-TCP particles and m-CP particles containing metal or metalloid ions 1. Preparation of m-CP particles containing metal or metalloid ions (1) A powder of β-TCP particles and a powder of metal (e.g., magnesium, silver) or metalloid (e.g., silicon, boron) salt particles are mixed in a weight ratio of 0.99-0.90 to 0.01-0.1, and the powder mixture is placed in a zirconia vessel (volume capacity 30-60 mL) of a planetary bead mill along with 15-20 mL of acetone and 35-50 g of beads with a diameter of 0.6-1.4 mm, and the planetary bead mill is rotated and revolved at a predetermined speed. (2) Upon impact with the beads, the β-TCP particles are pulverized, reducing their particle size and increasing their specific surface area, while the crystalline structure of the β-TCP particles is partially amorphous, resulting in m-CP particles. Metal or metalloid salt particles introduced into the zirconia vessel of a planetary bead mill are impacted by the beads, causing metal or metalloid ions to separate from the particles, and the separated positive ions coordinate to the phosphate ions (negatively charged) of the m-CP particles. (3) After continuing high-speed rotation of the planetary bead mill for a certain period of time, the mill is allowed to stand, whereby the ions separated from the metal or metalloid salt particles are immobilized in a coordinate bond with the phosphate ions of the m-CP particles. The mixed powder is then separated from the beads by sieving and washed away, and the mixture is placed in a 70°C oven overnight to remove the acetone, recovering the m-CP particles containing metal or metalloid ions.

[0039] 2. Spinning of biodegradable fibers containing β-TCP particles and m-CP particles, recovery of cotton-like bone regeneration material, and properties of the resulting biodegradable fiber / bone regeneration material. β-TCP particles, m-CP particles containing metal or metalloid ions, and PDLLGA were mixed in a weight ratio of 30-55:5-35:15-65 and dissolved in acetone to prepare a spinning solution. Biodegradable fibers were spun using a wet spinning method, and the spun biodegradable fibers were dried to obtain cotton-like Sample 2 (see Figure 1). The properties of the resulting biodegradable fiber / bone regeneration material were the same as those in Example 1, except that the m-CP particles contained metal or metalloid ions.

[0040] Experiment 1 <Contents of Experiment 1> Preparation of biodegradable fibers containing β-TCP particles, m-CP particles, and PDLLGA. β-TCP particles (manufactured by Taihei Chemical Industry Co., Ltd., diameter 0.5-5 μm, average 1.2 μm), m-CP particles (diameter 0.02-1.0 μm, average 0.4 μm), and PDLLGA were mixed in a weight ratio of 30:14:56, dissolved in acetone, and mixed overnight to prepare a spinning solution with a polymer concentration of 23.3%. Biodegradable fibers with fiber diameters of 100-120 μm were spun using the spinning solution prepared above by wet spinning. The cross-section of the spun biodegradable fibers was polished using a cooled cross-section polisher (CCP) (cooled to approximately -100°C and ion-milled using argon irradiation).

[0041] <Results of Experiment 1> SEM photographs of the cross section of the biodegradable fiber spun in the above experiment are shown in Figures 3 and 4. In the SEM photographs in Figures 3 and 4, the bright areas represent tricalcium phosphate particles (TCP), and the dark areas represent PDLLGA resin. Because there is no chemical bond between the biodegradable fiber and TCP and the elastic moduli differ significantly, the grinding process places a load on the large TCP particles, causing them to easily dislodge, leaving behind the matrix polymer, resulting in a cross section full of holes. Based on their size and shape, these holes are believed to be areas where TCP particles were originally embedded, and the polymer matrix remains (the dark areas). Since m-CP particles are small, on the submicron order, if they are completely embedded in the matrix, they will not dislodge. In Figure 4, the white arrows indicate m-CP particles near the surface of the holes. This photograph shows m-CP particles dispersed around β-TCP particles.

[0042] Experiment 2 <Contents of Experiment 2> Preparation of m-CP particles containing silver ions (1) β-TCP powder and Ag ３ P.O. ４The powders (both manufactured by Taihei Chemical Industry Co., Ltd.) were mixed in a weight ratio of 99:1 to prepare 1.8 g of mixed powder. (2) 40.5 g of 1 mm diameter beads and 13.5 g of acetone (= 17 ml) were placed in a zirconia vessel (volume capacity 45 ml) of a planetary ball mill. With the beads / acetone contained, the vessel was immersed to about 80% of its capacity. 1.8 g of the prepared mixed powder was then placed in the vessel, and the ball mill was rotated at high speeds of 400 rpm (revolution) and 800 rpm (rotation). (3) When the planetary ball mill was rotated at high speed, the β-TCP particles were finely pulverized, and the crystalline structure of the β-TCP particles was partially amorphized by impact from the beads. The impact from the beads caused Ag ３ P.O. ４ Silver ions were separated from the particles, and the separated silver ions (positive charge) were coordinated with the phosphate ions (negative charge) of the amorphous β-TCP particles (m-CP particles). (4) The planetary ball mill was rotated at high speed for 2 hours and then allowed to stand, whereby Ag was formed around the phosphate ions of the m-CP particles. ３ P.O. ４ The silver ions separated from the particles were fixed in a coordinated state. (5) After the fixation step, the zirconia beads were separated from the powder mixture by sieving and washing, and the m-CP particles containing silver ions were recovered.

[0043] <Results of Experiment 2> (i) The beads used were 1 mm in diameter. If the beads were 1 mm in diameter, they could be roughly recovered by simply passing them through a sieve with openings of about 125 μm and rinsing them with acetone. If beads with a diameter smaller than 1 mm are used, the crushing effect increases, but a sieve with openings too small to allow the beads to fall through must be used, which takes time to recover. (ii) Ag ３ P.O. ４ The silver ion concentration in the solution was measured using ICP-AES after immersing the powder of silver ions prepared by subjecting the silver ion-containing m-CP particles and β-TCP particles to a wet bead mill treatment in a HEPES buffer solution. The silver ion concentration increased sharply at first, then gradually decreased. (iii) The silver ion-containing m-CP particles prepared in Experiment 2 can be dispersed and incorporated into biodegradable fibers together with β-TCP particles, as in Experiment 1.

[0044] Experiment 3 <Contents of Experiment 3> Preparation of m-CP particles containing boron ions (1) β-TCP powder (manufactured by Taihei Chemical Industry Co., Ltd.) and B ２ O ３ Powders (special grade, manufactured by Kishida Chemical) were mixed in a weight ratio of 10-30:90-70 to prepare 1.8 g of mixed powder. (2) 40.5 g of beads with a diameter of 1 mm and 13.5 g of acetone (= 17 mL) were placed in a zirconia vessel (volume capacity 45 mL) of a planetary ball mill. With the beads / acetone contained, the vessel was immersed to about 80% of its capacity. 1.8 g of the mixed powder prepared above was added thereto, and the ball mill was rotated at high speeds of 400 rpm (revolution) and 800 rpm (rotation). (3) When the planetary ball mill was rotated at high speed, the crystal structure of the β-TCP particles was impacted by the beads and partially amorphized. At the same time, the impact of the beads caused B ２ O ３ (4) The planetary ball mill was rotated at high speed for 2 hours and then allowed to stand, resulting in the formation of amorphous β-TCP (m-CP). ２ O ３ (5) After the immobilization step, the treated product was separated by sieving and washing with acetone to recover calcium phosphate particles containing boron ions.

[0045] <Results of Experiment 3> (i) β-TCP powder and B ２ O ３ The particles obtained by grinding the powders together were approximately 0.1 μm to 1 μm in size and varied in shape. Furthermore, the number of agglomerated particles increased with increasing amounts of boron added. It is believed that agglomeration occurred when boron reacted with atmospheric water during solid-liquid separation and drying, resulting in a powder that is highly reactive with moisture. (ii) The m-CP particles containing boron ions prepared in Experiment 3 can be dispersed and incorporated into biodegradable fibers together with β-TCP particles.

[0046] Although the present invention has been described above with reference to examples, the present invention is not limited to these examples and is within the scope of the present invention as long as it has the structure or method described in the claims. Furthermore, the method for spinning the biodegradable fiber is not limited to the wet spinning method described in the examples, and other spinning methods such as electrospinning are also within the scope of the present invention as long as they can spin biodegradable fibers containing both β-TCP particles and m-CP particles.

[0047] 1 Biodegradable fiber 10 β-TCP particles 20 m-CP particles

Claims

1. A bone regeneration material comprising biodegradable fibers containing tricalcium phosphate particles, the bone regeneration material being composed of biodegradable fibers having an outer diameter of 60-200 μm entangled with one another to form a cotton-like shape, the biodegradable fibers containing 35-85% by weight of tricalcium phosphate particles and the remainder being 15-65% by weight of PLGA resin, the tricalcium phosphate containing β-phase tricalcium phosphate particles (β-TCP particles) having a diameter of 0.5-5 μm and tricalcium phosphate particles (m-CP particles) which have been modified to an amorphous phase by crushing the β-TCP particles to a diameter of 0.1-0.5 μm by bead milling in a weight ratio of 5-50:95-50, the biodegradable fibers being spun from a spinning solution prepared using an anhydrous solvent, and the m-CP particles being dispersed in the fibers surrounding the β-TCP particles without agglomeration.

2. The bone regeneration material according to claim 1, wherein the biodegradable fiber contains 50-75% by weight of tricalcium phosphate particles and 50-25% by weight or more of PLGA resin, and the tricalcium phosphate particles contain the β-TCP particles and the m-CP particles in a weight ratio of 10-25:90-75.

3. The bone regeneration material according to claim 1 or 2, wherein the PLGA resin is a PDLLGA resin containing a D-form, and the anhydrous solvent is acetone.

4. The bone regeneration material according to claim 1 or 2, wherein the m-CP particles are prepared by wet-grinding β-TCP particles with acetone.

5. The bone regeneration material according to claim 1 or 2, wherein the m-CP particles carry metal or semi-metal ions.

6. The bone regeneration material described in claim 1 or 2, wherein the m-CP particles carry silver ions.

7. The bone regeneration material according to claim 1 or 2, wherein the biodegradable fibers are spun using a wet spinning method.

8. A method for producing a bone regeneration material made of biodegradable fibers containing tricalcium phosphate particles, comprising the steps of: pulverizing β-phase tricalcium phosphate particles to a diameter of 0.1 to 0.5 μm using a bead mill to prepare tricalcium phosphate particles (m-CP particles) modified to an amorphous phase; adding 30 to 80% by weight of β-TCP particles having a diameter of 0.5 to 5 μm, 5 to 35% by weight of the m-CP particles, and 15 to 65% by weight of PLGA resin to acetone and stirring and mixing them to prepare a spinning solution; spinning the spinning solution using a wet spinning method to spin biodegradable fibers; and washing the spun biodegradable fibers with ethanol and drying them at room temperature to recover a cotton-like bone regeneration material.

9. The method for producing a bone regenerating material according to claim 8, wherein the m-CP particles are prepared by wet-grinding β-TCP particles with acetone.

10. The method for producing a bone regenerating material according to claim 8 or 9, further comprising a step of loading metal or metalloid ions onto the m-CP particles.

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