Biodegradable polymer composite tissue reconstruction material

Abstract

To provide a medical tissue reconstruction material, which is involved in tissue reconstruction and exhibits superior tissue affinity, tissue conductivity, and mechanical properties, and a method for producing the same.SOLUTION: The present invention provides a composite comprising a biodegradable polymer and calcium phosphate exhibiting one of scaly, acicular, grooved, or linear recessed structures, and / or calcium carbonate containing vaterite, the composite meeting specific conditions.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] The present invention relates to medical materials implanted in vivo. Specifically, it relates to medical tissue reconstruction materials involved in tissue reconstruction, such as bone fillers, barrier membranes, sponges, plates, screws, nerve regeneration tubes, sutures, etc., and methods for manufacturing the same. These medical tissue reconstruction materials are particularly useful for bone reconstruction, soft tissue reconstruction, and nerve regeneration.

Background Art

[0002] Biodegradable polymers represented by collagen, gelatin, polylactic acid, polyglycolic acid, etc. are rich in flexibility, decomposed or dissolved in vivo, and absorbed without causing serious problems in vivo, so their use as medical tissue reconstruction materials has been progressing. However, the tissue affinity and the like of these biodegradable polymers are not sufficient. On the other hand, some calcium phosphates represented by apatite are absorbed in vivo, and calcium phosphate and calcium carbonate are excellent in tissue affinity and tissue conductivity, but they are brittle materials. Therefore, the composite of the two has been proposed. Patent Document 1 discloses bone fixation pins, screws, etc. composed of a composite of polylactic acid and hydroxyapatite, etc., Patent Document 2 discloses a foam-like interconnected porous body, etc., and Patent Document 3 discloses a composite of collagen and hydroxyapatite, etc., but the tissue affinity and tissue conductivity are not sufficient.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0004] The present invention has been made in view of the above problems, and an object of the present invention is to provide a medical material having excellent tissue affinity, tissue conductivity, and mechanical properties. [Means for Solving the Problems]

[0005] As a result of intensive studies, the present inventors have found that a composite of a biodegradable polymer and calcium phosphate having any one of a scaly structure, a needle-like structure, a groove-like structure, and a linear recess structure, and / or calcium carbonate containing willemite, when satisfying specific conditions, the composite is a medical tissue reconstruction material having excellent tissue affinity, tissue conductivity, and mechanical properties, and also found that a specific production method is useful for the production of the composite, and thus completed the present invention.

[0006] That is, the present invention is as follows. (Hereinafter, the inventions of the following [1] to [4] may be referred to as the present inventions [1] to [4].) [1] A composite comprising a biodegradable polymer and a specific ceramic comprising calcium phosphate having any one of a scaly structure, a needle-like structure, a groove-like structure, and a linear recess structure on at least a part of the surface, and / or calcium carbonate containing willemite, which is a medical tissue reconstruction material satisfying any one of the following (A1) to (A3) and any one of (B) to (J). (A1) On the surface of the composite, specific ceramics having an area of 3.1×10 -12 m 2 or more are exposed. (A2) A part of the specific ceramics is buried in the biodegradable polymer, and the cut and / or polished specific ceramics are exposed on the surface of the composite. (A3) Provided with specific particles which are specific ceramics having a volume average diameter of 1 μm or more and 500 μm or less, the specific particles are coated with a biodegradable polymer, and the shortest distance between the surface of the composite and the specific particles is 10 μm or less. (B) The composite contains 30% by mass or more and 93% by mass or less of a specific ceramic, has a porosity of 50% or more, and has small pores with a major axis of the pores of 2 μm or more and 20 μm or less, and / or large pores with a major axis of the pores of 30 μm or more and 1000 μm or less, and is a sponge structure body. (C) The composite is a specific granule of a specific ceramic with a volume of 1.0×10 -13 m 3 or more and 5.0×10 -7 m 3 or less, a honeycomb structure body of a specific ceramic with a volume of 1.4×10 -11 m 3 or more and 5.0×10 -7 m 3 or less, having one or more through-holes extending in one direction, and a porous body of a specific ceramic with a volume of 1.4×10 -11 m 3 or more and 5.0×10 -7 m 3 or less, having a plurality of through-holes extending in a plurality of directions, and is a sponge structure body having a porosity of 50% or more and containing at least 10% by mass or more of at least one selected from the group consisting of the above. (D) The composite is a curable sponge structure body having a curable composition that cures to form calcium phosphate and / or calcium sulfate dihydrate, or a partially cured composition of the curable composition in the pore portion. (E) The composite is a sponge structure body in which 30% or more of the surface of the beam portion is covered with a specific ceramic having a thickness of 20 μm or more and having a porosity of 30% or more. (F) The composite is a plate-like or film-like sponge structure body in which at least one surface is covered with a specific ceramic. (G) The composite is a structure in which a honeycomb structure body of a specific ceramic having one or more through-holes extending in one direction or a communication structure body of a specific ceramic having a plurality of through-holes extending in a plurality of directions is penetrated by a biodegradable polymer sponge structure body having a porosity of 10% or more. (H) The composite is a biodegradable polymer on at least a part of the surface of the biodegradable polymer Comprising a composite layer composed of a marker and specific ceramics, On the surface of the composite layer, the depth of the groove formed between the exposed specific ceramics is 100 μm or less. (I) The composite body comprises a composite layer composed of at least a part of the surface of a biodegradable polymer and specific particles which are specific ceramics having a volume average diameter of 1 μm or more and 500 μm or less, and the degree of orientation of the central part of the biodegradable polymer is larger than the degree of orientation of the biodegradable polymer in the composite layer. (J) The composite body has a composite layer of a biodegradable polymer and specific particles which are specific ceramics having a volume average diameter of 1 μm or more and 500 μm or less on the surface, and at least a part of the biodegradable polymer exposed in the composite layer is bonded to metal ions and / or ammonium ions. [2] The medical tissue reconstruction material is characterized by satisfying any one of the following (K) to (M), as described in [1]. (K) In the specific ceramics, calcium phosphate is carbonate apatite containing 2% by mass or more of a carbonate group. (L) In the specific particles, the value obtained by dividing the area of the projected image on the composite body surface by the minimum circumscribed circle area is 0.8 or more, and / or the value obtained by dividing the weight of the specific particles having a hollow part by the weight of all the specific particles is 0.3 or more. (M) The biodegradable polymer is a polymer or copolymer of a compound selected from the group consisting of lactic acid, glycolic acid, caprolactone, lactide, dioxanone, dioxane, glycerol sebacate, malic acid, and hydroxycarboxylic acid, or the biodegradable polymer contains one selected from the group consisting of collagen, gelatin, chitin, chitosan, hyaluronic acid, chondroitin sulfate, fibronectin, vitronectin, and laminin. [3] The composite body is a porous body produced by a process including freeze-drying, or a porous body having a specific surface area of 0.2 m 2 / g or more, as described in any one of [1] or [2]. [4] A method for manufacturing the medical tissue reconstruction material according to [1] or [2], characterized by including any one of the following steps (O) to (T). (O) A material selected from specific particles, specific granules, a pore-forming material having a major axis of 300 μm or more and 1000 μm or less, specific ceramics having one or more through-holes extending in one direction, and specific ceramics having a plurality of through-holes extending in a plurality of directions, is suspended or dispersed in a biodegradable polymer solution, or a suspension of the biodegradable polymer solution and the specific particles is introduced into the through-holes, and then dried, freeze-dried, and / or subjected to a crosslinking treatment. (P) A biodegradable polymer suspension in which specific particles are suspended, is placed in a container having one or more beams extending in one direction or a container having a plurality of beams extending in a plurality of directions, and then dried, or is extruded with an extruder into a structure having one or more through-holes extending in one direction, and then dried or freeze-dried. (Q) A step of applying a curable composition that cures to form calcium phosphate and / or calcium sulfate dihydrate into the pores of a sponge structure having a porosity of 50% or more, and a step of partially curing the curable composition as necessary. (R) A step of applying calcium hydroxide paste to the surface of the beam portion of the sponge structure so as to ensure the sponge structure, or a step of applying calcium hydroxide paste to the pores on at least one side of the sponge structure, and subsequently, exposing it to carbon dioxide containing water and / or an organic solvent. (S) A step of applying a suspension of a biodegradable polymer containing specific particles to the surface of the biodegradable polymer, and then removing the solvent, and after this step, exposing the specific particles to the surface of the degradable polymer as necessary. (T) A step of exposing a composite containing a biodegradable polymer and specific ceramics to a solvent or a solution to dissolve the biodegradable polymer in the vicinity of the specific ceramics and expose the specific ceramics on the surface. Alternatively, a composite comprising a biodegradable polymer and a specific ceramic composed of calcium carbonate containing willemite is exposed to a phosphate solution to dissolve the biodegradable polymer in the vicinity of the calcium carbonate containing willemite, thereby exposing the calcium carbonate containing willemite on the surface of the composite and causing a compositional conversion of the calcium carbonate containing willemite into carbonated apatite.

Advantages of the Invention

[0007] The biodegradable polymer composite tissue repair material of the present invention is a medical tissue repair material excellent in tissue affinity, tissue conductivity, and mechanical properties, and is useful in the medical field, particularly in bone regeneration, soft tissue regeneration, and nerve regeneration. Further, the manufacturing method of the present invention is useful for manufacturing the biodegradable polymer composite tissue repair material.

Brief Description of the Drawings

[0008]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Mode for Carrying Out the Invention

[0009] Hereinafter, the present invention will be described. In the present invention, for simplicity, terms are defined. "Specific ceramics" means calcium carbonate containing calcium phosphate and / or willemite having at least a part of the surface presenting any one of a scaly structure, a needle-like structure, a groove-like structure, and a linear concave structure. It is preferable that the surface of the calcium phosphate has a structure such as a scaly structure in 20% or more. The value is more preferably 40% or more, and even more preferably 60% or more. It is ideal that the entire surface presents a scaly structure or the like. "Specific particles" means specific ceramics having a volume average diameter of 1 μm or more and 500 μm or less. The volume average diameter is a value defined in JIS-Z8819-2:2019. When differences occur due to measurement, the value measured by the zeta potential, particle size, and molecular weight measurement system ELSZ-2000ZS manufactured by Otsuka Electronics Co., Ltd. shall be used. "Specific granules" means specific ceramics having a volume of 1.0×10 -13 m 3 or more and 5.0×10 -7 m 3 or less. "Biodegradable polymer" refers to a polymer that is decomposed and absorbed in the living body and is sometimes called a bioabsorbable polymer. Synthetic polymers typified by polylactic acid, and natural polymers typified by collagen (including atelocollagen) and gelatin are all biodegradable polymers that are absorbed in the living body. "Composite layer" refers to a site where a biodegradable polymer and specific ceramics coexist. "Thickness of the composite layer" refers to the thickness of the site where the biodegradable polymer and specific ceramics coexist in the direction perpendicular to the surface of the composite layer. "Intercalated layer" refers to a site where any of the scaly structure, needle-like structure, and groove-like structure on the surface of specific ceramics is intercalated with a biodegradable polymer. The thickness of the intercalated layer is the thickness of the biodegradable polymer infiltrated into the uneven portion of any of the scaly structure, needle-like structure, and groove-like structure of specific ceramics.

[0010] <1 Basic conditions of the present invention> The material of the present invention is a medical tissue reconstruction material used in medicine. More specifically, it is a composite containing a biodegradable polymer and specific ceramics, and is a composite that satisfies specific conditions. By satisfying these conditions, a medical tissue reconstruction material excellent in tissue affinity, tissue conductivity, and mechanical properties can be provided, which can be used for tissue reconstruction and the like.

[0011] Specific ceramics whose composition is calcium phosphate must exhibit at least a part of any of a scaly structure, a needle-like structure, a groove-like structure, and a linear concave structure on the surface. The linear concave portion of the present invention is a linear concave portion formed when a plurality of substantially spherical bodies having different central points are joined. For example, a linear concave structure is formed when a plurality of substantially spherical specific ceramics are fused. A structure that exhibits any of a scaly structure, a needle-like structure, and a groove-like structure on the surface and forms a linear concave structure by the structure is more preferable. That is, the tissue affinity and osteoconductivity of calcium phosphate are greatly affected not only by the composition but also by the fine morphology. Calcium phosphate presenting any of a flaky structure, a needle-like structure, a groove-like structure, and a linear recess structure is excellent in tissue affinity and osteoconductivity. What these structures have in common is an uneven structure. It is preferable that the depth of the uneven structure, that is, the longest distance from the outermost part of the flaky structure, needle-like structure, groove-like structure, or linear recess structure, which is the convex part, to the bottom surface of the adjacent concave part is 0.02 μm or more. The longest distance is more preferably 0.05 μm or more, and even more preferably 0.1 μm or more. When the biodegradable polymer infiltrates into the uneven part, an engagement part is formed, and the length of the infiltrated uneven part becomes the thickness of the engagement part. Although the mechanism by which these structures affect the improvement of tissue affinity and osteoconductivity has not been fully elucidated, it is considered that cells recognize not only the composition but also the structure. Calcium phosphate presenting any of a flaky structure, a needle-like structure, and a groove-like structure is considered to affect the improvement of cell adhesion, proliferation, and differentiation. In addition, when the biodegradable polymer is a chemically synthesized material, an acid is formed by hydrolysis, causing an inflammatory reaction. Calcium phosphate presenting any of a flaky structure, a needle-like structure, a groove-like structure, and a linear recess structure has a large specific surface area and a high neutralizing ability against acids. Therefore, it neutralizes the acid formed by hydrolysis and suppresses the inflammatory reaction, which is also considered to contribute to excellent tissue affinity and osteoconductivity. In the composite of the present invention, a part of the specific ceramics may be processed by cutting or polishing. Also in that case, it is necessary to present at least a part of the surface with any of a flaky structure, a needle-like structure, a groove-like structure, and a linear recess structure.

[0012] Calcium phosphate having a linear recess structure has an advantage from the viewpoint of mechanical properties. When the exposed specific ceramics have linear recesses, when a bending stress or the like is applied to the composite, the specific ceramics can be prevented from breaking at the linear recesses and peeling off from the surface of the composite.

[0013] Witherite is one of the polymorphs of calcium carbonate and is a metastable phase, so it has high reactivity. In vivo, it may not only react with phosphate ions contained in body fluids to undergo a compositional conversion to carbonated apatite, but is also useful as a raw material when producing the above composite comprising carbonated apatite exhibiting any one of a flaky structure, a needle-like structure, a groove-like structure, and a linear concave structure. In the case where the specific ceramics is calcium carbonate containing witherite, since it reacts with phosphate ions in body fluids to become calcium phosphate exhibiting the above structure or becomes a raw material of the composite of the present invention where the specific ceramics is calcium phosphate, there is no restriction on the structure.

[0014] Calcium carbonate containing witherite is preferably pure witherite, but pure witherite is rare. Calcium carbonate containing witherite, such as a mixture with calcite, is preferable as calcium carbonate because of its high reactivity. The witherite content in calcium carbonate is preferably 10% or more, more preferably 30% or more, and even more preferably 50% or more.

[0015] For example, when producing a composite of a lactide-caprolactone copolymer and carbonated apatite, there may be a case where it is produced by immersing a composite of a lactide-caprolactone copolymer and calcium carbonate in an aqueous phosphate solution. When using stable-phase calcium carbonate (calcite), since the reactivity is low, the lactide-caprolactone copolymer may dissolve first and the calcium carbonate may fall off. On the other hand, if witherite, which is metastable-phase calcium carbonate, is used, since the reactivity is high, the witherite is less likely to fall off from the lactide-caprolactone copolymer, and it is easy to produce a composite of a lactide-caprolactone copolymer and carbonated apatite.

[0016] In order for the composite to exhibit excellent tissue affinity, tissue conductivity, and mechanical properties, it is necessary for the biodegradable polymer and the specific ceramics to be highly compounded. Generally, however, the binding force between the biodegradable polymer and calcium phosphate and / or calcium carbonate is limited. Therefore, it is necessary to highly compound the two by mechanical bonding. From this perspective, it is preferable that the biodegradable polymer has a composite layer capable of fixing the specific ceramics. The thickness of the composite layer is preferably 2 μm or more, more preferably 5 μm or more, even more preferably 10 μm or more, and particularly preferably 20 μm or more from the viewpoint of mechanical strength. Also, the thickness of the composite layer is preferably greater than the diameter of the specific ceramics contained in the composite layer. The specific ceramics having a calcium phosphate composition of the present invention have a scaly structure, needle-like structure, groove-like structure, or linear recess structure on the surface. Therefore, when the biodegradable polymer infiltrates into the structure having irregularities of the specific ceramics, an interpenetrating layer in which the biodegradable polymer and the specific ceramics interpenetrate is formed. Since the interpenetrating layer binds the biodegradable polymer and the specific ceramics more firmly, it is preferable to have an interpenetrating layer between the biodegradable polymer and the specific ceramics. The thickness of the interpenetrating layer is preferably 0.3 μm or more, more preferably 0.5 μm or more, and even more preferably 0.7 μm or more. This interpenetrating layer is usually formed at the boundary site and / or the buried portion in a mode where the specific ceramics of the present invention having a scaly structure or the like on the surface are buried in the biodegradable polymer. Note that in the material in which ceramics are deposited on the surface of the biodegradable polymer, there is substantially no composite layer or interpenetrating layer.

[0017] In the composite layer of the specific ceramics and the biodegradable polymer, it is preferable that the specific ceramics are densely present. Figure 1 shows a surface conceptual diagram of a composite in which a specific ceramic is coated with a biodegradable polymer. Here, a projection site of the near-specific ceramic with a shortest distance from the composite surface to the specific ceramic of 10 μm or less is defined as a modified portion. Figure 1 shows a surface conceptual diagram of a composite in which a specific ceramic is coated with a biodegradable polymer. When the specific ceramic is exposed on the surface of the composite, the exposed specific ceramic on the surface and the joint of the projection image of the specific ceramic from the composite surface to a depth of 10 μm are defined as the modified portion. Also, a site surrounded by the circumscribed line of a group of processing portions where the shortest distance between the modified portions is 2 times or less the volume-based median diameter of the specific ceramic is defined as a specific modified portion. Preferably, the value obtained by dividing the area of the specific modified portion by the surface area of the composite is 0.1 or more. More preferably, the value is 0.2 or more, and even more preferably, the value is 0.3 or more. Also, preferably, the value obtained by dividing the total area of the modified portions in the specific modified portion by the area of the specific modified portion is 0.2 or more. More preferably, the value is 0.3 or more, and even more preferably, the value is 0.4 or more.

[0018] It is an essential condition for the medical tissue reconstruction material of the present invention to satisfy any one of the above (A1) to (A3). When multiple conditions are satisfied, it may be more preferable. The above (A1) to (A3) are conditions regarding the positional relationship between the biodegradable polymer and the specific ceramic. Since the tissue affinity and tissue conductivity of the medical tissue reconstruction material of the present invention are mainly expressed by the specific ceramic, it is necessary that the specific ceramic is initially exposed on the composite surface or the biodegradable polymer dissolves when the composite is implanted in the body and the specific ceramic is exposed on the composite surface.

[0019] <1 Basic Conditions (A1) of the Present Invention> The above (A1) is a condition regarding the exposed area when the specific ceramic is exposed. Since the tissue affinity and tissue conductivity in the composite are caused by the specific ceramic, it is necessary that the specific ceramic is exposed at least partially on the composite surface. Although the mechanism by which the exposed area of the specific ceramics affects tissue affinity and tissue conductivity has not been elucidated, when the exposed area of the specific ceramics is less than 3.1×10 -12 m 2 , the cell adhesion is limited, and thus the influence on the tissue affinity and tissue conductivity of the composite is small. Therefore, the area should be 3.1×10 -12 m 2 or more. From the perspective of cell adhesion and the like, the area is preferably 2×10 -11 m 2 or more, more preferably 8×10 -11 m 2 or more, and even more preferably 3×10 -10 m 2 or more in some cases.

[0020] The area ratio of the exposed specific ceramics on the surface of the composite (the value obtained by dividing the sum of the areas of the exposed specific ceramics by the surface area of the composite) is not limited. However, since the specific ceramics mainly bear tissue affinity and tissue conductivity, a larger area ratio is preferred. The area ratio is preferably 0.2 or more, more preferably 0.4 or more, and even more preferably 0.6 or more.

[0021] <1 Basic Conditions (A2) of the Present Invention> The above (A2) is a condition when a part of the specific ceramics is buried in the biodegradable polymer and the processed specific ceramics are exposed. The bonding and embedding of the biodegradable polymer and the specific ceramics are as described above.

[0022] A part of the specific ceramics may be buried in the biodegradable polymer, and the exposed specific ceramics on the surface may be processed by grinding, polishing, etc. The biodegradable polymer may also be processed simultaneously. When a specific ceramic is processed by grinding or polishing, some or all of the flaky structure, needle-like structure, groove-like structure, and linear recess structure on the surface of the specific ceramic may disappear. As a result, the structural superiority of the specific ceramic exposed on the surface may decrease or disappear. On the other hand, the tissue affinity and tissue conductivity due to the composition of the specific ceramic are retained. Also, since the structure of the specific ceramic at the site buried in the biodegradable polymer is maintained, a structure with superior tissue affinity and tissue conductivity is exposed by the biodegradation of the biodegradable polymer.

[0023] <1 Basic Conditions (A3) of the Present Invention> The above (A3) is a condition when the specific ceramic is coated with a biodegradable polymer. When the specific ceramic is coated with a biodegradable polymer, after implanting the composite into the body, the biodegradable polymer needs to dissolve and the specific ceramic needs to be exposed on the surface of the composite. As described in (A1), from the viewpoints of tissue affinity and tissue conductivity, it is necessary for a specific ceramic with a large area to be exposed on the surface of the composite. Therefore, the specific ceramic coated with the biodegradable polymer needs to be the specific particles. Also, since the biodegradable polymer dissolves and the specific ceramic is exposed on the surface of the composite, it is necessary to provide the specific particles with the shortest distance between the surface of the composite and the specific particles being 10 μm or less. The shorter the shortest distance, the shorter the time required for the biodegradable polymer to dissolve and the earlier the specific particles are exposed on the surface of the composite. Therefore, the shortest distance is preferably 8 μm or less, more preferably 6 μm or less, and even more preferably 4 μm or less.

[0024] Also, it is preferable for tissue affinity and tissue conductivity that there are more specific particles exposed on the surface of the composite due to the dissolution of the biodegradable polymer. From this perspective, it is preferable that the value obtained by dividing the total area in the projection view of the specific particles with a shortest distance of 10 μm or less from the composite surface by the area of the composite surface is 0.1 or more. This value is more preferably 0.15 or more, and even more preferably 0.2 or more.

[0025] When a composite comprising specific particles coated with a biodegradable polymer is implanted into the body, the biodegradable polymer dissolves and the specific particles are exposed on the surface of the composite. In this case, it may be preferable that the specific particles are exposed on the surface of the composite within a certain period of time. Under the accelerating conditions of immersion in a 0.1 mol / L phosphate buffer solution at 60 °C and pH 7.4, on the surface of the composite, it may be preferable that the specific ceramics with an area of 2.8×10 -11 m 2 or more are exposed within 7 days.

[0026] In addition, similar to (A1), from the perspective of cell adhesion, the area of the exposed specific ceramics is preferably 3.1×10 -12 m 2 or more, more preferably 2×10 -11 m 2 or more, even more preferably 8×10 -11 m 2 or more, and particularly preferably 3×10 -10 m 2 or more in some cases.

[0027] Also, under the conditions of (A1) to (A3), in order for the specific ceramics to be uniformly dispersed on the surface of the biodegradable polymer, it may be preferable that it has a certain volume. From the perspective of dispersibility and the like, the volume average diameter is preferably 1.5 μm or more and 500 μm or less, more preferably 3 μm or more and 200 μm or less, and even more preferably 5 μm or more and 50 μm or less.

[0028] <1 Basic Conditions (B) to (K) of the Present Invention> The composite of the present invention needs to satisfy at least one of the conditions (B) to (K). In some cases, it is preferable to satisfy a plurality of conditions.

[0029] <1 Basic condition (B) of the present invention> The condition of (B) is a condition regarding the sponge structure. The sponge structure may also be expressed as a "cell structure having continuous pores". In the present invention, the sponge structure is divided into a pore part and a beam part around the pores. (B), the composite contains 30% by mass or more and 93% by mass or less of a specific ceramic. The content is preferably 45% by mass or more and 90% by mass or less, more preferably 50% by mass or more and 87% by mass or less, and still more preferably 65% by mass or more and 85% by mass or less. In some cases, it may be preferable that the specific ceramic is a specific particle or a specific granule.

[0030] In addition, in the porous composite, tissue is conducted into pores of a certain size. In the case of a sponge structure, there are cases where relatively small pores are desired and cases where relatively large pores are desired. Generally, a sponge structure having relatively large pores is a soft sponge structure. The small pores have a major axis of the pores of 2 μm or more and 20 μm or less. The large pores have a major axis of the pores of 30 μm or more and 1000 μm or less. The sponge structure needs to have small pores and / or large pores.

[0031] In addition, since tissue is conducted into the pores, the porosity needs to be 50% or more. A sponge structure having small pores and large pores is the softest sponge structure. In some cases, it may be preferable that the sponge structure has a considerable number of small pores or large pores. The pore size of the sponge structure may be measured by a known method. However, if doubts arise, the result of the pore size distribution measurement by the mercury intrusion method shall be used. The common logarithm of the differential pore volume is plotted against the pore diameter. In this figure, when peaks are obtained in the range of 2 μm or more and 20 μm or less, or 30 μm or more and 1000 μm or less, it is determined that there are a corresponding number of small pores or large pores, respectively.

[0032] When ensuring high tissue affinity and tissue conductivity, it is preferable that much of the surface of the composite is coated with calcium phosphate and / or willemite, which exhibits any one of a scaly structure, a needle-like structure, a groove-like structure, and a linear concave structure, but it lacks flexibility. Therefore, in some cases, it is necessary to expose some biodegradable polymers on the surface as well. From this perspective, it is preferable that 20% or more of the surface is coated with a specific ceramic. The coating rate is preferably 20% or more from the viewpoints of tissue affinity, tissue conductivity, and flexibility, but may be more preferably 40% or more, and even more preferably 60% or more.

[0033] <1 Basic Conditions (C) of the Present Invention> The condition (C) relates to a sponge structure containing specific ceramic particles and / or a porous body of a specific ceramic inside. When specific ceramic particles or the like are contained inside the sponge structure, tissue affinity and tissue conductivity are improved, but flexibility, which is an element of mechanical properties, is reduced. The volume of the specific ceramic is 1.0×10 -13 m 3 or more and 5.0×10 -7 m 3 or less. However, in the reconstruction of a relatively small tissue defect, from the balance between tissue affinity, tissue conductivity, and flexibility, the volume should be 5.0××10 -13 m 3 or more and 1.0×10 -8 m 3 or less, preferably 4.0××10 -12 m 3 or more and 3.0×10 -10 m 3 or less, more preferably 1.4××10 -11 m 3 or more and 5.0×10 -10 m 3 or less.

[0034] Even if the sponge structure includes specific ceramic particles, tissue orientation cannot be expected. On the other hand, when the sponge structure includes a honeycomb structure having one or more through-holes extending in one direction or a porous body having a plurality of through-holes extending in a plurality of directions, tissue orientation can be expected. Therefore, for example, it may be suitable for vertical or horizontal bone formation, nerve regeneration tubes, etc. The volume of the honeycomb structure and the porous body is 1.4×10 -11 m 3 or more and 5.0×10 -7 m 3 or less. In the reconstruction of a relatively small tissue defect, the volume should preferably be 1.0×10 -8 m 3 or less, more preferably 3.0×10 -10 m 3 or less, and even more preferably 1.1×10 -10 m 3 or less in some cases. In general, the honeycomb structure is a structure having a plurality of through-holes extending in one direction. However, in the present invention, for simplicity, a structure having one through-hole extending in one direction is also referred to as a honeycomb structure.

[0035] In a sponge structure containing specific ceramic particles and / or a porous body of specific ceramics inside, tissue affinity and tissue conductivity are mainly expressed by the specific ceramics. Therefore, the coating rate of the surface of the specific ceramics by the biodegradable polymer is preferably 0.7 or less. The coating rate is more preferably 0.5 or less, even more preferably 0.3 or less, and particularly preferably 0.2 or less. It is ideal that the coating rate is 0.

[0036] <1 Basic Conditions (D) of the Present Invention> The condition of (D) relates to a curable sponge structure that cures at the tissue defect site. Although the sponge structure is excellent in flexibility, it deforms under load, so the reconstructed tissue may become smaller than the desired volume. If the sponge structure cures at the tissue defect site, this problem can be solved. In addition, there may be a case where it is desired to form a plate-like or film-like sponge structure according to the shape of the jawbone or the like. If the sponge structure cures at this part, the desired shape can be ensured. In order to meet this object, a curable composition may be provided in the pores of the sponge structure. From the viewpoints of tissue affinity and tissue conductivity, it is necessary that the curable composition cures to form calcium phosphate and / or calcium sulfate dihydrate. Even if the curable composition is introduced into the sponge structure, a part of it may deviate from the sponge structure. Therefore, in some cases, it may be preferable to provide a partial curing composition of the curable composition in the pores of the sponge structure. The partial curing composition means a composition in which a part of the curable composition has cured and retains curability. The sponge structure provided with the partial curing composition is less likely to have the curable composition deviate from the pore part, and can be deformed according to the tissue defect form at the tissue defect site. The partial curing composition cures by reacting with water, body fluid, etc. at the tissue defect site. In order to provide a curable composition or a partial curing composition of the curable composition in the sponge structure, the porosity of the sponge structure excluding the curable composition and the partial curing composition needs to be 50% or more. From the viewpoint of ensuring sufficient curability, the porosity is preferably 60% or more, more preferably 70% or more, and even more preferably 80% or more. In addition, it is preferable that the curable composition or the partial curing composition is provided in 20% or more of the volume of the pore part of the sponge structure. The value is more preferably 30% or more, and even more preferably 40% or more. Note that the value is a percentage of the total volume (volume including the solid itself and the internal voids). The curable composition that hardens to form calcium phosphate is not particularly limited, and for example, α-tricalcium phosphate, a mixture of tetracalcium phosphate and calcium hydrogen phosphate, a mixture of α-tricalcium phosphate and calcium carbonate, etc. can be used. Among these, the curable composition that hardens to form carbonated apatite is particularly preferred. Examples of the curable composition that hardens to form calcium sulfate dihydrate include calcium sulfate hemihydrate.

[0037] <1 Basic Conditions (E) of the Present Invention> The condition of (E) relates to a sponge structure that is used for tissue fillers for the treatment of internal defects and is useful when tissue affinity and tissue conductivity are emphasized rather than flexibility. As described above, tissue affinity and tissue conductivity are mainly expressed by specific ceramics. Therefore, when the beam part of the sponge structure is coated with specific ceramics, tissue affinity and tissue conductivity are improved. The thickness of the specific ceramics to be coated is 20 μm or more, preferably 30 μm or more, and may be more preferably 50 μm or more in some cases. Also, the coating rate needs to be 30% or more, preferably 40% or more, and more preferably 50% or more. When the beam part of the sponge structure is coated with specific ceramics, the flexibility decreases. Therefore, it is important to balance the two according to the purpose of use. Due to the coating of the beam part with specific ceramics, the porosity of the sponge structure becomes smaller, but in order to ensure a certain flexibility and ensure connectivity, the apparent porosity (the percentage of the pore volume in the total volume) needs to be 30% or more, and this value is preferably 40% or more, more preferably 50% or more, and even more preferably 60% or more.

[0038] <1 Basic Conditions (F) of the Present Invention> The condition of (F) relates to a plate-like or membrane-like sponge structure in which at least one side is coated with specific ceramics. It is preferably that 80% or more of one side is coated, more preferably 90% or more is coated, and even more preferably substantially the entire surface is coated. The sponge structure is useful for barrier membranes and soft tissue management used in Guided Tissue Regeneration (GTR), Guided Bone Regeneration (GBR), etc. For example, in GBR, the barrier membrane is placed on the surface of the bone defect part and needs to prevent the invasion of soft tissue into the bone defect part. Since one side of the barrier membrane faces the bone defect part, it is preferable to promote the conduction of bone tissue. Therefore, it is necessary to cover substantially the entire surface with a specific ceramic. The barrier membrane also faces soft tissue. Therefore, it is preferable that it has high affinity for soft tissue. Since the specific ceramic is also excellent in soft tissue affinity, in some cases, it is more preferable that substantially the entire surface of both sides is covered with the specific ceramic.

[0039] <1 Basic Conditions of the Present Invention (G)> The condition of (G) relates to a composite in which the communication holes of a specific ceramic having communication holes are penetrated by a biodegradable polymer sponge structure having a porosity of 10% or more. The specific ceramic having communication holes is a honeycomb structure of a specific ceramic having one or more communication holes extending in one direction, or a communication structure of a specific ceramic having a plurality of communication holes extending in a plurality of directions. Basically, since the periphery of the biodegradable polymer is covered with a specific ceramic, it is excellent in tissue affinity and tissue conductivity. In addition, since the biodegradable polymer is provided inside the communication holes, it is possible to maintain integrity even when crushed. Also, in the case of the honeycomb structure, when it is broken so that the length becomes constant, it becomes a composite like a string of beads, and in some cases, it has excellent operability.

[0040] <1 Basic Conditions of the Present Invention (H)> The condition of (H) relates to a composite comprising a part of only the biodegradable polymer and a part of a composite layer composed of a degradable polymer and a specific ceramic, and having a composite layer composed of a biodegradable polymer and a specific ceramic on at least a part of the surface of the part of only the biodegradable polymer. A conceptual diagram is shown in FIG. 2. The composite of this condition is useful for, for example, plates and screws. When a biodegradable polymer and a specific ceramic are simply mixed, the mechanical strength decreases. Tissue affinity and tissue conductivity may be important initially, and in such cases, it is useful to provide a composite layer composed of a degradable polymer and a specific ceramic with excellent tissue affinity and tissue conductivity on the surface of a part made only of a biodegradable polymer with excellent mechanical strength. Also, the depth of the groove formed between the exposed specific ceramics and the adjacent exposed specific ceramics needs to be 100 μm or less. In other words, the height of the exposed specific ceramics from the composite layer surface needs to be 100 μm or less. For example, it may be screwed into bone tissue using a screw. At this time, if there are unnecessary recesses on the composite surface, there is a risk of entraining contaminated body fluids and unnecessary surrounding tissues. Therefore, the groove depth between adjacent exposed specific ceramics in the composite layer needs to be 100 μm or less. The groove depth is preferably 50 μm or less, more preferably 30 μm or less, and ideally there is substantially no groove.

[0041] In addition, due to the relationship between tissue conductivity and the fixation between the composite layer and the biodegradable polymer, etc., the volume average diameter of the specific ceramic may preferably be 1.5 μm or more and 500 μm or less. When the volume average system is less than 1.5 μm, the initial adhesion of osteoblasts may be small, and thus tissue conduction may be limited. From this perspective, the volume average system is more preferably 3 μm or more, and even more preferably 4 μm or more. On the other hand, if the thickness of the composite layer is thick, the bonding force with the central part formed only of the biodegradable polymer becomes weak. From this perspective, the volume average diameter may preferably be 500 μm or less. The volume average diameter is more preferably 200 μm or less, and even more preferably 100 μm or less.

[0042] From the viewpoints of tissue affinity and tissue conductivity, it is preferable that a specific ceramic is exposed on the surface of the composite. That is, a composite layer composed of a biodegradable polymer and a specific ceramic is provided on at least a part of the surface of the biodegradable polymer, the specific ceramic is exposed on the surface of the composite layer, and the depth of the groove formed between the exposed specific ceramics is 100 μm or less. A composite satisfying the condition of "is more preferable.

[0043] <1 Basic Conditions (I) of the Present Invention> The above (I) is a condition regarding a composite useful for plates, screws, etc. which are medical tissue reconstruction materials comprising biodegradable polymers with different degrees of orientation and require mechanical strength. When a biodegradable polymer is stretched, its degree of orientation increases and its mechanical strength increases. The tissue affinity and tissue conductivity of a biodegradable polymer are increased by mixing a specific ceramic, but simply melt-mixing or solution-mixing results in a decrease in the degree of orientation and a decrease in mechanical strength. Therefore, it may be useful to provide a composite layer composed of a biodegradable polymer and specific particles on at least a part of the surface of the biodegradable polymer. For example, if a specific ceramic is disposed on the surface by the method such as (S) on at least a part of the surface of a biodegradable polymer with a large degree of orientation obtained by a stretching treatment or the like, the mechanical strength is ensured by the biodegradable polymer with a large degree of orientation inside, and the tissue affinity and tissue conductivity are exhibited by the biodegradable polymer with a small degree of orientation containing the specific ceramic in the surface layer portion. In this method, the degree of orientation of the biodegradable polymer in the central portion is larger than the degree of orientation of the biodegradable polymer in the composite layer. The degree of orientation of a biodegradable polymer can be evaluated by known methods such as infrared spectroscopy, Raman spectroscopy, X-ray diffraction, dichroism, and polarized microscopy.

[0044] Similar to the above (H), from the viewpoints of tissue affinity and tissue conductivity, it is preferable that a specific ceramic is exposed on the surface of the composite. That is, a composite satisfying the condition of "having a composite layer composed of a biodegradable polymer and specific particles on at least a part of the surface of the biodegradable polymer, the degree of orientation of the central part of the biodegradable polymer being larger than the degree of orientation of the biodegradable polymer in the composite layer, and the specific ceramic being exposed" is more preferable.

[0045] <1 Basic Conditions (J) of the Present Invention> The condition of the above (J) relates to a hydrophilic medical tissue reconstruction material. For cell adhesion related to tissue affinity and tissue conductivity, a hydrophilic surface is suitable. When the surface of the biodegradable polymer has metal ions and / or ammonium ions, the metal ions and / or ammonium ions are dissociated in the body fluid, so hydrophilicity is ensured. Although the metal ions and / or ammonium ions on the surface of the biodegradable polymer are considered to be bonded to the functional groups of the biodegradable polymer, the details have not been clarified.

[0046] <2 Preferred Medical Tissue Reconstruction Materials> The medical tissue reconstruction material of the present invention is a composite of a biodegradable polymer and a specific ceramic, and preferably satisfies any one of the above (K) to (M). It may satisfy a plurality of them.

[0047] <2 Preferred Medical Tissue Reconstruction Materials (K)> When the specific ceramic is calcium phosphate, carbonated apatite containing 2% by mass or more of a carbonate group is preferable. Although the mechanism has not been fully elucidated, it is considered to be because the inorganic composition of bone is carbonated apatite, osteoclastic resorption, and the neutralization ability of carbonated apatite against acid is high. When the biodegradable polymer is a chemically synthesized material, an acid is formed by hydrolysis, causing an inflammatory reaction. Since carbonated apatite has a high neutralization ability against acid, it neutralizes the acid formed by hydrolysis and suppresses the inflammatory reaction. Furthermore, since the surface of the apatite carbonate produced by the wet method may have a flaky structure, a needle-like structure, or a groove-like structure rich in irregularities, it has a large specific surface area and a high neutralizing ability against acids. In addition, these structures are excellent in the ability to fit with biodegradable polymers. As a result, apatite carbonate is likely to be retained on the surface of the biodegradable polymer. Since the osteoclastic resorption and the neutralizing ability against acids are greater, the carbonate group content is more preferably 3% by mass or more, and even more preferably 5% by mass or more. Since the content of the carbonate group in the apatite structure of adult bone is 6 to 9% by mass, 6% by mass or more is particularly preferable. In addition, the apatite carbonate referred to in the present invention is defined as apatite containing a carbonate group. The basic structure of apatite carbonate is Ca 10-a (PO4) 6-b (CO3) c (OH) d (a, b, c, d are indefinite numbers), and in addition to this basic structure, it may contain Na, K, Mg, HPO4, voids, etc. Apatite carbonate can be considered, for example, as apatite in which part or all of the phosphate group or hydroxyl group of hydroxyapatite having Ca 10 (PO4)6(OH)2 as the basic structure is substituted with a carbonate group, as described in Japanese Patent No. 4854300.

[0048] <2 Preferred medical tissue reconstruction materials (L)> If the sphericity of the specific particles is high, the filling rate in the composite with the bioabsorbable polymer will be high. As a result, the tissue affinity will be high. As an index of the sphericity, in the projected image of the specific particles, the value obtained by dividing the area of the projected image by the area of the minimum circumscribed circle is used. Under this condition, the value is 0.8 or more, but the value is preferably 0.85 or more, and more preferably 0.9 or more. In addition, it is preferable that the specific particles are uniformly dispersed in the biodegradable polymer. On the other hand, since the density of the ceramics is higher than that of the biodegradable polymer, the specific particles are likely to settle in the step of mixing the specific particles into the biodegradable polymer solution. Therefore, specific particles having a hollow portion and a small apparent density may be preferable. Under these conditions, for specific particles, the value obtained by dividing the area of the projection image by the area of the minimum circumscribed circle should be 0.8 or more, and / or the value obtained by dividing the weight of the specific particles having a hollow part by the weight of all the specific particles should be 0.3 or more. Preferably, the value is 0.4 or more, more preferably 0.5 or more, and even more preferably 0.6 or more.

[0049] <2 Preferred medical tissue reconstruction materials (M)> The biodegradable polymers specified by the above (M) are preferred. These biodegradable polymers have an appropriate degradation rate, and safety and usefulness are ensured.

[0050] <3 Preferred medical tissue reconstruction materials: freeze-drying> The present invention [3] may be preferred. The medical tissue reconstruction material produced by a process including freeze-drying has a fine porous structure due to freezing and sublimation of the solvent. The fine porous structure not only improves flexibility but also improves the wettability of the medical tissue reconstruction material and the permeability of body fluid into the medical tissue reconstruction material. In addition, since a fine and uniform porous structure is formed, a composite having uniform mechanical properties can be produced. Some effects of freeze-drying can also be expected by adding a fine pore-forming material. That is, if a pore-forming material is added so that the specific surface area becomes 0.2 m 2 / g or more, some effects of freeze-drying can be expected. The specific surface area is more preferably 0.5 m 2 / g or more, and even more preferably 1.0 m 2 / g or more. Either the value measured by the BET method or the mercury intrusion method may satisfy the conditions.

[0051] <4 Method for producing medical tissue reconstruction material> The method for producing the medical tissue reconstruction material of the present invention is not particularly limited. However, the above-mentioned present invention [4] may be preferred.

[0052] <4 Method for producing medical tissue reconstruction material (O)> The above (O) is useful as a process for manufacturing a medical tissue reconstruction material that is a sponge structure. It is also effective when the sponge structure includes specific particles, specific granules, specific ceramics having one or more through-holes extending in one direction, or specific ceramics having a plurality of through-holes extending in a plurality of directions. When the sponge structure includes specific granules, specific ceramics having one or more through-holes extending in one direction, or specific ceramics having a plurality of through-holes extending in a plurality of directions, it may be preferable to reduce the contact area with the biodegradable polymer from the viewpoints of tissue affinity and tissue conductivity. In that case, a material coated with a water-soluble material such as sodium chloride may be preferable. Such an aspect is also included in the above (O). Water-soluble materials such as sodium chloride can be removed by processes such as immersion in water or an aqueous solution. In addition, a pore-forming material having a major axis of 300 μm or more and 1000 μm or less is used when forming the above large pores. When the pore-forming material is not used, only the small pores are formed by freeze-drying. The pore-forming material is, for example, sodium chloride. The pore-forming material can also be removed by processes such as immersion in water or an aqueous solution. In addition, in freeze-drying, when the temperature is slowly lowered to the freezing point, relatively large pores are formed. Note that drying means normal temperature drying, heat drying, or vacuum drying. (The same applies hereinafter). Crosslinking treatment is useful for improving the mechanical strength and stability of collagen and gelatin.

[0053] <4 Manufacturing Method of Medical Tissue Reconstruction Material (P)> The above (P) is useful as a process for manufacturing a medical tissue reconstruction material that is a honeycomb-like sponge structure having one or more through-holes extending in one direction, or a sponge structure having a plurality of through-holes extending in a plurality of directions. To manufacture the sponge structure having the above through-holes, a female mold (mold frame) of the sponge structure to be manufactured is used. Put a biodegradable polymer suspension in which specific particles are suspended into a container having one or more beams extending in one direction or a container having a plurality of beams extending in a plurality of directions. After drying the solvent, if the beams and the container are removed, a honeycomb structure in which one or more through-holes extending in one direction are partitioned from each other by a partition wall, or a sponge structure having a plurality of communication holes extending in a plurality of directions can be manufactured. In the case of a honeycomb-like sponge structure having one or more communication holes extending in one direction, it is also possible to manufacture by extrusion molding using a mold such as a die and then drying. Note that the drying process is preferably freeze-drying.

[0054] <4 Manufacturing method of medical tissue reconstruction material (Q)> The above (Q) is a process useful for the production of the above (D). A curable composition that cures to form calcium phosphate and / or calcium sulfate dihydrate is applied to the pores of the sponge structure. The method of applying the curable composition to the pores of the sponge structure is not limited. Generally, the curable composition is applied into the pores of the sponge structure by vibration. A method of sucking from one direction of the sponge structure and applying the curable composition into the pores of the sponge structure is also effective. Also, a method using a slurry of the curable composition is useful. After a slurry of the curable composition is applied to the pores of the sponge structure, it is dried. In this method, it is necessary to select an appropriate solvent or solution in consideration of the curing reaction of the curable composition. In order to prevent the curable composition from escaping from the pores of the sponge structure, the curable composition may be partially cured. Partial curing is a step of stopping the curing before the curing reaction of the curable composition is completed. For example, when calcium sulfate hemihydrate and water are reacted, calcium sulfate dihydrate is formed and cured. If water is removed before the curing reaction is completely completed, a mixture of calcium sulfate hemihydrate and calcium sulfate dihydrate can be obtained as a partially cured product in the pores of the sponge structure.

[0055] <4 Method for manufacturing medical tissue reconstruction material (R)> The above (R) is a process useful for manufacturing a sponge structure coated with specific ceramics such as the above (E) and (F). First, a calcium hydroxide paste is applied to the surface of the beam portion of the sponge structure or to the pores of at least one side. When applying calcium hydroxide to the surface of the beam portion, calcium hydroxide is applied so as to ensure the sponge structure. The method of applying calcium hydroxide is not particularly limited. When applying calcium hydroxide to the surface of the beam portion, for example, the sponge structure may be immersed in the calcium hydroxide paste, and the excess calcium hydroxide paste may be removed by a vibrator or air blow. When applying the calcium hydroxide paste to the pores of at least one side, for example, the calcium hydroxide paste may be rubbed with a spatula or the like.

[0056] After applying the calcium hydroxide paste to the surface of the beam portion of the sponge structure or to the pores of at least one entire side, it is exposed to carbon dioxide containing water and / or an organic solvent. In this step, calcium hydroxide hardens as calcium carbonate. When calcium hydroxide is exposed to carbon dioxide containing water, calcite is formed, and when exposed to carbon dioxide containing an organic solvent such as ethanol, vaterite or calcium carbonate containing vaterite is formed. In addition, when forming vaterite or calcium carbonate containing vaterite, it is preferable to manufacture the calcium hydroxide paste using an organic solvent or an organic solvent containing water.

[0057] <4 Method for manufacturing medical tissue reconstruction material (S)> The above (S) is a process useful for manufacturing composites that emphasize mechanical strength such as the above (I) and (J). A suspension of a biodegradable polymer containing specific particles is applied to the surface of a biodegradable polymer whose mechanical strength has been improved by orientation treatment or the like, and the solvent is removed. In this process, the biodegradable polymer that has been compounded with the biodegradable polymer whose mechanical strength has been improved and the specific particles adheres. The solvent is not limited as long as it can dissolve the biodegradable polymer, and examples thereof include dichloromethane and toluene. Another solvent such as isopropanol may be added to these solvents in order to control the drying time. The method for removing the solvent is not limited either, but drying is common. Heat drying is preferred, but it is necessary to dry at a temperature that does not affect the mechanical strength of the biodegradable polymer whose mechanical strength has been improved. In this process, specific particles coated with a biodegradable polymer are formed. In some cases, it may be preferable to perform a process of exposing the specific particles on the surface of the biodegradable polymer from the viewpoints of improving tissue affinity and tissue conductivity. Examples of this process include a process of dissolving the biodegradable polymer coated with specific particles by immersing it in a solvent or a solution, and a process of removing the biodegradable polymer coated with specific particles by grinding or polishing.

[0058] <4 Method for manufacturing medical tissue reconstruction material (T)> The above (T) is a process of dissolving specific ceramics coated on a biodegradable polymer with a solvent or a solution to expose the specific ceramics on the surface of the composite. In particular, when the solution is a phosphate solution, it is a process of converting the calcium carbonate containing the willemite of the composite into carbonated apatite, increasing the interlocking force between the biodegradable polymer and the carbonated apatite, and further improving the hydrophilicity of the biodegradable polymer.

Examples

[0059] Hereinafter, the present invention will be described in more detail based on examples, but the scope of the present invention is not limited to the examples. The composition was analyzed using a D8 ADVANCE powder X-ray diffractometer manufactured by BRUKER under the conditions of an output of 40 kV, 40 mA, and an X-ray source of CuKα (λ = 0.15418 nm). For samples where apatite carbonate was thought to be formed, a JASCO 6200 Fourier transform infrared spectrophotometer was used to confirm that it was apatite carbonate. The structure was analyzed using a Hitachi High-Tech S3400N scanning electron microscope or an Olympus MVX10 stereomicroscope. The surface elements were analyzed using an energy dispersive X-ray analyzer (EDAX) attached to the scanning electron microscope. The specific surface area etc. was measured by the mercury intrusion method. The pore distribution, specific surface area, etc. were calculated with the advancing contact angle and receding contact angle of mercury and the material being 130° and the surface tension of mercury being 485 mN / m.

[0060] As calcium carbonate, calcite powder with an average volume diameter of about 1 μm manufactured by Ube Materials (hereinafter sometimes referred to as calcite powder), and witterite powder with an average volume diameter of 5 μm manufactured by Sakai Chemical Industry (Karumaru: hereinafter sometimes referred to as witterite particles) were used. The calcite powder is cubic powder, and the witterite particles are spherical particles. The value obtained by dividing the projected image of the witterite particles by the minimum circumscribed circle area is approximately 1.0.

[0061] The apatite carbonate powder and particles were produced by immersing calcite powder and witterite particles in a 1 mol / L Na2HPO4 aqueous solution at 80°C for 4 days. From the above calcite powder, apatite carbonate powder with an average volume diameter of about 1.1 μm was produced, and from the above witterite particles, apatite carbonate particles with an average volume diameter of about 6 μm were produced. The values obtained by dividing the area of the projected image on the composite surface by the minimum circumscribed circle area in the above apatite carbonate powder with an average volume diameter of about 1.1 μm and about 6 μm were both approximately 1.0. All of the produced apatite carbonates exhibited a flaky structure or an aggregate structure of needle-like structures on the surface, and were apatite carbonates containing about 11% of carbonate groups. Also, calcium carbonate blocks produced by compacting calcite powder at 30 MPa and heat-treating at 500 °C for 12 hours were pulverized to produce calcium carbonate granules, which were immersed in a 1 mol / L aqueous Na2HPO4 solution at 80 °C for 14 days, sieved to obtain calcium carbonate granules having a volume-average diameter of about 70 μm and a volume of about 6.5×10 -11 m 3 and spherical calcium carbonate apatite granules such as these were produced. All of the produced calcium carbonate apatite exhibited a scaly structure or an aggregate structure of needle-like structures on the surface, and was calcium carbonate apatite containing about 11% of carbonate groups. Even when the calcium carbonate apatite was compounded with a biodegradable polymer, there were no variations in the surface structure or the carbonate group content of the calcium carbonate apatite. For simplicity, the surface structure and the carbonate group content may not be described in the examples and the like. Some of the calcium carbonate apatite granules were stirred for 24 hours using a planetary ball mill to produce calcium carbonate apatite granules having a relatively smooth surface (hereinafter referred to as surface-smooth calcium carbonate apatite). The surface-smooth calcium carbonate apatite granules were sieved to produce surface-smooth calcium carbonate apatite granules having a volume-average diameter of about 500 μm and the like. The calcium carbonate honeycomb structure was produced according to Example 1 disclosed in Japanese Patent Application No. 2021-126320. All of the produced calcium carbonate honeycomb structures exhibited a scaly structure or an aggregate structure of needle-like structures on the surface, and were calcium carbonate apatite containing about 11% of carbonate groups. As the biodegradable polymer, LSCL-1002 (hereinafter referred to as PLACL), a L-lactic acid-caprolactone copolymer (LA:CL - 8:2, molecular weight of about 300,000) manufactured by Takaki Chemical, polylactic acid 4060D (hereinafter referred to as PLA) manufactured by Ingeo, and atelocollagen for cosmetics (2%) (hereinafter referred to as atelocollagen) manufactured by Koken were used. As the calcium carbonate cement, an equimolar mixture of α-tricalcium phosphate powder having an average volume diameter of about 1 μm and batellite particles (Karumaru; average volume diameter of about 5 μm) was used. The tissue reaction of the composite was evaluated by reconstructing a bone defect formed in the tibia of a rabbit. Four weeks after the reconstruction surgery, the composite was excised together with the surrounding tissue, and decalcified tissue sections were prepared in the usual manner, stained with hematoxylin and eosin (HE staining), and subjected to histopathological analysis.

[0062] [Example 1] 1.4 g of PLACL was dissolved in 10 mL of dioxane, and 4.2 g of wollastonite particles were added to produce a suspension. Further, as a pore-forming material, NaCl granules with a diameter of about 500 to 600 μm were added in a bulk volume of 0.085 cm 3 and dispersed. Next, it was frozen at -20°C for 5 hours and then freeze-dried for 48 hours. Thereafter, it was immersed in distilled water for 30 minutes to dissolve and remove NaCl, which was the pore-forming material, and then dried. As a result of powder X-ray diffraction analysis, calcium carbonate was mainly wollastonite, and calcium carbonate other than wollastonite was calcite. It had large pores with a major axis of the pores of 300 to 600 μm and small pores with a major axis of the pores of 20 to 30 μm, a porosity of about 80%, and a specific surface area of 1.0 m 2 / g. A composite of a biodegradable polymer and wollastonite was produced, and both had a composite layer with a thickness of 20 μm or more and a sponge structure with continuous pores. As shown in Fig. 3a), spherical wollastonite particles were coated with PLACL, and the value obtained by dividing the area of the projection image on the composite surface by the minimum circumscribed circle area was 0.9 or more. Also, the coating thickness, that is, the shortest distance between the composite surface and the specific ceramics was about 2 to 5 μm. The wollastonite content was about 75% by mass.

[0063] Next, the composite was immersed in a 0.3 mol / L Na2HPO4 aqueous solution at 10°C for 5 days, washed with water, and dried. As a result of powder X-ray diffraction analysis, all of the calcium carbonate had been compositionally converted to carbonated apatite. Also, the carbonate group content of the carbonated apatite was about 11% by mass. Figure 4 shows the results of pore size distribution analysis by mercury intrusion porosimetry. Peaks are obtained at 2 μm or more and 20 μm or less, and 30 μm or more and 1000 μm or less, indicating that the sample has a significant number of small pores and large pores. The composite has large pores with a major axis of 300 - 600 μm shown in Fig. 3b) and small pores with a major axis of 20 - 30 μm shown in Fig. 3c). The porosity is about 80%, and the specific surface area is 1.1 m 2 / g. Also, as a result of EDAX analysis, it was confirmed that Na is present on the surface of the biodegradable polymer. A composite of a biodegradable polymer and calcium carbonate apatite was prepared. The composite has both a composite layer with a thickness of 20 μm or more and an intercalated layer with a thickness of 0.6 μm or more, and a sponge structure with continuous pores was fabricated. The content of calcium carbonate apatite was about 77% by mass. As shown in Figs. 3c and d), on the surface of the composite, exposed sites of calcium carbonate apatite presenting an aggregate of needle-like structures, a scaly structure, and a linear concave structure without being covered by PLACL were confirmed. Also, as shown in Fig. 3e), inside the composite, the volume is 6.5×10 -17 m 3 ~5.2×10 -16 m 3 and calcium carbonate apatite presenting an aggregate of needle-like structures or a scaly structure is exposed on the surface. As shown in Fig. 3f), in calcium carbonate apatite with a scaly structure or an aggregate of needle-like structures, the depth of the uneven structure, that is, the longest distance from the outermost center of the aggregate of needle-like structures or the scaly structure (which are the convex parts) to the bottom surface of the adjacent concave part, is 0.1 μm or more.

[0064] The sample was implanted into a φ6 mm depth 4 mm defect in a rabbit tibia. The μ-CT image immediately after implantation is shown in Fig. 5a). Immediately after implantation, the defect part shows a CT transmission image. Fig. 5b) is the μ-CT image at 4 weeks after implantation, and vigorous bone formation was observed from the CT non-transmission image. In the histological analysis, almost no bone formation was observed even at the 4th week in the case of the PLACL sponge structure without calcium apatite. However, as seen in the HE staining image of Fig. 5c), active bone formation was confirmed in the PLACL sponge structure with calcium apatite.

[0065] [Example 2] 0.8 g of spherical calcium apatite particles with an average volume diameter of about 1.1 μm were dispersed in 10 g of a 2% by mass atelocollagen aqueous solution, and freeze-dried at -20°C. Then, cross-linking treatment, washing, and drying were performed with 1% by mass glutaraldehyde. The spherical calcium apatite was coated with atelocollagen, the composite layer thickness was 3 μm or more, and the coating thickness was 1 - 2 μm. The sponge structure contained 80% by mass of calcium apatite, had small pores with a major axis of about 10 μm for the pores, and the porosity was 75%.

[0066] [Example 3] 0.8 g of a calcium apatite honeycomb with a volume of 4×10 -11 m 3 or more and 7×10 -11 m 3 or less was dispersed in 10 g of a 2% by mass atelocollagen aqueous solution, freeze-dried at -20°C, and then cross-linked, washed, and dried with 1% by mass glutaraldehyde. The calcium apatite honeycomb structure was partially coated with atelocollagen, the composite layer thickness was 0.6 mm or more, and the coating thickness was 10 - 20 μm. The sponge structure contained 80% by mass of calcium apatite, and the porosity was 75%.

[0067] [Example 4] 1.4 g of PLACL was dissolved in 10 mL of dioxane, and the volume was about 6.5×10 -11 m 30.5 g of spherical calcium apatite was added and dispersed, frozen at -20°C for 5 hours, and then freeze-dried for 48 hours. A sponge structure was produced in which spherical calcium apatite and PLACL had a composite layer with a thickness of about 500 μm, the PLACL was coated with calcium apatite particles, the shortest distance between the composite surface and the calcium apatite particles was 5 to 10 μm, the calcium apatite content was 26% by mass, and the porosity was about 75%.

[0068] Next, the composite was immersed in water at 10°C for 3 days and then dried. A sponge structure was produced in which spherical calcium apatite and PLACL had a composite layer with a thickness of about 500 μm, and on the surface of the composite, calcium apatite with a scaly structure or an aggregate of needle-like structures on the surface and an area of about 2×10 -7 m 2 was exposed. The calcium apatite content of the sponge structure was about 28% by mass, and the porosity was about 77%.

[0069] [Comparative Example 1] Using spherical surface-smooth calcium apatite, a sponge structure in which calcium apatite with a smooth surface and an area of about 2×10 -7 m 2 was exposed was produced in the same process as in Example 4. The sponge structures with exposed calcium apatite produced in Example 4 and Comparative Example 1 were implanted into a φ6 mm depth 4 mm defect in the rabbit tibia. At the 4th week after implantation, vigorous bone formation was observed in both cases, but the amount of bone formation was greater in the sponge structure of Example 4. From the comparison between the two, it was found that a composite of calcium apatite presenting any of a scaly structure, a needle-like structure, a groove-like structure, and a linear concave structure on the surface and a biodegradable polymer was superior in osteoconductivity compared to a composite of calcium apatite with a smooth surface and a biodegradable polymer.

[0070] [Experimental Example 1] In order to evaluate the acid neutralizing ability of apatite exhibiting any of a scaly structure, a needle-like structure, a groove-like structure, and a linear recessed structure and surface-smooth apatite, 1 g of apatite having a volume average diameter of about 500 μm was added to 10 mL of 0.1 mol / L acetic acid, and the pH change was measured. The initial pH was about 3, but the pH increased in all cases with the addition of apatite. The pH increase rate was faster for apatite exhibiting a scaly structure or a needle-like structure than for surface-smooth apatite. From this, it was found that apatite exhibiting any of a scaly structure, a needle-like structure, a groove-like structure, and a linear recessed structure has a high effect of neutralizing the acid formed with the decomposition of biodegradable polymers such as polylactic acid and suppressing the inflammatory reaction.

[0071] [Example 5] A 1.7 g / mL suspension of apatite cement was produced using 50% by volume isopropanol (50% by volume is water) or an aqueous solution of disodium hydrogen phosphate with a concentration of 0.2 mol / L. While vibrating with a vibrator, the suspension was introduced into the pores of the sponge structure in which the apatite produced in Example 1 processed to a thickness of 2 mm was exposed. Then, it was freeze-dried to remove 50% by volume isopropanol or water, and a sponge structure containing apatite cement was produced. Next, the sponge structure was fixed so as to be wound around a stainless steel rod. The sponge structure produced with the apatite cement suspension using an aqueous solution of disodium hydrogen phosphate with a concentration of 0.2 mol / L was partially cured, and no powder escaped even when the sponge structure was wound around the stainless steel rod. On the other hand, the sponge structure produced with the apatite cement suspension using 50% by volume isopropanol was not partially cured, and a small amount of powder escaped when the sponge structure was wound around the stainless steel rod. From this result, it was found that the partial curing of the curable composition is effective in preventing escape from the sponge structure. Next, the sponge structure fixed to the stainless steel rod was wetted with water and stored in a constant temperature bath at a humidity of 100% and 37 °C simulating the in-vivo environment for about 3 hours. All the sponge structures hardened while maintaining the shape of the outer periphery of the stainless steel rod.

[0072] [Example 6] A sponge structure with exposed calcium apatite produced in Example 1 processed to a thickness of 2 mm was immersed in a 1.4 g / mL calcium hydroxide suspension prepared using 90% ethanol, and the pressure was reduced to introduce the calcium hydroxide suspension into the pores. Next, the sponge structure was taken out of the suspension, vibrated with a vibrator to remove the excess calcium hydroxide suspension, and a sponge structure with the calcium hydroxide suspension adhering to the beam portion was produced. Next, the sponge structure with the calcium hydroxide suspension adhering to the beam portion was exposed to 90% ethanol-saturated carbon dioxide in a desiccator for 24 hours. As a result of powder X-ray diffraction, it was confirmed that calcium hydroxide had been compositionally converted to willeminite. The amount of willeminite in calcium carbonate was 90 mass% or more. A plate-shaped sponge structure with a porosity of 65% was produced in which the entire surface of the beam portion was covered with willeminite with a thickness of 100 μm or more.

[0073] Next, the plate-shaped sponge structure with the surface of the beam portion covered with willeminite was immersed in a sodium hydrogen phosphate aqueous solution at 10°C for 8 hours, washed with water, and then dried. As a result of powder X-ray diffraction, it was confirmed that willeminite had been compositionally converted to calcium apatite. The carbonate content of calcium apatite was 11 mass%. A plate-shaped sponge structure with a porosity of 60% was produced in which the entire surface of the beam portion was covered with calcium apatite with a thickness of 120 μm or more.

[0074] [Example 7] A 1.7 g / mL calcium hydroxide paste prepared using 90 vol% ethanol (10 vol% is water) was applied to the entire one-sided or both-sided surface of a sponge structure with exposed calcium apatite produced in Example 1 processed to a thickness of about 2 mm. Next, it was exposed to 90 vol% ethanol-saturated carbon dioxide in a desiccator for 24 hours. As a result of powder X-ray diffraction, it was confirmed that calcium hydroxide was compositionally converted into a zeolite. The amount of zeolite in calcium carbonate was 90% by mass or more. That is, the sponge structure was coated with calcium carbonate containing zeolite on one side, the entire surface, or both sides. Next, the sponge structure with the surface of the beam portion coated with zeolite was immersed in an aqueous solution of disodium hydrogen phosphate at 10 °C for 8 hours, washed with water, and then dried. As a result of powder X-ray diffraction, it was confirmed that the zeolite was compositionally converted into carbonated apatite. The carbonate content of the carbonated apatite was 11% by mass, and the surface structure of the carbonated apatite was a scaly structure or a structure in which needle-like structures were aggregated. Fig. 6 shows the behavior of a plate-like sponge structure with one side entirely coated with carbonated apatite when it was pressed against the rabbit muscle around the femur and then tried to be removed from the soft tissue. Thus, it was found that carbonated apatite presenting any of a scaly structure, a needle-like structure, a groove-like structure, and a linear recessed structure on at least a part of the surface shows a certain binding force with muscle tissue. From this, it was found that a medical tissue reconstruction material provided with calcium phosphate presenting any of a scaly structure, a needle-like structure, a groove-like structure, and a linear recessed structure on at least a part of the surface is also useful for soft tissue management.

[0075] [Example 8] 1.4 g of PLACL was dissolved in 10 mL of dioxane, and 4.2 g of carbonated apatite particles with an average volume diameter of about 6 μm were added to produce a suspension. Next, the suspension was injected with a syringe from one of the communication holes of the carbonated apatite honeycomb, frozen at -20 °C for 5 hours, and then freeze-dried for 48 hours. When the composite was broken along a plane perpendicular to the communication holes of the carbonated apatite honeycomb, it was found that a filamentous sponge structure penetrated through the carbonated apatite honeycomb. In addition, the carbonated apatite particles were coated with PLACL, and the coating thickness was 1 to 3 μm. Further, the two formed a composite layer with a thickness of about 30 μm, and the porosity of the filamentous sponge structure was about 70 to 80%. When the composite was fractured along a plane perpendicular to the through-holes of the hydroxyapatite honeycomb, a bead-like structure in which a filamentous sponge structure penetrated into the hydroxyapatite honeycomb was produced.

[0076] [Example 9] Polylactic acid (4060D) made by Ingeo was vacuum-dried at 80 °C, processed into a rod shape, and softened at 120 °C. Then, it was uniaxially drawn to twice its original length in the longitudinal direction in liquid paraffin at 120 °C, and processed to produce a cylindrical polylactic acid with a diameter of 5 mm and a thickness of 3 mm. Hydroxyapatite with a carbonate group content of 11% by mass, a volume average diameter of 1.1 μm, 6 μm, 70 μm, and having a scaly structure or an aggregate of needle-like structures on the surface was suspended or dispersed in a dichloromethane-isopropanol solution of polylactic acid, applied to a uniaxially drawn plate-like polylactic acid, and dried, and then the surface was polished. As a result of polishing, a composite was produced in which a part of the hydroxyapatite was buried in the biodegradable polymer and the polished hydroxyapatite was exposed on the surface. The thickness of the composite layer was 10 - 100 μm. As a result of the orientation measurement, it was confirmed that the in-plane orientation degree of the polylactic acid in the surface layer was smaller than that of the polylactic acid in the central part of the composite. According to the general method, each product was implanted into a bone defect with a diameter of 5 mm and a depth of 3 mm formed in a rabbit tibia, removed together with the surrounding tissue 4 weeks later, decalcified and stained, and analyzed histopathologically. The bone contact rate of the samples was 3% for polylactic acid alone, and 9%, 15%, and 21% for composites formed with a composite layer of a mixture of hydroxyapatite with a volume average diameter of 1.1 μm, 6 μm, 70 μm and polylactic acid. From these results, it was found that better osteoconductivity is achieved when a larger area of hydroxyapatite is exposed on the surface of the biodegradable polymer.

Claims

1. A composite comprising a biodegradable polymer and a specific ceramic composed of calcium phosphate and / or calcium carbonate containing at least one of a scaly structure, a needle-like structure, a groove-like structure, and a linear concave structure on at least a part of the surface, and a specific ceramic, which is a medical tissue reconstruction material satisfying any one of the following (A1) to (A3) and any one of (B) to (J). (A1) On the surface of the composite, specific ceramics with an area of 3.1×10 -12 m 2 or more are exposed. (A2) A part of the specific ceramic is buried in the biodegradable polymer, and the cut and / or polished specific ceramic is exposed on the surface of the composite. (A3) Comprising specific particles that are specific ceramics with a volume average diameter of 1 μm or more and 500 μm or less, the specific particles are coated with a biodegradable polymer, and the shortest distance between the surface of the composite and the specific particles is 10 μm or less. (B) The composite contains 30% by mass or more and 93% by mass or less of specific ceramics, has a porosity of 50% or more, and has small pores with a major axis of the pores of 2 μm or more and 20 μm or less and / or large pores with a major axis of the pores of 30 μm or more and 1000 μm or less, and is a sponge structure. (C) The composite contains specific granules that are specific ceramics with a volume of 1.0×10 -13 m 3 or more and 5.0×10 -7 m 3 or less, specific honeycomb structures that are specific ceramics with a volume of 1.4×10 -11 m 3 or more and 5.0×10 -7 m 3 or less and having one or more through-holes extending in one direction, and at least one selected from porous bodies that are specific ceramics with a volume of 1.4×10 -11 m 3 or more and 5.0×10 -7 m 3 or less and having a plurality of through-holes extending in a plurality of directions, and is a sponge structure with a porosity of 50% or more. (D) The composite is a curable sponge structure having a curable composition that cures to form calcium phosphate and / or calcium sulfate dihydrate, or a partially cured composition of the curable composition in the pore portion. (E) The composite is a sponge structure in which 30% or more of the surface of the beam portion is coated with a specific ceramic having a thickness of 20 μm or more and having a porosity of 30% or more. (F) The composite is a plate-like or film-like sponge structure in which at least one side is coated with a specific ceramic. (G) The composite is a honeycomb structure of a specific ceramic having one or more through-holes extending in one direction, or a structure in which the through-holes of a communication structure of a specific ceramic having a plurality of through-holes extending in a plurality of directions are penetrated by a biodegradable polymer sponge structure having a porosity of 10% or more. (H) At least a part of the surface of the biodegradable polymer of the composite has a composite layer composed of a biodegradable polymer and a specific ceramic. And the depth of the groove formed between the exposed specific ceramics on the surface of the composite layer is 100 μm or less. (I) The composite has a composite layer composed of a biodegradable polymer and specific particles that are specific ceramics having a volume average diameter of 1 μm or more and 500 μm or less on at least a part of the surface of the biodegradable polymer, and the degree of orientation of the central portion of the biodegradable polymer is larger than the degree of orientation of the biodegradable polymer in the composite layer. (J) The composite has a composite layer of a biodegradable polymer and specific particles that are specific ceramics having a volume average diameter of 1 μm or more and 500 μm or less on the surface, and at least a part of the biodegradable polymer exposed in the composite layer is bonded to metal ions and / or ammonium ions. (J) The composite has a composite layer of a biodegradable polymer and specific particles that are specific ceramics having a volume average diameter of 1 μm or more and 500 μm or less on the surface, and at least a part of the biodegradable polymer exposed in the composite layer is bonded to metal ions and / or ammonium ions. And at least a part of the biodegradable polymer exposed in the composite layer is bonded to metal ions and / or ammonium ions.

2. The medical tissue reconstruction material is the medical tissue reconstruction material according to claim 1, characterized by satisfying any one of the following (K) to (M). (K) In the specific ceramic, calcium phosphate is a carbonate apatite containing 2% by mass or more of a carbonate group. (L) In the specific particles, the value obtained by dividing the area of the projected image on the composite surface by the area of the minimum circumscribed circle is 0.8 or more, and / or the value obtained by dividing the weight of the specific particles having a hollow portion by the weight of all the specific particles is 0.3 or more. (M) The biodegradable polymer is a polymer or copolymer of a compound selected from the group consisting of lactic acid, glycolic acid, caprolactone, lactide, dioxanone, dioxane, glycerol sebacate, malic acid, and hydroxycarboxylic acid, or the biodegradable polymer contains one selected from the group consisting of collagen, gelatin, chitin, chitosan, hyaluronic acid, chondroitin sulfate, fibronectin, vitronectin, and laminin.

3. The composite is a porous body produced by a process including freeze-drying, or a porous body having a specific surface area of 0.2 m 2 / g or more, and the medical tissue reconstruction material according to any one of Claims 1 and 2.

4. A method for producing the medical tissue reconstruction material according to Claim 1 or 2, characterized by including any one of the following steps (O) to (T). (O) A material selected from specific particles, specific granules, a pore-forming material having a major axis of 300 μm or more and 1000 μm or less, specific ceramics having one or more through-holes extending in one direction, and specific ceramics having a plurality of through-holes extending in a plurality of directions is suspended or dispersed in a biodegradable polymer solution, or a suspension of the biodegradable polymer solution and the specific particles is introduced into the through-holes, and then dried, freeze-dried, and / or crosslinked. (P) A biodegradable polymer suspension in which specific particles are suspended is placed in a container having one or more beams extending in one direction or a container having a plurality of beams extending in a plurality of directions, and then dried, or extruded with an extruder into a structure having one or more through-holes extending in one direction, and then dried or freeze-dried. (Q) A step of applying a curable composition that cures to form calcium phosphate and / or calcium sulfate dihydrate into pores of a sponge structure having a porosity of 50% or more, and a step of partially curing the curable composition as necessary. (R) A step of applying calcium hydroxide paste to the surface of the beam portion of the sponge structure so as to ensure the sponge structure, or a step of applying calcium hydroxide paste to the pores on at least one side of the sponge structure, and A subsequent step of exposing to carbon dioxide containing water and / or an organic solvent. (S) A step of applying a suspension of a biodegradable polymer containing specific particles to the surface of the biodegradable polymer and then removing the solvent, and after this step, a step of exposing the specific particles to the surface of the degradable polymer as necessary. (T) A step of exposing a composite containing a biodegradable polymer and specific ceramics to a solvent or a solution to dissolve the biodegradable polymer in the vicinity of the specific ceramics and expose the specific ceramics on the surface, or a step of exposing a composite containing a biodegradable polymer and specific ceramics composed of calcium carbonate containing willemite to a phosphate solution to dissolve the biodegradable polymer in the vicinity of the calcium carbonate containing willemite and expose the calcium carbonate containing willemite on the surface of the composite, and a step of compositionally converting the calcium carbonate containing willemite into carbonated apatite.

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