JP2018019944A - Bone regeneration material comprising biodegradable fiber, and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safer bone regeneration material, comprising a biodegradable fiber that consists of PLGA and β-phase tricalcium phosphate particles.SOLUTION: This invention relates to a bone regeneration material, comprising a biodegradable fiber, wherein the biodegradable fiber substantially consists only of a poly(lactic-co-glycolic acid) copolymer and β-phase tricalcium phosphate particles. The β-phase tricalcium phosphate particles are prepared such that an amorphous site is high in purity that does not substantially exist, by calcinating amorphous calcium phosphate, the precursor, at substantially last-minute temperature before the β-phase in the tricalcium phosphate is changed into an α-phase. The β-phase tricalcium phosphate particles are dispersed within the biodegradable fiber in such a state that calcium ion and a functional group of the poly(lactic-co-glycolic acid) copolymer are not coordinated.SELECTED DRAWING: Figure 3(2)

Description

The present invention relates to a bone regeneration material composed of biodegradable fibers and a method for producing the bone regeneration material.

In the field of bone regenerative medicine, biodegradable fibers produced by incorporating bone-forming factors into biodegradable resins such as polylactic acid (hereinafter referred to as PLA) and polylactic acid-glycolic acid copolymer (hereinafter referred to as PLGA) A method for embedding a bone regeneration material comprising a bone defect in a bone defect part has been implemented. After the bone regeneration material is implanted in the body, it is decomposed in contact with the body fluid, and the contained bone morphogenetic factors are released gradually, and the bone resorption material is absorbed and disappears over time. Can be obtained and the burden on the patient can be reduced.

In order for the bone regeneration material to be implanted in a human body and exhibit bone forming activity, the matrix resin is required to be able to carry the bone forming factor as a scaffold so that it can be sustainedly released. As an osteogenesis factor, calcium triphosphate, particularly β-phase tricalcium phosphate (hereinafter referred to as β-TCP) has excellent osteogenic activity and is preferably used. In order to smoothly exhibit bone resorption and replacement by β-TCP, the matrix resin is contacted with body fluids and hydrolyzed as soon as possible to start the sustained release of tricalcium phosphate, and then rapidly decomposed and absorbed. It is desirable to disappear. PLGA is excellent in promoting early absorption and bone replacement of β-TCP because it is rapidly absorbed and decomposed after being implanted in the human body.

β-TCP is generally manufactured by sintering and crystallizing a precursor amorphous calcium phosphate. When the sintering temperature is set to 800 ° C. to 1100 ° C., β-phase TCP is obtained, and when the temperature is set higher than 1200 ° C., the crystal of TCP transitions to α-phase. Since α-TCP has a high absorption rate in the body, TCP disappears early and is often not replaced by bone, and thus is not suitable as a bone defect filling material for orthopedics. Since β-TCP has a slower absorption rate in the body than α-TCP, and sufficient bone replacement is obtained, it is preferably used as a bone defect filling material for orthopedics.

The β-TCP porous material has excellent bone formation activity and is used as a bone filling material. However, in order to avoid the crystal phase from transitioning from β to α by sintering calcium phosphate in manufacturing. The firing temperature cannot be raised above 1100 ° C. As a result, there is a problem that the skeleton portion of the porous body of β-TCP is not sufficiently sintered and the mechanical strength is weaker than that of other porous calcium phosphates. However, if β-TCP is not used alone but is used as a bone regeneration material consisting of biodegradable fibers containing β-TCP in a biodegradable resin, the mechanical strength of β-TCP porous material is insufficient. Will not be a problem. Therefore, recently, biodegradable fibers containing β-TCP particles are being developed as effective bone regeneration materials.

Inclusion of β-TCP in a biodegradable resin, however, poses another challenge regarding the safety of bone regeneration materials. Since an orthopedic bone regeneration material is used by being implanted in a human body, it is extremely important to ensure the safety of the compound constituting the material to the human body. In bone regeneration materials composed of biodegradable fibers, both inorganic particles and biodegradable resins, which are bone-forming factors, are chemically safe even if they are safe materials that have received safety approval under the Pharmaceutical Affairs Law. When bound to form a compound, the safety of the material in the form of the compound must be further verified.

In the process of producing a composite of β-TCP and a biodegradable resin, it has been pointed out that calcium of calcium phosphate may be ionized to form a chemical bond with the functional group of the biodegradable resin. “Chemical Interaction in β-Calcium Phosphate / Polylactic Acid Copolymer Complex” Masaki Kikuchi et al. Journal of the Ceramic Society of Japan 108 [7] 642-645 (2000) ”using β-TCP and CPLA using a kneader It is disclosed that when a composite is produced by kneading, the carbonyl group of CPLA reacts with the calcium ion of TCP to form a weak bond. In this document, calcium phosphate was synthesized using a wet synthesis method using Ca (OH) ₂ and H ₃ PO ₄ as starting materials, and sintered at 1073K (= 800 ° C) and 1373K (= 1100 ° C). β-TCP ₁₀₇₃ and β-TCP ₁₃₇₃ are prepared. However, what measures that the document exists Chemical Bonding between the TCP of Ca ²⁺ and C = O ^.sigma. in IR spectrum is only for beta-TCP _1073.

Chemical interaction in β-calcium phosphate / polylactic acid copolymer complex Masaki Kikuchi et al. Journal of the Ceramic Society of Japan 108 [7] 642-645 (2000)

When biodegradable fiber containing β-TCP in biodegradable resin is used as a bone regeneration material, if there is any chemical bond between β-TCP and biodegradable resin, it has the bond Therefore, the existence of chemical bonds is not desirable from the viewpoint of ensuring safety as a bone regeneration material. However, the biodegradable resin has functional groups such as a carboxyl group and a carbonyl group, and these functional groups are likely to form a bond with calcium ions. In particular, when a biodegradable resin and β-TCP complex is made into a biodegradable fiber using a method such as electrospinning, the biodegradability is achieved in the process of kneading and stirring with the resin solution. This is an important problem in practice because it tends to cause a bond between the functional group of the resin and the calcium ion of β-TCP.

Under the circumstances as described above, in order to make the bone regeneration material consisting of biodegradable fibers containing β-TCP and biodegradable resin commercially practical, a new safety issue can be cleared. There has been a demand for a material for bone regeneration and a method for producing the same.

In order to solve the above problems, the inventors of the present invention have conducted extensive experiments and as a result, β-TCP is crystallized with high purity so as not to substantially contain an amorphous phase. It was discovered that there was no chemical bond between the functional group of the biodegradable resin and the calcium ion of β-TCP. Based on the discovery, the inventors have made the biodegradable resin functional group of the biodegradable resin by adding β-TCP obtained by crystallizing calcium phosphate into β phase with high purity into the biodegradable resin. It was conceived that a bone regeneration material composed of biodegradable fibers that were not chemically bound to calcium ions of β-TCP could be produced.

One embodiment of the present invention is a bone regeneration material comprising biodegradable fibers, wherein the biodegradable fibers are substantially composed only of PLGA resin and β-TCP fine particles, and the β-TCP fine particles Is obtained by firing the precursor amorphous calcium phosphate at a temperature substantially immediately before the transition of the β phase of TCP to the α phase. -TCP is prepared from the biodegradable fiber dispersed in the biodegradable fiber in a state where the calcium ion and the functional group of the PLGA resin are not coordinated. It is a material for bone regeneration.

Preferably, the biodegradable fiber is substantially composed of about 30 to 60% by weight of PLGA and about 70 to 40% by weight of β-TCP fine particles, and the β-TCP fine particles are contained in the biodegradable fiber. Almost uniformly dispersed without agglomeration.

One embodiment of the present invention is a method for producing a bone regeneration material comprising biodegradable fibers,
A precursor of amorphous calcium phosphate is calcined at a temperature substantially immediately before the transition of the β-phase of TCP to the α-phase. Preparing fine particles,
After the PLGA resin is softened by heating with a kneader at a temperature above the glass transition point, the β-TCP fine particles are put into the kneader, mixed, kneaded by applying thermal and mechanical energy, and then cooled and solidified. To produce a composite in which the β-TCP fine particles are dispersed in the PLGA resin,
Creating a spinning solution by dissolving the composite in a solvent;
By spinning the spinning solution, a biodegradable fiber in which the β-TCP fine particles are dispersed in a state where the calcium ion of the β-TCP and the functional group of the PLGA resin are not coordinated is prepared. ,
This is a method for producing a bone regeneration material comprising biodegradable fibers.

Preferably, the PLGA is added to the kneader in an amount of about 30 to 60% by weight and the β-TCP fine particles are about 70 to 40% by weight, kneaded, and then cooled and solidified. Create a composite with fine particles dispersed almost uniformly,
Creating a spinning solution by dissolving the composite in a solvent;
By spinning the spinning solution by an electrospinning method, the β-TCP fine particles are almost uniformly dispersed without agglomeration in a state where the calcium ion of the β-TCP and the functional group of the PLGA are not coordinated. A biodegradable fiber is produced.

In the preparation of the spinning solution, a process of kneading the heated and softened PLGA resin with β-TCP fine particles together with β-TCP fine particles with heat and mechanical energy is performed, so that β- An amount of about 70 to 40% by weight of TCP fine particles can be uniformly dispersed in the PLGA resin without agglomerating the particles. The kneading step is an extremely effective method for uniformly dispersing β-TCP fine particles in the PLGA resin, but on the other side, the possibility of causing a bond between the functional group of PLGA and calcium ions is increased. . However, since TCP is crystallized in a β phase with high purity, even when exposed to a functional group of PLGA, coordination with calcium ions does not occur.

Preferably, the PLGA is a copolymer of PLA and PGA containing only L form.

Preferably, the PLGA is a copolymer of PLA and PGA in which L-form and D-form are mixed.

Preferably, the ratio of lactic acid to glycolic acid in the PLGA is about 85-50: 15-50.

Preferably, the outer diameter of the β-TCP particles is 0.5 to 4 μm.

Preferably, the outer diameter of the biodegradable fiber is 10 to 150 μm.

The material for bone regeneration according to the present invention consists only of β-TCP and PLGA, which are safe materials approved by the Pharmaceutical Affairs Law, and since no chemical bond is formed between the two, safety is ensured. It can be commercially used as the secured bone regeneration material.

It is an outline photograph of the material for bone regeneration which is an example of the present invention. It is a general-view photograph of the biodegradable fiber of the material for bone regeneration which is an Example of this invention. The result of having measured NMR about sample (1) and (2) is shown. The figure which expanded and matched the peak around the carbonyl group (C = O; -170 ppm) of FIG. 3 (1) is shown. The result of having measured the NMR of sample (3) is shown. The figure which expanded and matched the phase around the carbonyl group (C = O; -170 ppm) of FIG. 3 (3) is shown. The result of the XRD measurement of β-TCP used in the present invention is shown.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings.

<Biodegradable resin>
PLA and PLGA can be used for the biodegradable fiber resin of the bone regeneration material of the present invention, and PLGA is particularly preferably used. In the present invention, PLGA widely includes copolymers of polylactic acid and polyglycolic acid.

When PLGA is used as the biodegradable resin of the present invention, the ratio of lactic acid to glycolic acid in PLGA is appropriately selected as necessary, and includes 85:15, 75:25, 50:50.

For polylactic acid (PLA), poly-L-lactic acid (PLLA) obtained by polymerizing only the L isomer and poly-D-lactic acid (PDLA) obtained by polymerizing only the D isomer, both D and L Although there is PDLA mixed with lactic acid, the PLGA of the present invention may be a copolymer of any of these types of polylactic acid and polyglycolic acid. In this application, a copolymer of PLLA and PGA is referred to as PLLGA, and a copolymer of PDLA and PGA is referred to as PDLGA.

<Β-TCP>
Β-TCP fine particles are preferably used as the bone forming factor used in the bone regeneration material of the present invention. β-tricalcium phosphate (β-TCP) is suitable as a substance that becomes a scaffold for proliferation and differentiation of osteoblastic cells. The appearance of β-TCP is powdery. The diameter of the particles constituting the powder is preferably 0.5 to 4 μm. Considering that the outer diameter of the fibers constituting the bone regeneration material of the present invention is 10 to 150 μm, the particle diameter is preferably about 4 μm or less.

As the β-TCP of the present invention, it is preferable to use a product produced by firing amorphous calcium phosphate and crystallizing it into a β phase with high purity. If TCP is crystalline and has almost no amorphous phase, bonding with the functional group of the resin does not occur even after kneading with the biodegradable resin. As a result of repeated experiments, the inventors obtained high-purity β-TCP with almost no amorphous phase when calcium phosphate is calcined at a high temperature immediately before the β phase transitions to the α phase. It was discovered that when it is contained in a functional resin to form a composite, no chemical bond is formed between them.

According to the knowledge of the inventors, the reason why no chemical bond is formed between the high-purity β-TCP and the biodegradable resin is that the atomic arrangement is random when the calcium phosphate is in an amorphous phase. Yes, it is in a state of higher energy than crystals, and calcium exists as ions, so some of the calcium ions are likely to move and coordinate with a carbonyl group to reduce energy. On the other hand, when TCP is in the crystalline phase, the atoms are in a state of being aligned and aligned, so that the atoms do not cut the bond and form a bond with the functional group of the biodegradable resin. It is thought that.

<Manufacture of biodegradable fiber>
The method for producing a biodegradable fiber forming the bone regeneration material of the present invention is not particularly limited as long as a fiber having an outer diameter of several microns to several tens of microns containing β-TCP fine particles in a biodegradable resin can be spun. . The electrospinning method can be suitably used as an embodiment of the present invention because a biodegradable fiber having a thin outer diameter can be produced commercially with simple equipment.

1. Electrospinning method (1) Preparation of composite by kneading Pellet PLGA resin is put into a kneader and heated to a temperature at which PLGA is sufficiently softened. Next, powdery β-TCP fine particles are put into a kneader, mixed with PLGA, and kneaded for a certain period of time to produce a composite of β-TCP fine particles and PLGA.

The weight ratio of the composite is preferably about 30 to 60% by weight of PLGA and about 70 to 40% by weight of β-TCP fine particles. More preferably, PLGA is about 30 to 50% by weight and β-TCP fine particles are about 70 to 50% by weight. More preferably, PLGA is about 30% by weight and β-TCP fine particles are about 70% by weight.
In the present invention, it is difficult to strictly control an appropriate weight ratio of PLGA and β-TCP fine particles to a single-digit% level, so 5% before and after the above numerical range should be considered as within the range. .

In order to increase the osteogenic activity of the bone regeneration material, it is desirable to increase the content of β-TCP fine particles as much as possible. However, in the case of using the electrospinning method, if the amount of β-TCP fine particles is substantially over 70% by weight, for example, 80% by weight, a spinning solution can be prepared from the composite and spun by electrospinning. It becomes difficult.

When β-TCP fine particles are mixed with softened PLGA, they agglomerate. However, when kneaded with PLGA of a certain viscosity with thermal and mechanical energy for a certain time in a kneader, the aggregation of β-TCP fine particles is physically When pulverized, the polymer enters between the particles, and a state in which the calcium phosphate fine particles are dispersed substantially uniformly in the PLGA can be obtained. Here, applying thermal and mechanical energy means that the PLGA resin is softened by heating to knead under high viscosity. By kneading in a highly viscous state, the aggregates of β-TCP fine particles contained in the resin are physically crushed.

As the kneader used in the present invention, a kneader of a type suitable for kneading with high viscosity or kneading involving solid grinding is suitable. In order to efficiently disintegrate β-TCP fine particles in high-viscosity PLGA, for example, two screw-type blades are sheared and mixed by blades and walls in a non-uniform motion of cutting, and a particularly strong pulverization kneading is performed. A PBV type kneader is suitable. In addition, it is desirable that a cartridge heater or the like be provided so that the resin can be heated to the melting point of the resin in a short time.

In order to apply thermal and mechanical energy to β-TCP fine particles with a kneader, it is necessary that PLGA heated and softened has a certain viscosity or more. The heating temperature required to obtain an appropriate viscosity varies depending on the type of PLGA. For PLLGA (85:15), a temperature around 160 ° C. is preferred. Even when the heating temperature is lower (for example, 140 ° C. with PLLGA), it is possible to disintegrate the aggregates of the contained fine particles as long as the PLGA can be softened and kneaded with a kneader. However, in that case, the viscosity of PLGA becomes high, so a stronger force is required to knead with a kneader.

If the heating temperature is further increased (for example, if the temperature is increased from around 160 ° C. to 190 ° C. or higher with PLLGA), the viscosity of PLGA will decrease, resulting in less mechanical energy being applied by kneading and agglomeration of β-TCP fine particles. It becomes difficult to disintegrate, and as a result, it becomes difficult to uniformly disperse β-TCP fine particles in PLGA.

In the present invention, PLGA is first charged in a kneader and heated, and then TCP fine particles are charged and kneaded, and PLGA and β-TCP fine particles may be simultaneously charged in a kneader and mixed and kneaded, or PLGA and TCP A mixture in which fine particles are mixed may be charged into a kneader and kneaded. When using PLGA with low crystallinity, the viscosity when heated is low, so it is better to put PLGA into a kneader and knead it at the same time without heating the PLGA first. Easy to apply mechanical energy.

(2) Cooling and solidifying the composite The composite prepared above is taken out of the kneader and cooled at room temperature to solidify.

When PLGA and TCP fine particles softened in a kneader are kneaded and subjected to thermal and mechanical energy to disperse β-TCP fine particles, the number of PLGA molecule ends increases and many nuclear sites are formed in the process. Therefore, it is considered that PLGA crystal growth proceeds from the many nuclear sites as a starting point in the process of cooling the composite. However, PLGA, especially PDLGA, which is a block copolymer, is originally amorphous and slow in crystallization, so even if many nucleation sites are formed through kneading, β-TCP fine particles are used as nuclei. It is thought that crystal growth does not progress so much.

(3) Dissolution of complex with solvent The complex produced above is put into a solvent solution and stirred to dissolve the complex to prepare a spinning solution. In order to obtain a spinning solution for electrospinning, the composite must be almost completely dissolved by a solvent. Therefore, in order to dissolve the composite, it is desirable to stir in a solvent solution for 4 hours or more using a magnetic stirrer or the like.

As the solvent used in the present invention, chloroform can be suitably used because it has good solubility in PLGA and can efficiently evaporate the solvent from the fiber during the electrospinning process.

The resin concentration of the spinning solution dissolved in the solvent is appropriately selected and adjusted as necessary, but is preferably 8% by weight to 12% by weight for spinning by electrospinning.

When dissolved in a solvent, the molecular chains of PLGA are unwound and disperse without any binding force between the molecular chains, and the arranged molecular chains are given a degree of freedom. It is thought that PLGA molecules of biodegradable fibers, which have been solvent-removed through electrospinning, are rearranged as the fibers solidify.

The spinning solution prepared above is filled into a syringe of an electrospinning apparatus, and the spinning solution is ejected into a fiber form under a certain method / condition by applying an electric charge to the nozzle. Spin.

As the electrospinning method of the present invention, a dry-wet-electrospinning method can be suitably used. In the dry-wet-electrospinning method, fibers are blown from a nozzle, and the fibers evaporated and solidified during flight are incident on the liquid level of the ethanol liquid in the collector so that the fibers are precipitated in the liquid collector. Deposit in a cotton-like form. The biodegradable resin is dissolved in chloroform to form an ES spinning solution, but is not dissolved in ethanol filling the collector bowl, so that fibers are deposited in the liquid phase. Study on the Morphologies and Formational Mechanism of Poly (hydroxybutyrate-co-hydroxyvalerate) Ultrafine Fibers by Dry-Jet-Wet-Electrospinning, Shuqi et al. Journal of Nanomaterials Volume 2012 Hindwi Publishing Corporation October 2012, and Japanese Patent Application Laid-Open No. 2012-161363, US Pat. No. 8,853298, and the like.

In a preferred embodiment of the present invention, the fibers emitted from the nozzle are deposited in a collector vessel filled with ethanol solution and deposited on the plate of the collector vessel. Chloroform is removed from the surface of the biodegradable fiber in the ethanol solution, so that the fibers deposited on the collector plate can be prevented from adhering to each other. A cotton-like product can be obtained. The cotton-like bone regeneration material comprising the biodegradable fiber of the present invention has a bulk density of about 0.001 to 0.1 g / cm ³ . Preferably, it is 0.01-0.1 g / cm < ³ >, More preferably, it is 0.01-0.04 g / cm < ³ >. FIG. 3 shows an example of use of the bone regeneration material of the present invention. The bone regeneration material of the present invention has excellent handleability because the outer diameter of the fibers is in the range of 10 to 150 μm and the bulk density of the cotton is in the above range.

2. Other production method of biodegradable fiber The production method of the biodegradable fiber of the present invention is not limited to the electrospinning method, and can be produced by other conventionally known spinning methods.

<Biodegradable fiber>
FIG. 1 shows the appearance of a cotton-like bone regeneration material manufactured using electrospinning according to an embodiment of the present invention. FIG. 2 shows a photograph of the appearance of a biodegradable fiber manufactured using electrospinning according to an embodiment of the present invention. The outer diameter of the fibers varies and is generally in the range of 10 to 150 μm, but the preferred average diameter is 10 to 50 μm. When spinning by electrospinning, the fiber generally tends to have an outer diameter of several μm or less, but the biodegradable fiber of the bone regeneration material of the present invention is thicker than that. By setting the outer diameter of the fiber to 10 μm or more, it becomes possible to create a space (gap) between the fibers necessary for cells to enter the inside of the cotton-like porous body of the present invention.

The bone regeneration material made of the biodegradable fiber of the present invention has a high hydrolysis rate and starts to degrade immediately after being implanted into a human body, and then is absorbed into the body and disappears within a few months.

The biodegradable fiber of the bone regeneration material of the present invention has numerous fine pores formed on the fiber surface. In spinning by electrospinning, fine pores are formed on the fiber surface in the process of volatilization of the spinning solution injected into the fiber form from the nozzle. In the bone regeneration material of the present invention, the contact area between the contained ceramic particles (bone forming factor) and the body fluid is remarkably increased due to the formation of ultrafine pores in the biodegradable fiber, resulting in high levels. Bone-forming ability is obtained.

<Sterilization treatment>
It is desirable that the bone regeneration material of the present invention is formed into a cotton shape by electrospinning and then sterilized by wrapping in aluminum after being separated into a desired size / weight using tweezers or the like. Sterilization methods include radiation sterilization (gamma rays, electron beams), ethylene oxide gas sterilization, high pressure steam sterilization, and the like. In the present invention, radiation sterilization with γ rays is preferably used.

Experiment 1) Details of the experiment
Samples of biodegradable fibers consisting of PLGA and β-TCP (1) 70TCP-30PLGA, (2) 100PLGA, (3) 70TCP-30PLGA (without kneading) were prepared, and between each sample's PLGA and β-TCP The presence or absence of chemical bonding was examined by NMR measurement. (1) is a fiber in which PLGA: β-TCP is kneaded with a kneader so as to be 30:70 and spun by electrospinning. (2) is a fiber in which only PLGA is kneaded by a kneader and spun by electrospinning. Fiber. (3) is a sample having the same composition as (1), in which PLGA and β-TCP are directly dissolved in chloroform and not subjected to a kneader process, and prepared by electrospinning.

(1) 70TCP-30PLGA
(2) 100PLGA
(3) 70TCP-30PLGA (without kneading)

<Materials used for sample preparation>
Β-TCP (Ca3 (PO4) 2): β-TCP-100 manufactured by Taihei Chemical Industry Co., Ltd. was used. A product having a particle size of 1.7 mm or less and pulverized to about 4 μm (β-TCP pulverized product) was used.
FIG. 4 shows the result of XRD measurement of β-TCP used in the experiment. The presence of a clear peak indicates that β-TCP used in the present invention has high crystallinity and almost no amorphous portion.
-PLGA: Evonik's RESOMER LG855S was used.

<Sample preparation conditions>
-Kneader condition kneader: Table kneader PBV-0.1 (provided by Irie Shokai Co., Ltd.).
Temperature: 160 ° C
Time: For sample (1), PLGA alone was mixed for 1.5 minutes, and then β-TCP was added for 11 minutes, for a total of 14 minutes and a half.
Sample (2) was kneaded for 14 and a half minutes only with PLGA.
Sample (3) was not subjected to a kneader process, and PLGA and β-TCP were directly put into chloroform to prepare a spinning solution.

・ ES condition
ES equipment: NANON (provided by MECC Corporation)
Solvent: Chloroform Resin concentration in solvent: 8wt%
Voltage Sample (1), (2): 28kV
Sample (3): 25kV
Extrusion speed: 15ml / h
Needle thickness: 18G
The flight distance from the nozzle to the collector was 25 cm. The collector vessel was filled with ethanol solution and received and deposited by electrospun yarn. Thereafter, the deposited biodegradable fibers were collected from the collector, washed, and dried to obtain samples (1), (2), and (3).

<NMR measurement>
In Samples (1), (2), and (3), it was investigated by NMR whether or not coordination occurred between the calcium ions of PLGA and TCP.
FIG. 3 (1) shows the results of measuring 13C CP / MAS-NMR spectra of samples (1) and (2). FIG. 3 (2) is an enlarged view of the peak around the phase around the carbonyl group (C═O; ˜170 ppm) in FIG. 3 (1).
Moreover, the result of having measured the 13C CP / MAS-NMR spectrum of a sample (3) is shown in FIG. 3 (3). FIG. 3 (4) is an enlarged view of the peak around the phase around the carbonyl group (C═O; ˜170 ppm) in FIG. 3 (3).

Samples (1), (2), and (3) were separated (Gaussian) into a broad peak indicated by a thick broken line and a peak topped at 170.4 ppm indicated by a thin broken line. The separation line indicated by the thick broken line is considered to be a background that affects the phase matching and, although not certain, may be caused by fluctuation due to high amorphousness. Therefore, as the peak of the carbonyl group, it can be discussed with the separated peak of the thin broken line. In either case, no low magnetic field shifted peak is observed, and therefore it can be said that no Ca2 + ion is coordinated to the carbonyl group (COO-ester bond portion).
It is reported that when divalent ions such as Ca2 + ions are coordinated, a peak shifted to the low magnetic field side appears in addition to this peak (Asada M, Asada N, Toyoda A, Ando I, Kurosu H. Side-chain structure of poly (methacrylic acid) and its zinc salts in the solid state as studied by high-resolution solid-state 13C NMR spectroscopy. J Mol Struct 1991; 244: 237-48.).

Claims (15)

A bone regeneration material composed of biodegradable fibers,

The biodegradable fiber substantially consists of a polylactic acid-glycolic acid copolymer and β-phase tricalcium phosphate particles,

The β-phase tricalcium phosphate fine particles are obtained by firing the amorphous calcium phosphate as a precursor at a temperature substantially immediately before the β-phase of the tricalcium phosphate transitions to the α-phase. It is prepared as a high-purity β-phase tricalcium phosphate that does not substantially exist,

The β-phase tricalcium phosphate fine particles are dispersed in the biodegradable fiber in a state where calcium ions and the functional group of the polylactic acid-glycolic acid copolymer are not coordinated.

A bone regeneration material comprising the biodegradable fiber.
The bone regeneration material according to claim 1, wherein the biodegradable fiber is produced by an electrospinning method.
The biodegradable fiber substantially comprises only about 30 to 60% by weight of a polylactic acid-glycolic acid copolymer and about 70 to 40% by weight of β-phase tricalcium phosphate fine particles, and the β-phase tricalcium phosphate The bone regeneration material according to claim 1 or 2, wherein the fine particles are dispersed almost uniformly without being aggregated in the biodegradable fiber.
The bone regeneration material according to any one of claims 1 to 3, wherein the polylactic acid-glycolic acid copolymer is a copolymer of lactic acid and glycolic acid containing only L-form.
The bone regeneration material according to any one of claims 1 to 4, wherein the polylactic acid-glycolic acid copolymer is a copolymer of lactic acid and glycolic acid in which L and D isomers are mixed.
The bone regeneration material according to any one of claims 1 to 5, wherein a ratio of lactic acid to glycolic acid in the polylactic acid-glycolic acid copolymer is about 85-50: 15-50.
The bone regeneration material according to any one of claims 1 to 6, wherein the β-phase tricalcium phosphate particles have an outer diameter of 0.5 to 4 µm.
The bone regeneration material according to any one of claims 1 to 7, wherein an outer diameter of the biodegradable fiber is 10 to 150 µm.
A method for producing a bone regeneration material comprising biodegradable fibers,

The amorphous calcium phosphate precursor is prepared by firing at a temperature substantially immediately before the β phase of the tricalcium phosphate transitions to the α phase,

After the polylactic acid-glycolic acid copolymer is softened by heating with a kneader at a temperature equal to or higher than the glass transition point, a high-purity β-phase tricalcium phosphate containing substantially no amorphous part in the kneader The β-phase tricalcium phosphate fine particles are not homogeneously aggregated in the polylactic acid-glycolic acid copolymer by being thermally kneaded with heat and mechanical energy, and then cooled and solidified. Make a dispersed composite,

Creating a spinning solution by dissolving the composite in a solvent;

By spinning the spinning solution by an electrospinning method, the β-phase phosphorus in the state where the calcium ions of the β-phase tricalcium phosphate and the functional group of the polylactic acid-glycolic acid copolymer are not coordinated. Producing biodegradable fiber in which tricalcium acid fine particles are dispersed,

A method for producing a bone regeneration material comprising biodegradable fibers.
10. The bone regeneration according to claim 9, wherein the kneader is charged with an amount of about 30 to 60 wt% of the polylactic acid-glycolic acid copolymer and about 70 to 40 wt% of the β-phase tricalcium phosphate fine particles and kneaded. Method of manufacturing materials.
The method for producing a bone regeneration material according to claim 9 or 10, wherein the polylactic acid-glycolic acid copolymer is a copolymer of lactic acid and glycolic acid containing only L-form.
The method for producing a bone regeneration material according to any one of claims 9 to 11, wherein the polylactic acid-glycolic acid copolymer is a copolymer of lactic acid and glycolic acid in which L and D isomers are mixed. .
The method for producing a bone regeneration material according to any one of claims 9 to 12, wherein a ratio of lactic acid to glycolic acid in the polylactic acid-glycolic acid copolymer is approximately 85 to 50:15 to 50.
The method for producing a bone regeneration material according to any one of claims 9 to 13, wherein an outer diameter of the β-phase tricalcium phosphate particles is 0.5 to 4 µm.
The method for producing a bone regeneration material according to any one of claims 9 to 14, wherein an outer diameter of the biodegradable fiber is 10 to 150 µm.