Bone regeneration material and method for producing bone regeneration material

Abstract

This bone regeneration material comprises a composite containing octacalcium phosphate and a lactic acid / glycolic acid copolymer, wherein the composite is a compact body.

Description

Bone regeneration material, method for manufacturing bone regeneration material

[0001] This invention relates to a bone regeneration material and a method for producing a bone regeneration material.

[0002] In the field of bone therapy, various types of artificial bone materials, including ceramic, metal, and calcium phosphate-based materials, have been developed and are being applied clinically. Calcium phosphate-based artificial bone materials, in particular, are widely used in bone graft treatments because they generally possess osteoconductivity (the property of directly bonding and integrating with the patient's own bone), a characteristic not found in other types of artificial bone materials.

[0003] Currently, the two main types of calcium phosphate-based materials are hydroxyapatite (HAp) and β-tricalcium phosphate (β-TCP). Furthermore, in recent years, octacalcium phosphate (OCP) has attracted attention as a calcium phosphate-based material due to its higher bioabsorption and osteoinducing ability (the property of the material itself to promote bone regeneration) that HAp and β-TCP lack. OCP is highly regarded academically for its bone regeneration ability. On the other hand, OCP has hardly been used industrially because stable large-scale synthesis is difficult. The present inventors have succeeded in developing a mass production process for OCP and have reached a stage where it can be stably supplied as a raw material (see, for example, Patent Document 1).

[0004] Japanese Patent Publication No. 2016-166125, Japanese Patent Publication No. 3115642

[0005] T. Kawai et al., J. Tissue Eng. 2020;11:1-15. Legeros RZ, Calcif Tissue Int 37:194-197, 1985. Ishihara, Kazuhiko et al., "Fundamentals of Biomaterials," Nippon Igakukan, 2010. 11. Oizumi et al., Acta Biomatteria 124:357-373, 2021.

[0006] While OCP possesses excellent bone regeneration capabilities, its structure contains crystalline water, making it unsuitable for molding using sintering methods, which are used for molding HAp and other materials. Therefore, OCP needs to be compounded with biopolymers (amino acids, proteins) such as gelatin or collagen for molding. However, when using these biopolymers, it is difficult to obtain high strength in molded bodies containing OCP, and currently reported applications of OCP are limited to the treatment of non-load-bearing areas (see, for example, Non-Patent Document 1).

[0007] The present invention has been made in view of the above circumstances, and aims to provide a bone regeneration material applicable to load-bearing areas and a method for manufacturing the bone regeneration material.

[0008] The present invention has the following embodiments: [1] A bone regeneration material comprising a composite containing octacalcium phosphate and a lactic acid-glycolic acid copolymer, wherein the composite is a dense body. [2] The bone regeneration material according to [1], wherein the open porosity of the dense body is 10% or less. [3] The density of the dense body is 1.2 g / cm³. ３ 2.5g / cm or more ３The bone regeneration material according to [1] or [2], which is as follows: [4] The bone regeneration material according to any one of [1] to [3], wherein the content of octacalcium phosphate relative to the total amount of the composite is 10% by mass or more and 35% by mass or less. [5] The bone regeneration material according to any one of [1] to [4], wherein the weight-average molecular weight of the lactic acid-glycolic acid copolymer is 20,000 or more and 200,000 or less. [6] The bone regeneration material according to any one of [1] to [5], wherein the dense body has a bending strength of 0.2 MPa or more and a compressive strength of 40 MPa or more and 150 MPa or less. [7] The bone regeneration material according to any one of [1] to [6], wherein the lactic acid-glycolic acid copolymer comprises two or more compounds with different molecular weights. [8] The bone regeneration material according to any one of [1] to [7], which is used as a raw material for a 3D printer. [9] A bone fixation jig comprising the bone regeneration material according to any one of [1] to [7].

[10] A method for producing a bone regeneration material, comprising a heating and kneading step of heating and kneading octacalcium phosphate and a lactic acid-glycolic acid copolymer to obtain a composite containing the octacalcium phosphate and the lactic acid-glycolic acid copolymer.

[11] The method for producing a bone regeneration material according to

[10] , wherein in the heating and kneading step, the heating temperature of the octacalcium phosphate and the lactic acid-glycolic acid copolymer is 40°C or higher and 250°C or lower.

[0009] According to the present invention, it is possible to provide a bone regeneration material applicable to load-bearing areas and a method for manufacturing the bone regeneration material.

[0010] This is a photograph showing the test specimen prepared in Experimental Example 6. This is a photograph showing the test specimen prepared in Experimental Example 2. This is a photograph showing the composite prepared in Experimental Example 2. This is a photograph showing the composite prepared in Experimental Example 2. This is a diagram showing the relationship between the molecular weight of PLGA and the flexural strength of a test specimen made of PLGA alone in Experimental Example 3. This is a diagram showing the relationship between the molecular weight of PLGA and the flexural modulus of a test specimen made of PLGA alone in Experimental Example 3. This is a diagram showing the relationship between the molecular weight of PLGA and the compressive strength of a test specimen made of PLGA alone in Experimental Example 3. This is a diagram showing the relationship between the OPC content and the flexural strength of a dumbbell-shaped test specimen in Experimental Example 4. This is a diagram showing the relationship between the OPC content and the flexural modulus of a dumbbell-shaped test specimen in Experimental Example 4. This is a diagram showing the relationship between the molecular weight of PLGA and the flexural strength of a strip-shaped test specimen in Experimental Example 5. This is a diagram showing the relationship between the molecular weight of PLGA and the flexural modulus of a strip-shaped test specimen in Experimental Example 5. This figure shows the relationship between the molecular weight of PLGA and the compressive strength of the strip-shaped test piece in Experimental Example 5.

[0011] Embodiments of the bone regeneration material and the method for producing the bone regeneration material of the present invention will be described below. These embodiments are provided specifically to allow for a better understanding of the spirit of the invention and do not limit the present invention unless otherwise specified.

[0012] [Bone regeneration material] A bone regeneration material according to one embodiment of the present invention is octacalcium phosphate (Ca ８ H ２ (PO ４ ) ６ ・5H ２ It consists of a complex containing O (hereinafter sometimes referred to as "OCP") and a lactic acid-glycolic acid copolymer (hereinafter sometimes referred to as "PLGA"), and the complex is a dense material.

[0013] The shape of the composite can be arbitrarily determined, taking into consideration the shape and size of the affected area to be filled. For example, the composite is preferably a rectangular prism (block), cube, cylindrical, plate-shaped, screw, nut, tablet-shaped, or granular. Plate-shaped, screw, or nut is more preferred. The screw may be fixed on its own or fixed in combination with a nut.

[0014] OCP is a known substance and can be prepared, for example, by Legeros' dropwise method (Legeros RZ, Calcif Tissue Int 37:194-197, 1985: Non-Patent Literature 2), or by a method using a synthesis apparatus (tri-tube) described in Japanese Patent Publication No. 3115642.

[0015] PLGA is a random copolymer of lactic acid (LA) and glycolic acid (GA), and is a bioabsorbable material that, in living organisms, is broken down into monomers by hydrolysis and ultimately into water and carbon dioxide through metabolism. Due to these characteristics, PLGA is often used, especially in drug delivery systems (DDS), and its clinical use is increasing under the approval of the U.S. Food and Drug Administration (FDA) and other authorities. It is also known that the degradation rate and mechanical properties of PLGA change depending on the ratio of LA to GA during copolymerization.

[0016] The weight-average molecular weight (Mw) of PLGA is preferably 20,000 to 200,000, more preferably 30,000 to 200,000, and even more preferably 40,000 to 100,000. If the weight-average molecular weight of PLGA is below the lower limit, the degradation rate in vivo slows down, and if the weight-average molecular weight of PLGA exceeds the upper limit, the mechanical strength that is a characteristic of the present invention cannot be obtained.

[0017] The weight-average molecular weight of PLGA is measured using gel permeation chromatography (GPC).

[0018] The bone regeneration material of this embodiment may contain two or more compounds with different molecular weights as PLGA. PLGA has different mechanical strengths and decomposition rates depending on its molecular weight. Furthermore, since compounding by kneading is a physical mixing, the molecular weights of the PLGA do not change through kneading. Therefore, by using a combination of two or more PLGAs with different molecular weights, the strength and decomposition rate of the molded body can be arbitrarily changed.

[0019] The weight-average molecular weight of two or more PLGAs with different molecular weights is preferably 20,000 to 200,000, more preferably 30,000 to 200,000, and even more preferably 40,000 to 100,000. Depending on the strength and decomposition rate of the target molded article, a combination of PLGAs with a small molecular weight and a large molecular weight may be used, a combination of two or more different PLGAs with small molecular weights may be used, or a combination of two or more different PLGAs with large molecular weights may be used.

[0020] The OCP content relative to the total amount of the composite is preferably 10% by mass or more and 35% by mass or less, more preferably 20% by mass or more and 35% by mass or less, and even more preferably 25% by mass or more and 35% by mass or less. If the OCP content is below the lower limit, there will be insufficient bonding between polymers to maintain strength. If the OCP content exceeds the upper limit, the effects obtained by the composite, such as an improvement in elastic modulus, will not be observed.

[0021] The PLGA content relative to the total amount of the composite is preferably 65% ​​by mass or more and 90% by mass or less, more preferably 65% ​​by mass or more and 80% by mass or less, and even more preferably 65% ​​by mass or more and 75% by mass or less. If the PLGA content is below the lower limit, there will be insufficient bonding between polymers to maintain strength. If the PLGA content exceeds the upper limit, the properties will be equivalent to those of PLGA alone.

[0022] Here, a dense body refers to a molded body with a porosity below a certain level.

[0023] The open porosity of the dense material is preferably 10% or less, more preferably 1% or less, and even more preferably 0.1% or less. If the open porosity of the dense material exceeds the above upper limit, the strength, which is a characteristic of the present invention, cannot be sufficiently obtained.

[0024] The open porosity is the ratio of the volume occupied by the open pores to the outer volume of the sample. The open porosity of a dense body can be measured using the Archimedes method. The open porosity of a dense body using the Archimedes method can be calculated from the dry weight of the dense body, the weight of the dense body in water, and the saturated water weight of the dense body (the weight in the state where the dense body has absorbed water and is saturated). The open porosity of a dense body is calculated using the following formula (1).

[0025]

[0026] In the above formula (1), P is the open porosity (%) of the dense body, and W ３ is the saturated water weight of the dense body, W １ is the dry weight of the dense body, and W ２ is the weight of the dense body in water.

[0027] The measurement procedure for the open porosity of a dense body will be described. The open porosity of a dense body is carried out according to the following measurement procedures (1) to (4). Measurement procedure (1) Measure and record the dry weight of the dense body. Measurement procedure (2) Place a centrifuge tube containing pure water and the dense body in a pressure-resistant container, evacuate and degas the inside of the pressure-resistant container, and allow the dense body to absorb pure water. The time for the dense body to absorb pure water is set to 30 minutes. Measurement procedure (3) After allowing the dense body to absorb pure water, carry it while immersed in pure water, take out the dense body from the pure water immediately before measuring the saturated water weight in water of the dense body, and measure the saturated water weight in water of the dense body. Measurement procedure (4) After measurement procedure (3), gently wipe off the moisture on the surface of the dense body and measure the saturated weight. When wiping the surface of the dense body, wipe it to such an extent that water that has entered the pores is not removed.

[0028] The density of the dense body is preferably 1.2 g / cm ３ or more and 2.5 g / cm <00​​​​​​​​​​​​​

[0030] The bending strength of the dense body is preferably 0.2 MPa or more and 150 MPa or less, and more preferably 50 MPa or more and 150 MPa or less. A bending strength of 50 MPa or more and 150 MPa or less is equivalent to the bending strength of human autologous bone (hereinafter referred to as natural bone) (Fundamentals of Biomaterials (Nippon Medical School)). If the strength is excessively higher than that of natural bone, atrophy of the surrounding natural bone may occur in some cases.

[0031] The bending strength of the dense body was measured by the three-point bending test described in JIS K7171.

[0032] The bending elastic modulus of the dense body is preferably 5 GPa or more and 30 GPa or less, and more preferably 7 GPa or more and 30 GPa or less. A bending elastic modulus of 7 GPa or more and 30 GPa or less is equivalent to that of natural bone (Ishihara Kazuhiko et al., "Fundamentals of Biomaterials", Nippon Medical School, November 2010: Non-Patent Document 3).

[0033] The method for measuring the bending elastic modulus of the dense body conforms to JIS K7171.

[0034] [[ID=!]] The compressive strength of the dense body is preferably 50 MPa or more and 250 MPa or less, and more preferably 100 MPa or more and 250 MPa or less. A compressive strength of 100 MPa or more and !50 MPa or less is equivalent to that of natural bone (Ishihara Kazuhiko et al., "Fundamentals of Biomaterials", Nippon Medical School, November 2010: Non-Patent Document 3).

[0035] The method for measuring the compressive strength of the dense body conforms to JIS K!181.

[0036] The bone regeneration material of the present embodiment can be used as it is, but if necessary, it can be processed into a filament shape optimal for the use of each 3D printer, or mixed with a solvent or the like, and used as a 3D printer raw material.

[0037] Examples of the solvent include acetone, 1,4-dioxane, and the like.

[0038] When the bone regeneration material of the present embodiment is used as a 3D printer raw material, the !D printer raw material may contain an additive in addition to the bone regeneration material and the solvent. Examples of the additive include a photocurable resin and the like. It should be noted that there seems to be an error in the original text where "!50 MPa" and "!181" are likely incorrect notations. I have translated the text as accurately as possible based on the given content.

[0039] The bone regeneration material of this embodiment may contain components generally found in bone regeneration materials, as long as the effects of the present invention are not hindered. Examples of such components include collagen, gelatin, alginic acid, hyaluronic acid, chitosan, bioabsorbable polymers (polylactic acid, polylactic acid-polyethylene glycol copolymer, etc.), bioabsorbable calcium phosphate (β-tricalcium phosphate (β-TCP), α-tricalcium phosphate (α-TCP), tetracalcium phosphate (Ca) ４ (PO ４ ) ２ O; TTCP), calcium hydrogen phosphate (CaHPO) ４ DCP), calcium hydrogen phosphate dihydrate (CaHPO) ４ ・2H ２ Examples include O; DCPD), low-crystalline HA, nano-HA, carbon dioxide-containing HA, etc., and bioabsorbable materials (HA ceramics, etc.).

[0040] The bone regeneration material of this embodiment consists of a composite material containing OCP and PLGA, and because the composite material is dense, it has sufficient bending strength and compressive strength and can be applied to load-bearing parts of living organisms.

[0041] [Method for producing bone regeneration material] A method for producing bone regeneration material according to one embodiment of the present invention includes a heating and kneading step in which octacalcium phosphate and a lactic acid-glycolic acid copolymer are heated and kneaded to obtain a composite containing octacalcium phosphate and a lactic acid-glycolic acid copolymer.

[0042] The blending of OCP and PLGA is such that the content of OCP relative to the total amount of the complex, and the content of PLGA relative to the total amount of the complex, fall within the above ranges.

[0043] In the method for producing the bone regeneration material of this embodiment, two or more compounds with different molecular weights may be used as PLGA. When heating and kneading OCP and PLGA, OCP and two or more PLGA compounds with different molecular weights may be simultaneously introduced into a kneading apparatus, or they may be kneaded separately beforehand and the composites of two or more OCP and PLGA compounds may be combined to form a single molded body.

[0044] The method for heating and kneading OCP and PLGA can be either by placing each material into a device equipped with a heating and kneading mechanism, or by placing pre-mixed raw materials into a molding machine and then heating them.

[0045] In the heating and kneading process, the heating temperature of OCP and PLGA is preferably 40°C to 250°C, more preferably 80°C to 200°C, and even more preferably 100°C to 200°C. If the heating temperature is below the lower limit, the PLGA will not dissolve sufficiently and the OCP and PLGA will not be compounded.

[0046] According to the method for producing bone regeneration material of this embodiment, the bone regeneration material of the above-described embodiment can be obtained.

[0047] [Bone Fixation Jig] A bone fixation jig according to one embodiment of the present invention is made of the bone regeneration material of the above embodiment.

[0048] The bone fixation jig of this embodiment is formed by molding the bone regeneration material of the above-described embodiment into a predetermined shape. Examples of bone fixation jigs include screws, nuts, plates, etc., used when joining bones.

[0049] For example, the bone fixation jig of this embodiment can be molded (manufactured) using methods such as injection molding, machining, or 3D printing.

[0050] According to the bone fixation jig of this embodiment, since it is made of the bone regeneration material of the above-described embodiment, it has sufficient bending strength and compressive strength and can be applied to the fixation of load-bearing parts of living organisms.

[0051] The present invention will be described in more detail below with reference to experimental examples, but the present invention is not limited to the following experimental examples.

[0052] [Experimental Example 1] A preliminary prototype was prepared to determine whether a composite containing OCP and PLGA could be obtained by the kneading method. Here, PLGA with a weight-average molecular weight (Mw) of 100,000 was used, and the composite was prepared with OPC content of 10% by mass, 20% by mass, or 30% by mass. A small extruder, MinLab3, manufactured by ThermoFisher, was used as the kneader. The kneader is a device that softens (dissolves), shears, mixes, and stirs the main material (resin, etc.) and additives by passing them between two screws while heating. The heating temperature of the main material and additives and the rotation speed of the screws were set in the kneader. First, based on the information on Mitsui Chemicals, Inc.'s website (https: / / jp.mitsuichemicals.com / jp / service / product / plga / index.htm), we assumed that the glass transition temperature of PLGA is 45°C to 55°C and attempted to knead OCP and PLGA at a heating temperature of 60°C. However, the kneading of OCP and PLGA did not progress. Therefore, we gradually increased the heating temperature, and finally kneaded OCP and PLGA at a heating temperature of 150°C and a screw rotation speed of 100 rpm. This is thought to be because there was a large difference in glass transition temperature due to the molecular weight of PLGA. Using the obtained kneaded material, we molded a dumbbell-shaped test piece as a composite, as shown in Figure 1, by injection molding. As shown in Figure 1, it was confirmed that it is possible to produce a composite by the kneading method.

[0053] [Experimental Example 2] Since Experimental Example 1 confirmed that it is possible to fabricate a composite, a mold for strip-shaped test specimens (JIS K7139, see Figure 2) was procured and test specimens were fabricated for the purpose of conducting a bending test. As PLGA is expected to have different strengths and solubility depending on its molecular weight, six types of PLGA (manufactured by Taki Chemical Co., Ltd.; the same applies hereafter) with weight-average molecular weights (Mw) of 10,000, 20,000, 30,000, 50,000, 100,000, or 200,000 were prepared and mixed with OCP. After preliminary testing, it was found that OCP could be mixed up to 35% by mass, and since a higher amount of OCP is considered advantageous in bone regeneration, the mixing ratio of PLGA to OCP in the strip-shaped test specimens was set to PLGA:OCP = 65% by mass:35% by mass. During the mixing process, the appropriate heating temperature varied depending on the molecular weight. For example, a temperature of approximately 50°C was used for PLGA with a weight-average molecular weight (Mw) of 10,000, approximately 150°C for PLGA with a weight-average molecular weight (Mw), and approximately 180°C for PLGA with a weight-average molecular weight (Mw). In the preparation of strip-shaped test pieces using PLGA with different molecular weights, the compound containing PLGA with a weight-average molecular weight (Mw) of 10,000 had a very low melting point. The equipment used was insufficient to cool the compound (molded body) adequately, making it impossible to remove it from the mold while maintaining its shape (see Figure 3). It appears that a separate cooling device would be necessary to remove the compound made from the compound containing PLGA with a weight-average molecular weight (Mw). Therefore, the physical property evaluation could not be performed on the compound made from the compound containing PLGA with a weight-average molecular weight (Mw) of 10,000. Composites made from kneaded materials containing PLGA with a weight-average molecular weight (Mw) of 20,000 or more could be removed from the mold in the shape of strip-shaped test specimens. However, strip-shaped test specimens with lower molecular weights did not appear to have sufficient strength, and partial chipping or breakage sometimes occurred during removal (see Figure 4). In addition, regardless of the weight-average molecular weight (Mw), PLGA did not appear to expand or contract much with heat, and considerable force was required to remove them from the mold.

[0054] [Experimental Example 3] The target values ​​for the strength, elasticity, and other mechanical properties of the OCP and PLGA composite were set to be equivalent to those of natural bone. The mechanical properties of natural bone are shown in Table 1.

[0055]

[0056] Strip-shaped test specimens similar to those in Experimental Example 2 were prepared using only PLGA. The weight-average molecular weight (Mw) of PLGA was set to 20,000, 30,000, 50,000, 100,000, or 200,000. The compressive strength, flexural strength, and flexural modulus were measured for the obtained strip-shaped test specimens. The compressive strength was measured according to JIS K7181. The flexural strength was measured according to the three-point bending test of JIS K7171. The flexural modulus was measured according to JIS K7171. The measurement results are shown in Table 2, Figures 5, 6, and 7. Figure 5 shows the relationship between the molecular weight of PLGA and the flexural strength of the strip-shaped test specimen made of only PLGA. Figure 6 shows the relationship between the molecular weight of PLGA and the flexural modulus of the strip-shaped test specimen made of only PLGA. Figure 7 shows the relationship between the molecular weight of PLGA and the compressive strength of a strip-shaped test specimen made solely from PLGA.

[0057]

[0058] The results shown in Table 2, Figures 5, 6, and 7 indicate that the bending strength of strip-shaped test specimens made solely of PLGA was 14.5 MPa when the weight-average molecular weight (Mw) was 20,000, and 24.99 MPa when the weight-average molecular weight (Mw) was 30,000. These values ​​were lower than the target bending strength of natural bone (50 MPa to 150 MPa). When the weight-average molecular weight (Mw) was 50,000, the bending strength was 93.67 MPa, which was equivalent to the target bending strength of natural bone. It was found that the bending strength remained almost constant at weight-average molecular weight (Mw) of 50,000 or higher (100,000 and 200,000), and remained around 100 MPa. Furthermore, it was found that the flexural modulus was almost constant regardless of the weight-average molecular weight (Mw), and the compressive strength was also almost constant at weight-average molecular weight (Mw) of 30,000 or higher.

[0059] [Experimental Example 4] The effect of OPC content on PLGA with a weight-average molecular weight (Mw) of 100,000 was evaluated by combining the strength test results of test specimens with OPC content of 10,000, 20, or 30% by mass prepared in Experimental Example 1, and the test results of test specimens with an OPC content of 35% by mass prepared thereafter. The bending strength and bending modulus were measured for the obtained test specimens. The measurement of bending strength was the same as in Experimental Example 3. The measurement of bending modulus was the same as in Experimental Example 3. The above measurement results are shown in Table 3, Figure 8, and Figure 9. Figure 8 shows the relationship between OPC content and the bending strength of the test specimen. Figure 9 shows the relationship between OPC content and the bending modulus of the test specimen.

[0060]

[0061] The results shown in Table 3, Figure 8, and Figure 9 indicate that the flexural strength was around 100 MPa for OCP content from 0 to 30 mass%, showing that the OCP content had little effect on flexural strength. On the other hand, the flexural strength of the specimen with an OCP content of 35 mass% dropped sharply to 73.18 MPa. This is thought to be because the ratio of PLGA to volume was insufficient, resulting in less bonding between the resins. While flexural strength was hardly affected by the OCP content, the flexural modulus increased proportionally with the OCP content from 0 to 30 mass%, reaching the lower limit of the target value of 7 GPa at an OCP content of 30 mass%. From the above, it was found that the optimal value for OCP content relative to the total amount of composite is 30 mass%, and that this content yields flexural strength and flexural modulus close to that of natural bone, which are the target values.

[0062] [Experimental Example 5] PLGA with weight-average molecular weight (Mw) of 20,000, 30,000, 50,000, 100,000, or 200,000 was mixed with OCP to obtain a compound, and this compound was injection molded to obtain strip-shaped test specimens. The strip-shaped test specimens used in Experimental Example 5 had an OCP content of 35% by mass. The bending strength, bending modulus, and compressive strength of the obtained strip-shaped test specimens were measured. The measurement of bending strength was the same as in Experimental Example 3. The measurement of bending modulus was the same as in Experimental Example 3. The measurement of compressive strength was the same as in Experimental Example 3. The results of these measurements are shown in Table 4, Figure 10, Figure 11, and Figure 12. Figure 10 shows the relationship between the molecular weight of PLGA and the bending strength of the strip-shaped test specimen. Figure 11 shows the relationship between the molecular weight of PLGA and the bending modulus of the strip-shaped test specimen. Figure 12 shows the relationship between the molecular weight of PLGA and the compressive strength of the strip-shaped test specimen.

[0063]

[0064] The results shown in Table 4, Figures 10, 11, and 12 confirm that in strip-shaped test specimens with a weight-average molecular weight (Mw) of 50,000 or more, which have high flexural strength, the flexural strength was lower than that of PLGA alone, as confirmed in Experimental Example 4. On the other hand, in strip-shaped test specimens with a weight-average molecular weight (Mw) of 20,000 or 30,000, which originally have low flexural strength, the flexural strength was slightly improved compared to that of PLGA alone. It is possible that because PLGA with a low molecular weight has lower viscosity (higher fluidity) in the dissolved state compared to PLGA with a high molecular weight, the polymers bond more easily, and therefore the bonding between polymers was sufficient even when the OCP content was higher.

[0065] [Experimental Example 6] "Preparation of Porous Materials" Two types of porous materials were prepared: one consisting solely of PLGA, and another with an OCP content of 30% by mass or 35% by mass. The PLGA used had a weight-average molecular weight (Mw) of 100,000. The OCP used was manufactured by Nippon Fine Ceramics Co., Ltd. A PLGA solution was prepared by dissolving PLGA in 1,4-dioxane heated to 60°C according to the formulation shown in Table 5. The 1,4-dioxane used was manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. A specified amount of OCP was added to the obtained PLGA solution and stirred to disperse the OCP in the PLGA solution, preparing a dispersion. The obtained dispersion was cooled to -20°C using a -20°C freezer and allowed to stand for at least one hour. Then, it was freeze-dried using a freeze-dryer (Tokyo Rikakikai Co., Ltd., FDM-100) to obtain a frozen product. Furthermore, the frozen material was cooled to -80°C using a -80°C freezer and left to stand for more than one hour. This frozen material was dried in a vacuum dryer at a vacuum of 4 Pa ​​or less for 48 hours to obtain a porous material (I Oizumi et al., Acta Biomaterialia 124:357-373, 2021: Non-patent Literature 4). The obtained porous material was cut with a cutter and processed into strips to make test pieces.

[0066]

[0067] "Preparation of dense materials" Two test specimens were prepared as dense materials: one made solely of PLGA and another with an OCP content of 35% by mass. The PLGA used had a weight-average molecular weight (Mw) of 100,000. The OCP used was manufactured by Nippon Fine Ceramics Co., Ltd. These test specimens were prepared in the same manner as in Experimental Example 2.

[0068] "Measurement of Open Porosity" The open porosity of porous and dense materials was measured using the Archimedes method. The open porosity of porous and dense materials was calculated using the above formula (1). In the above formula (1), P is the open porosity of the porous and dense materials, and W is the open porosity of the porous and dense materials. ３ The saturated weight of porous and dense materials is W. １ The dry weight of the porous and dense materials is W ２The values ​​shown are the water weights of the porous and dense materials. The open porosity of the porous and dense materials was measured according to the following measurement procedures (1) to (5). Measurement procedure (1) The dry weight of the porous or dense material was measured and recorded. A precision electronic balance (A&D Corporation, GH-202) was used to measure the dry weight of the porous or dense material. Measurement procedure (2) A centrifuge tube containing pure water and the porous or dense material was placed in a pressure vessel, and the pressure vessel was evacuated to remove air, allowing the porous or dense material to absorb the pure water. The time for the porous or dense material to absorb the pure water was set to 30 minutes. A 50 mL Bioremo centrifuge tube (AS ONE Corporation) was used as the centrifuge tube. An acrylic container was used as the pressure vessel. A vacuum pump (ULVAC Corporation, model number: DTC-41) was used to evacuate the pressure vessel. Measurement Procedure (3) After impregnating the porous or compact material with pure water, the porous or compact material was transported while immersed in the pure water. Immediately before measuring the saturated weight of the porous or compact material in pure water, the porous or compact material was removed from the pure water, and the saturated weight of the porous or compact material was measured. A precision electronic balance (A&D Corporation, GH-202) was used to measure the saturated weight of the porous or compact material. Measurement Procedure (4) After Measurement Procedure (3), the moisture on the surface of the porous or compact material was lightly wiped off, and the saturated weight was measured. When wiping the surface of the porous or compact material, the wiping was limited to the extent that water that had entered the pores was not removed. A precision electronic balance (A&D Corporation, GH-202) was used to measure the saturated weight of the porous or compact material. In addition, the density of the porous and compact materials was measured by the water displacement method (Archimedes method). For the density of porous and compact materials, assuming that water is at approximately 26°C from room temperature, the density of water at 26°C is 0.997 cm³. ３ The calculation was performed using / g. The results are shown in Table 6. In Table 6, *1 indicates that the porous material did not sink in water and therefore the underwater weight could not be measured.

[0069]

[0070] The results shown in Table 6 indicate that the dense material composed of the OCP and PLGA composite has an open porosity of 0.06% or less.

[0071] [Experimental Example 7] "Preparation of Porous Materials" In the same manner as in Experimental Example 6, test specimens made solely of PLGA and test specimens with OCP content of 30% by mass or 35% by mass were prepared as porous materials.

[0072] "Measurement of Bending Strength of Porous Materials" A three-point bending test was performed on a porous material specimen with an OCP content of 35 mass%. Due to manufacturing constraints, the specimen was not the size compliant with JIS standards, so a jig designed for small specimens was used. Although the three-point bending test was performed, the deformation of the specimen was large, and the jig came into contact with other parts before fracture, making the test unsuccessful. Therefore, the test was stopped after one 35 mass% specimen.

[0073] "Measurement of Fracture Stress of Porous Materials" The fracture stress was measured for test specimens made solely of PLGA and test specimens with OCP content of 30% by mass or 35% by mass. The fracture stress was measured by tensile testing. In the measurement of fracture stress, there was no yield point, and the test ended when the test specimen tore at the maximum load, so the maximum tensile stress was taken as the fracture stress. The results are shown in Table 7.

[0074]

[0075] The results shown in Table 7 indicate that the fracture stress of the porous material does not change even when the OCP content is varied.

[0076] [Experimental Example 8] In the same manner as in Experimental Example 1, using PLGA with a weight-average molecular weight (Mw) of 100,000, test specimens consisting of PLGA alone, a composite of PLGA and OPC with an OPC content of 10% by mass, a composite of PLGA and OPC with an OPC content of 20% by mass, and a composite of PLGA and OPC with an OPC content of 30% by mass were prepared.

[0077] In accordance with JIS K7161-1 and JIS K7161-2, the tensile strength, tensile fracture strain, and tensile modulus of the test specimens were measured. The results are shown in Table 8.

[0078] In the "Bending Test," the bending strength and bending modulus of the test specimen were measured in accordance with JIS K7171. The results are shown in Table 8.

[0079]

[0080] The results shown in Table 8 confirm that when the OCP content is 20% by mass or more, the tensile strength, flexural strength, and flexural modulus become equivalent to or greater than those of the case with PLGA alone.

Claims

1. A bone regeneration material comprising a composite containing octacalcium phosphate and a lactic acid-glycolic acid copolymer, wherein the composite is a dense material.

2. The bone regeneration material according to claim 1, wherein the open porosity of the dense body is 10% or less.

3. The density of the dense material is 1.2 g / cm³. ３ 2.5g / cm or more ３ The bone regeneration material according to claim 1, which is as follows:

4. The bone regeneration material according to claim 1, wherein the content of octacalcium phosphate relative to the total amount of the composite is 10% by mass or more and 35% by mass or less.

5. The bone regeneration material according to claim 1, wherein the weight-average molecular weight of the lactic acid-glycolic acid copolymer is 20,000 or more and 200,000 or less.

6. The bone regeneration material according to claim 1, wherein the dense material has a bending strength of 0.2 MPa or more and 150 MPa or less, and a compressive strength of 100 MPa or more and 150 MPa or less.

7. The bone regeneration material according to claim 1, wherein the lactic acid-glycolic acid copolymer comprises two or more compounds with different molecular weights.

8. A bone regeneration material according to any one of claims 1 to 7, which is used as a raw material for a 3D printer.

9. A bone fixation jig comprising the bone regeneration material described in any one of claims 1 to 7.

10. A method for producing a bone regeneration material, comprising a heating and kneading step of heating and kneading octacalcium phosphate and a lactic acid-glycolic acid copolymer to obtain a composite containing the octacalcium phosphate and the lactic acid-glycolic acid copolymer.

11. The method for producing a bone regeneration material according to claim 10, wherein in the heating and kneading step, the heating temperature of the octacalcium phosphate and the lactic acid-glycolic acid copolymer is 40°C or higher and 250°C or lower.

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