Bone regeneration materials

Abstract

A bone regeneration material with excellent osteoconductivity is provided. [Solution] The bone regeneration material is constructed to contain octacalcium phosphate (Ca8H2(PO4)6·5H2O) (OCP) and poly(lactic acid-co-glycolic acid) (PLGA).

Description

[Technical Field]

[0001] The present invention relates to a bone regeneration material. [Background technology]

[0002] Hydroxyapatite (Ca 10 Previous research has shown that octacalcium phosphate (Ca8H2(PO4)6·5H2O, hereafter sometimes abbreviated as "OCP"), a precursor of (PO4)6(OH)2, hereafter sometimes abbreviated as "HA," has excellent bioabsorbability and excellent bone regeneration ability (Non-Patent Document 1).

[0003] Amorphous calcium phosphate (Ca3(PO4)2·nH2O, hereafter sometimes abbreviated as "ACP") is thought to be another precursor of HA in bone mineralization and has been reported to have higher solubility than OCP under physiological conditions (see Non-Patent Document 2). ACP is the first inorganic solid phase formed from a supersaturated solution of calcium and phosphate, which is then converted to OCP and subsequently to HA.

[0004] Patent Document 1 describes octacalcium phosphate (octacalcium phosphate) (Ca8H2(PO4)6·5H2O), amorphous calcium phosphate (Ca3(PO4)2·nH2O), calcium hydrogen phosphate (anhydrous calcium phosphate) (CaHPO4), calcium hydrogen phosphate dihydrate (calcium phosphate dihydrate) (CaHPO4·2H2O), and low-crystalline hydroxyapatite (Ca 10 This paper describes an artificial bone material characterized by containing mixed calcium phosphate consisting of octacalcium phosphate (Ca8H2(PO4)6·5H2O) or poorly crystalline octacalcium phosphate (Ca8H2(PO4)6·5H2O).

[0005] On the other hand, in bone treatment, metal fixation devices such as bone pins are used, and fixation devices made of biocompatible polymers are also used. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2010-110404 [Non-patent literature]

[0007] [Non-Patent Document 1] Suzuki O. et al., Tohoku J. Exp. Med., 1991, 164: 37-50. [Non-patent document 2] Meyer JL et al., Calcif. Tissue Res. 1978, 25, 59-68, Summary of the Invention [Problem to be solved by the invention]

[0008] However, fixation devices such as bone pins made of metals or biocompatible polymers have poor osteoconductivity and are not sufficient from the perspective of bone regeneration. Furthermore, calcium phosphate octaphosphate (Ca8H2(PO4)6·5H2O) exhibited the highest osteoconductivity among the calcium phosphates described in Non-Patent Document 1, but there was room for improvement as a bone regeneration material from the perspective of bone regeneration and moldability.

[0009] An object of the present invention is to provide a bone regeneration material having excellent osteoconductivity. [Means for solving the problem]

[0010] The present inventors have conducted extensive research to achieve the above-mentioned object, and as a result have discovered that a bone regeneration material with excellent osteoconductivity can be obtained by blending a predetermined amount of poly(lactic acid-co-glycolic acid) (hereinafter, sometimes abbreviated as "PLGA") with OCP, thereby arriving at the present invention.

[0011] That is, the present invention is as follows. (1) Contains octacalcium phosphate (Ca8H2(PO4)6·5H2O) (OCP) and poly(lactic acid-co-glycolic acid) (PLGA), The OCP is added based on the total amount of the OCP and the PLGA. 20% by mass or more and 40% by mass or less , the PLGA 80% by mass or less 60% by mass or more A bone regeneration material characterized by containing the following in a ratio of: ( 2 ) characterized by having a porous structure, (1 ) The bone regeneration material described herein. [Effects of the Invention]

[0012] According to the present invention, PLGA has excellent bioabsorbability, and by mixing it with OCP, which has excellent osteoconductivity, to form a bone regeneration material, a bone regeneration material with excellent osteoconductivity can be obtained due to the synergistic effect of the bioabsorbability of PLGA and the osteoconductivity of OCP. [Brief explanation of the drawings]

[0013] [Figure 1] 1 is a graph showing the ratio of newly formed bone area when a bone regeneration material is implanted. [Figure 2A] This is a μ-CT image showing a cross section of a bone regenerative material implanted into a bone defect in a rat's femur. [Figure 2B] This is a μ-CT image showing a frontal cross section of a rat femur after implanting a bone regenerative material into a bone defect. [Figure 3] 1 is a graph showing the change in pH when PLGA / OCP is immersed in a phosphate buffer solution. [Figure 4] 1 is a graph showing the weight change when PLGA / OCP is immersed in a phosphate buffer solution. DETAILED DESCRIPTION OF THE INVENTION

[0014] In the bone regeneration material of the present invention, the ratio of OCP to PLGA is not particularly limited, but for example, based on the total amount of OCP and PLGA, the OCP content is 20 to 65% by mass, preferably 20 to 40% by mass, and the PLGA content is 80 to 35% by mass, preferably 80 to 60% by mass. This balances the osteoconductivity of the OCP and the bioresorbability of the PLGA, resulting in a bone regeneration material with excellent osteoconductivity.

[0015] The bone regeneration material of the present invention may contain components typically found in bone regeneration materials, provided that the effects of the present invention are not impaired. Examples of such components include collagen, gelatin, alginic acid, hyaluronic acid, chitosan, bioabsorbable polymers (such as polylactic acid and polylactic acid-polyethylene glycol copolymer), bioabsorbable calcium phosphates (such as β-tricalcium phosphate (β-TCP), α-tricalcium phosphate (α-TCP), tetracalcium phosphate (Ca4(PO4)2O; TTCP), calcium hydrogen phosphate (CaHPO4; DCP), calcium hydrogen phosphate dihydrate (CaHPO4·2H2O; DCPD), low-crystalline HA, nano-HA, and carbonate-containing HA), and non-bioresorbable materials (such as HA ceramics).

[0016] The bone regeneration material of the present invention can be in any form. For example, the bone regeneration material may be a mixture of OCP granules and PLGA granules, a coprecipitate of OCP and PLGA, or the like, but preferably has a porous structure. In this case, newly formed bone is embedded into the porous structure, resulting in a bone regeneration material with excellent osteoconductivity.

[0017] The porous bone regenerating material can be produced, for example, as follows.

[0018] Commercially available PLGA and other biodegradable polymers (e.g., polycaprolactone (PCL), poly-L-lactic acid (PLLA)) are completely dissolved in 1,4-dioxane as a solvent at 45°C or higher to obtain a biodegradable polymer solution. While the molecular weight of PLGA is not particularly specified, a weight-average molecular weight of 10,000 to 200,000, and more preferably 20,000 to 150,000, is preferably used. The proportion of lactic acid in PLGA is selected from the range of 5 to 85 mol%.

[0019] Next, the OCP is added in the form of granules to the biodegradable polymer solution so that the OCP content in the bone regeneration material to be obtained is, for example, 20 to 65 mass %. The particle size of the OCP granules is, for example, 53 to 300 μm.

[0020] The biodegradable polymer solution containing the OCP is then stirred at 10°C or below for one day to disperse the OCP granules and freeze the biodegradable polymer solution, which is then further cooled at 0°C or below for at least one night.

[0021] The mixture is then freeze-dried for 12 hours or more to remove the solvent, 1,4-dioxane, yielding a porous OCP / biodegradable polymer composite bone regeneration material.

[0022] The pore size of the bone regeneration material is, for example, 10 to 500 μm, and the porosity is 0 to 95%.

[0023] The bone regeneration material can then be appropriately molded for use. The molding method is not particularly limited. Examples include a method in which the bone regeneration material is placed in an appropriate mold and hardened, or a method in which pressure is applied during hardening. The shape of the molded product is not particularly limited. Examples include disks, blocks, and sheets. The size of the disk is not particularly limited. For example, the diameter is usually 3 to 20 mm, preferably 5 to 10 mm. For example, the thickness is usually 0.5 to 5 mm, preferably 1 to 2 mm. The size of the block is not particularly limited. For example, the length is 5 to 15 mm, the width is 5 to 50 mm, and the height is 5 to 100 mm, preferably 8 to 12 mm, the width is 10 to 30 mm, and the height is 10 to 50 mm.

[0024] The molded article is appropriately shaped according to the shape of the bone defect, and is sterilized by, for example, ethylene oxide gas sterilization, radiation sterilization, autoclaving, etc., before being implanted in the bone defect. However, autoclaving affects the crystalline phase of OCP or PLGA, so the application site of the bone defect should be considered in that case. [Example]

[0025] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0026] First, a PLGA biodegradable polymer solution was prepared according to the manufacturing method described above. Next, OCP granules were added to this solution so that the OCP content in the bone regeneration material was 20, 30, or 40% by mass. After freezing and drying, the 1,4-dioxane was removed to obtain a porous OCP / biodegradable polymer composite bone regeneration material. The porosity of the resulting bone regeneration material was 75-85% (measured using a pycnometer) and the average pore diameter was 40-70 μm (measured using a SEM).

[0027] For reference, a bone regeneration material consisting of only PLGA without OCP granules was prepared. The porosity of this material was 84.9% (measured using a pycnometer) and the average pore diameter was 58.9 ± 1.9 μm (measured using a scanning electron microscope (SEM)).

[0028] Next, the above bone regeneration material (Φ3×5mm) was embedded in a through-hole (diameter 3mm) created in the rat femur for 4 and 8 weeks, and the bone regeneration ability was evaluated by μ-CT and histological examination.

[0029] Figure 1 is a graph showing the newly formed bone area (%) 4 and 8 weeks after implantation of the bone regeneration material into rat femurs. As is clear from Figure 1, the bone regeneration material containing OCP had a higher newly formed bone area percentage than the bone regeneration material containing PLGA alone, and the highest newly formed bone area was found when the OCP content was 40% by mass.

[0030] Figure 2 shows μ-CT images of a bone regeneration material containing 40% OCP. Both the transverse and coronal sections show that newly formed bone penetrates into the bone regeneration material, and the impermeable area due to calcified tissue increases, especially after 8 weeks. This indicates that the bone regeneration material of this example has excellent osteoconductivity.

[0031] Figure 3 is a graph showing the pH value of the PBS supernatant after immersion in phosphate buffer solution (PBS) (pH 7.4, 37°C) of 40% by weight OCP and 60% by weight PLGA isolated with a membrane filter, 20% by weight OCP granules and 80% by weight PLGA isolated with a membrane filter, PLGA alone, and OCP granules alone (equivalent to 40% by weight of OCP). Figure 4 is a graph showing the weight change of PLGA after immersion in phosphate buffer solution (PBS) (pH 7.4, 37°C) of 40% by weight OCP and 60% by weight PLGA isolated with a membrane filter, 20% by weight OCP granules and 80% by weight PLGA isolated with a membrane filter, and PLGA alone.

[0032] As shown in Figure 3, the pH value of PBS containing 40% or 20% by mass of filtered OCP granules and PLGA soaked in the PBS decreased over time. As shown in Figure 4, the weight of PLGA coexisting with OCP decreased more over time than that of PLGA alone. This indicates that the degradability (resorbability) of PLGA is increased by incorporating OCP into PLGA to form a complex. This indicates that the synergistic effect of the bioresorbability of PLGA and the osteoconductivity of OCP allows the production of a bone regeneration material with excellent bone replacement properties.

[0033] Although several embodiments of the present invention have been described above, these embodiments are presented as examples and are not intended to limit the scope of the invention. These novel embodiments can be embodied in various other forms, and various omissions, substitutions, and modifications can be made without departing from the spirit of the invention. These embodiments and their modifications are included within the scope and spirit of the invention, and are also included in the scope of the invention and its equivalents as defined in the claims.

Claims

1. Octacalcium phosphate (calcium phosphate 8) (Ca ８ H ２ (P.O. ４ ) ６ ・5H ２ O) (OCP) and lactic acid-co-glycolic acid copolymer (PLGA), The OCP is contained in an amount of 20% by mass or more and 40% by mass or less, and the PLGA is contained in an amount of 80% by mass or less and 60% by mass or more, based on the total amount of the OCP and the PLGA, A bone regeneration material characterized in that the weight average molecular weight of the PLGA is 20,000 or more and 150,000 or less.

2. The bone regeneration material according to claim 1, characterized in that it has a porous structure.

Images