Method for producing bioceramic porous body

Abstract

To provide a method for producing a bioceramic porous body that has a structure favorable for bone regeneration.SOLUTION: A method for producing a bioceramic porous body comprises: a mold preparation step of preparing a mold including a core portion that is a resin structure having columnar pillars; a material filling step of dissolving a plurality of bioceramic particles in a chemical species, further dissolving the particles with a solvent to obtain a kneaded material, and filling the kneaded material into the mold; a solidification step of solidifying the kneaded material by heating while applying pressure together with the mold to obtain a bioceramic molded body; and a mold removal step of immersing the bioceramic molded body and the mold in a liquid to dissolve and remove the mold and obtain a bioceramic porous body.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for producing a porous bioceramic body. [Background technology]

[0002] Bone grafts are used to treat bone tumors, osteoarthritis of the knee, complex fractures, etc. Autologous bone harvested from the patient is often used as the bone graft material, but there are drawbacks such as a limited amount that can be harvested and pain, so artificial bone is used as the graft material. Calcium phosphates such as hydroxyapatite (HAp) and beta-tricalcium phosphate (β-TCP) are commonly used as artificial bone materials. However, existing artificial bones have lower bone regeneration capacity than autologous bone, so there is a need to improve bone regeneration capacity.

[0003] It has been reported that by making artificial bone porous, capillaries and cells involved in bone regeneration can quickly penetrate into the interior of the implant, improving bone regeneration ability. The porous structure refers to a structure having a plurality of pores (open holes or pores) that communicate from one end surface to the other end surface. The communicating pores may be a single continuous pore or a plurality of pores that communicate with each other, resulting in a state in which the pores communicate from one end surface to the other end surface.

[0004] As a method for producing porous artificial bones, for example, Patent Document 1 discloses a method in which a raw material powder of a calcium phosphate compound is mixed with a pyrolysis substance and a foaming agent, and in a state in which bubbles are generated by the foaming agent, the pyrolysis substance is removed and the raw material powder is sintered to produce a porous body. In recent years, calcium phosphates such as dibasic calcium phosphate (DCPA) and octabasic calcium phosphate (OCP) have attracted attention as calcium phosphates with higher bone regeneration potential than conventional calcium phosphates. Patent Document 2 describes a technique known as cold sintering of ceramic materials. A mixture of ceramic powder and a solvent such as water, or a solvent containing dissolved acids and bases, is filled into a mold, and sintered at a predetermined pressure under a temperature condition of 200°C or less in a uniaxial press equipped with a heater mechanism. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2013 / 035690 [Patent Document 2] Patent Publication No. 2021-107324 Summary of the Invention [Problem to be solved by the invention]

[0006] Calcium phosphates such as DCPA and OCP undergo a phase transition at temperatures above 400°C, and therefore the porous formation method of sintering at high temperatures as in Patent Document 1 cannot be applied. Although Patent Document 2 mentions that hydroxyapatite can be used as a raw material for ceramic materials, it focuses on densification and does not disclose or suggest a method for producing a porous body.

[0007] Therefore, an object of the present invention is to provide a method for producing a porous bioceramic body having a structure advantageous for bone regeneration. [Means for solving the problem]

[0008] The present invention provides a method for producing a porous bioceramic body, comprising the steps of: a mold preparation step of preparing a mold including a core portion, which is a resin structure having columnar pillars; a material filling step of dissolving a plurality of bioceramic particles in a chemical species, and further dissolving the resulting material in a solvent to form a kneaded material, and filling the kneaded material into the mold; a solidification step of solidifying the kneaded material and the mold by heating while applying pressure to obtain a bioceramic formed body; and a mold removal step of immersing the bioceramic formed body and the mold in a liquid to dissolve and remove the mold, thereby obtaining a porous bioceramic body.

[0009] In the present invention, in the mold preparing step, the mold may be prepared by additive manufacturing.

[0010] Furthermore, in the material filling step, water may be used as the solvent.

[0011] Furthermore, in the solidification step, the kneaded material may be solidified by heating at 20° C. or higher and 200° C. or lower and applying pressure of 50 MPa or higher.

[0012] Furthermore, in the template removal step, the template may be dissolved and removed by immersion in an aqueous solution having a pH of 10 or higher.

[0013] Furthermore, in the template removal step, the template may be dissolved and removed by immersion in an organic solvent. [Effects of the Invention]

[0014] It is possible to produce a porous bioceramic body with a structure that is advantageous for bone regeneration. [Brief explanation of the drawings]

[0015] [Figure 1] 1 is a flowchart showing an example of a method for producing a porous bioceramic body according to an embodiment. [Figure 2] 1A to 1C are diagrams schematically illustrating a part of a method for producing a porous bioceramic body according to an embodiment. [Figure 3] FIG. 1 is a diagram showing the shape of a template used in the examples. [Figure 4] 2 is a photograph showing one embodiment of a front view (a) and a side view (b) of the porous bioceramic material produced in Example 1. [Figure 5] 3 is a photograph showing one form of a front view (a) and a side view (b) of the porous bioceramic material produced in Example 2. [Figure 6] FIG. 1 is a diagram showing the shape and dimensions of a porous bioceramic body prepared in an example. [Figure 7] 1 is a graph showing an X-ray diffraction pattern measured with CuKα radiation for the bioceramic porous body of Example 1, and a plot of the diffraction angle of monetite (calcium hydrogen phosphate, CaHPO4) registered as 00-009-0080. DETAILED DESCRIPTION OF THE INVENTION

[0016] Hereinafter, embodiments of the present invention will be described in detail. <Method for manufacturing porous bioceramics> A method for producing a porous bioceramic body will now be described. As shown in Fig. 1, the method for producing a porous bioceramic body of this embodiment includes a mold preparation step (S1), a material filling step (S2), a solidification step (S3), and a mold removal step (S4). Fig. 2 is a diagram schematically illustrating part of the manufacturing process for a porous bioceramic body 40. Each step will be described below.

[0017] [Mold preparation process (S1)] First, in the mold preparation step, a mold 10 is prepared that includes a core portion 11, which is a resin structure that is the inverse structure of the porous bioceramic body (FIG. 2(A)). The mold 10 consists of a core portion 11 that defines the external shape of the porous bioceramic body, and a solidification mold portion 12. The core portion 11 can be produced using methods such as molding, cores, NC cutting, and additive manufacturing using a 3D printer. In particular, additive manufacturing using a 3D printer can be used to produce complex shapes. When resin is photocured to produce a shape, output is possible with a resolution of about several micrometers, making this method preferable for producing fine structures. Resin is used as the material of the core portion 11. Examples of resin materials that can be used for additive manufacturing using a 3D printer include nylon, polylactic acid, ABS, polycarbonate, polypropylene, and polyamide.

[0018] Generally, when a kneaded material containing bioceramic particles (described later) is filled into a mold including a core and molded, the solidified kneaded material has the inverse structure of the mold. Therefore, in this embodiment, the mold 10 including the core 11 having columnar pillars that are the inverse shape of the pores to be formed in the bioceramic porous body is integrally molded with the kneaded material 20, and then the mold 10 is removed to form pores in the mold 10 in areas that correspond to the inverse shapes of the pores. For example, if a pinholder-shaped pillar array shape in which columnar pillars are arranged perpendicular to a base is used as the core 11 and the kneaded material 20 is molded, and the mold 10 is removed, a ceramic body with a porous structure in which cylindrical, interconnected pores (open pores or fine pores) are aligned is obtained. It has been confirmed that porous bioceramics with these oriented, interconnected pores are easily permeable to blood and biological tissues that undergo bone formation, resulting in rapid vascular invasion and bone regeneration. Therefore, if bioceramics with an oriented, interconnected pore structure can be obtained, it is expected that they will exhibit excellent bone regeneration capabilities.

[0019] The shape of the core portion 11 can be, in addition to the pillar array shape described above, a lattice shape in which pillars are arranged to intersect perpendicularly with each other, or a shape such as a lattice, gyroid, schwarz, or diamond shape in which periodic, regular patterns are repeated three-dimensionally. The pores and the distance between walls of the porous bioceramic body can be adjusted by adjusting the diameter of the columnar pillars formed in the core portion 11 that correspond to the pores of the porous bioceramic body and the spacing of the pores. The pore occupancy rate of the porous ceramic body formed in the mold 10 can be adjusted by adjusting the volume fraction of the structures corresponding to the pores of the porous bioceramic body formed in the core portion 11 in the molding space formed by the solidification mold portion 12.

[0020] [Material filling process (S2)] In the material filling process, a kneaded material is first prepared from a plurality of bioceramic particles, one or more chemical species serving as dissolution / precipitation accelerators that dissolve the plurality of bioceramic particles, and a solvent that dissolves and ionizes the dissolution / precipitation accelerator. The dissolution / precipitation accelerator and the ionizable solvent may be premixed before mixing with the bioceramic particles. The mixing method is not particularly limited, but examples include mortar mixing using a grinder, or mixing using a mixer or kneader. The material of the bioceramic particles is not particularly limited as long as it is biocompatible. For example, hydroxyapatite, calcium phosphate such as β-tricalcium phosphate and calcium hydrogen phosphate, carbonate apatite, calcium carbonate, etc. are usable. Bioabsorbable β-tricalcium phosphate is particularly preferred. The method for preparing the bioceramic particles is not particularly limited. The raw material particles may be used as they are, or may be used after being pulverized in a mortar or ball mill. The raw material powder may also be used after being granulated or granulated. As the dissolution / precipitation promoter, a chemical species that promotes the dissolution and reprecipitation of bioceramic particles is selected. For example, acids such as hydrochloric acid and phosphoric acid, and bases such as sodium hydroxide can be used as the promoter of dissolution of bioceramic particles. For the promoter of particle precipitation, one or more calcium compounds and phosphate compounds that are soluble in the selected solvent can be selected. Examples of the calcium compounds include calcium chloride and calcium nitrate, and examples of the phosphate compounds include sodium dihydrogen phosphate and disodium hydrogen phosphate. The ionizable solvent may be any solvent that ionizes the dissolution / precipitation accelerator, such as water, alcohol, etc. As the water, for example, industrial purified water can be used. can be done.

[0021] Next, the prepared kneaded material 20 is filled into the mold 10 including the core portion 11 and the solidification mold portion 12 prepared in the mold preparation step (FIG. 2(B)). The filling method is not particularly limited. In consideration of ease of filling, the kneaded material 20 may be diluted with a liquid such as water before being filled into the mold 10. The solidifying mold part 12 is not particularly limited as long as it has a shape and material that can withstand pressure and heat. It may be a metal mold or a resin mold. Materials that can be used for the mold include, for example, cemented carbide, SUS, and SKD11. Materials that can be used for the resin mold include, for example, silicone and acrylic. The surface of the solidifying mold part 12 may be subjected to a surface treatment from the viewpoint of corrosion resistance. The manufacturing method is not particularly limited. For example, it may be manufactured by machining, three-dimensional additive manufacturing, or injection molding. The solidifying mold part 12 may also be substituted with a pressure device, which will be described later.

[0022] [Solidification process (S3)] Next, in the solidification step, the mold 10 filled with the kneaded material 20 is heated while being pressurized, thereby solidifying the kneaded material 20 and obtaining a bioceramic molded body. The pressing method may be uniaxial pressing or isotropic pressing. When uniaxial pressing is performed (FIG. 2(C)), the mold 10 filled with the kneaded material 20 is placed in the space formed by the lower punch 32 and side plate 33 of the uniaxial pressing die 30, and then pressing is performed by the upper punch 31 and the lower punch 32. This pressing device may be a manual press or an inverter press, and the mold may be pressed via gas or liquid such as water or oil. The pressure applied during pressing should be 50 MPa or more, preferably 375 MPa to 625 MPa, which allows the production of a porous bioceramic body with superior mechanical strength. The heating temperature may be 20°C or higher and 200°C or lower, preferably 70°C to 90°C. Since ions dissolved in the solvent diffuse through the solvent and re-precipitate, it is better for a liquid phase to remain during the reaction. For this reason, the heating temperature is preferably below the boiling point of the solvent. The heating method is not particularly limited as long as the kneaded material 120 can be heated to a desired temperature. For example, a press machine equipped with a heating mechanism may be used, or a mold may be heated using heating equipment such as a band heater. Heating may also be performed via gas or liquid such as water or oil. The pressurization and heating time is preferably 1 minute or more in order to obtain the mechanical strength required for the porous bioceramic body.

[0023] [Template removal step (S4)] Next, the mold 10 is removed from the integrally formed body of the mold 10 and bioceramic produced in the solidification step S3 to obtain a porous bioceramic body 40 having pores 41 (FIG. 2(D)). The porous bioceramic body 40 has an inverse structure to that of the mold 10. The template 10 can be removed by dissolving it in a basic solution or an acidic solution, or by dissolving it in an organic solvent. (basic aqueous solution) The mold 10 is dissolved and removed using a basic solution with a pH of 10 or higher, which is higher than the pH of the kneaded material and solvent filled in the material filling process. Examples of bases that can be used include sodium hydroxide and calcium hydroxide. Examples of solvents for the base include water. One or a mixture of two or more of these bases may also be used. (acidic aqueous solution) The mold 10 is dissolved and removed using an acidic solution with a pH of 6 or less, which is lower than the pH of the kneaded material and solvent filled in the material filling process. The acid can be an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as methanesulfonic acid. The solvent for the acid can be water. One or a mixture of two or more of these acids can also be used. (organic solvent) This organic solvent is different from the solvent used in the material filling process and is a solvent for organic materials, including aqueous organic solvents. Examples of organic solvents that can be used include alcohols, ketone-based solvents such as acetone and methyl ethyl ketone, ether-based solvents such as diethyl ether and tetrahydrofuran, chlorinated hydrocarbon-based solvents such as chloroform and carbon tetrachloride, ester-based solvents such as ethyl acetate and butyl acetate, and aromatic hydrocarbon solvents such as benzene, toluene, and xylene. One or a mixture of two or more of these solvents may be used. Dissolution of the mold can be promoted by heating the liquid to 25° C. or higher. The heating temperature is preferably below the phase transition temperature of the components contained in the bioceramics.

[0024] (Post-processing) The porous bioceramic body obtained by removing the template is finally washed and dried to obtain a porous bioceramic body. When treated with an acidic or basic solution, washing with pure water at room temperature or heated is preferred. When treated with an organic solvent, washing with a solvent capable of removing the organic solvent is preferred, followed by washing with pure water at room temperature or heated. Drying can be done by natural drying or drying in a dryer. When the bioceramic porous body of this embodiment is to be embedded in a living body, it is preferable to carry out a sterilization treatment after the mold preparation step S1 to the mold removal step S4. Examples of the sterilization treatment include gamma ray irradiation and sterilization using a gas such as ethylene oxide. The method for producing a porous bioceramic body of this embodiment may include a step of adding components other than the bioceramic particles, dissolution / precipitation promoter, and solvent to improve bioabsorbability. It may also include a step of processing the molded bioceramic. For example, it may include a step of adding a bone formation promoter such as bone morphogenetic proteins (BMPs), an antibacterial agent such as Ag ions or Ag nanoparticles, or an antibiotic such as vancomycin.

[0025] [X-ray diffraction pattern] The porous bioceramic material preferably contains a peak of calcium hydrogen phosphate in the X-ray diffraction pattern measured with CuKα radiation. When this peak is present, it contains calcium hydrogen phosphate, which has high solubility, and therefore Ca 2+ The elution rate of ions is improved, and the bioabsorbability of the bioceramic porous body can be increased. [Example]

[0026] Example 1 In Example 1, epoxy and acrylate compound materials were used to create a pinholder-shaped core (Figure 3) with 1 mm diameter cylindrical pillars arranged at equal intervals on a 10 mm diameter circular base using a resin 3D printer (Sat Systems, SmaPri Sonic 8K XM). This core was then placed in the molding space of the solidification mold (a round mold with a diameter of 10 mm) to form a casting mold. Beta-tricalcium phosphate (β-TCP) powder was used as the bioceramic particles. Calcium chloride (CaCl2) and sodium dihydrogen phosphate (NaH2PO4) were used as the chemical species to dissolve the bioceramic particles. Industrially purified water was used as the ionizable solvent. Calcium chloride (CaCl2) and sodium dihydrogen phosphate (NaH2PO4) were dissolved in industrially purified water in advance to prepare aqueous solutions. The β-TCP powder and the aqueous solution were weighed out so that the ratio was 60% by mass and 20% by mass, respectively, and mixed in a mortar for 5 minutes to obtain a kneaded material. The kneaded material was packed into the molding space of the mold. The mold filled with the kneaded material was pressed using a press machine (H300-05, manufactured by AS ONE) with heating mechanisms on the top and bottom plates. A band heater was attached to the mold, and it was heated from the side of the die as well (80°C, 500 MPa, maintained for 3 hours). After heating, the mold was removed from the press machine and removed from the frame to obtain a ceramic molded body integrated with a cylindrical resin core. The ceramic molded body was immersed in a 10 mass percent aqueous solution of sodium hydroxide for 12 hours to dissolve and remove the resin mold, thereby obtaining a bioceramic porous body having an oriented interconnected structure as shown in FIG.

[0027] <Example 2> In Example 2, unlike Example 1, the ceramic molded body in which the solidified kneaded material and the resin core were integrated was removed by immersion in an organic solvent (Solgas EP-110, manufactured by Sankyo Chemical Industry Co., Ltd.). Other steps were the same as in Example 1 to produce ceramics, and a porous ceramic body with an oriented interconnected structure as shown in Fig. 5 was obtained.

[0028] <Shape and dimensions of bioceramic porous bodies> 6 is a schematic diagram showing the shape and dimensions of each part of the porous bioceramic body. The diameter of the porous bioceramic body is A and the pore size is B. The diameter A of the porous bioceramic material obtained in Example 1 was 10.0 mm, and the pore size B was 0.99 to 1.10 mm. The diameter A of the porous bioceramic material obtained in Example 2 was 10.0 mm, and the pore size B was 0.99 to 1.10 mm.

[0029] <Evaluation of the crystalline phase of porous bioceramics> The bioceramic porous body obtained in Example 1 was measured using an X-ray diffractometer (PANalytical, X'Pert Pro) under the following measurement conditions: tube voltage 45 kV, tube current 40 mA, CuKα diffraction angle 2θ = 20° to 80°, step size 0.0084°, mask 5 mm, divergence slit 1 / 4°, anti-scatter slit 1 / 2°. Figure 7 shows the measured X-ray diffraction pattern and a plot of calcium hydrogen phosphate. As shown in Figure 7, in addition to the peak of β-tricalcium phosphate (β-TCP) in the bioceramic particles, a peak of calcium hydrogen phosphate (DCPA) was also confirmed. This indicates that Example 1 contains calcium hydrogen phosphate. In this example, it was found that a porous bioceramic body was produced that was made of calcium phosphate containing dibasic calcium phosphate (DCPA), which has high bone regeneration capacity, and had interconnected pores oriented in almost the same direction, and that it had a structure and composition that was advantageous for bone regeneration.

[0030] Although the present invention has been described using the above-mentioned embodiment, the present invention is not limited to the above-mentioned embodiment and can be modified within the technical scope of the present invention as defined in the claims. [Explanation of symbols]

[0031] 10: Mold 11: Core part 12: Solidification mold part 20: Mixing materials 30: Uniaxial press mold 31: Upper punch 32: Down punch 33: Side panel 40: Bioceramic porous body 41: Hole A: Diameter of the bioceramic porous body B: Aperture

Claims

1. a mold preparation step of preparing a mold including a core portion which is a resin structure having columnar pillars; a material filling step of dissolving a plurality of bioceramic particles in a chemical species and then dissolving the same in a solvent to prepare a kneaded material, and filling the kneaded material into the mold; a solidification step of solidifying the kneaded material and the mold by heating while applying pressure to obtain a bioceramic molded body; a mold removal step of immersing the bioceramic green body and the mold in a liquid to dissolve and remove the mold, thereby obtaining a bioceramic porous body; A method for producing a porous bioceramic body, comprising:

2. In the mold preparation step, the mold is prepared by additive manufacturing; 2. The method for producing a porous bioceramic body according to claim 1,

3. using water as the solvent in the material filling step; 2. The method for producing a porous bioceramic body according to claim 1,

4. In the solidification step, the kneaded material is heated at 20°C or higher and 200°C or lower and pressurized at 50 MPa or higher to solidify the kneaded material; 2. The method for producing a porous bioceramic body according to claim 1,

5. 2. The method for producing a porous bioceramic body according to claim 1, wherein in the template removal step, the body is immersed in an aqueous solution having a pH of 10 or more to dissolve and remove the template.

6. In the template removal step, the template is dissolved and removed by immersion in an organic solvent; 2. The method for producing a porous bioceramic body according to claim 1,

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