WO2017092540A1 - 利用天然含镁的方解石制备可降解的人工骨材料的方法 - Google Patents

利用天然含镁的方解石制备可降解的人工骨材料的方法 Download PDF

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WO2017092540A1
WO2017092540A1 PCT/CN2016/104298 CN2016104298W WO2017092540A1 WO 2017092540 A1 WO2017092540 A1 WO 2017092540A1 CN 2016104298 W CN2016104298 W CN 2016104298W WO 2017092540 A1 WO2017092540 A1 WO 2017092540A1
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artificial bone
bone material
calcite
natural magnesium
hours
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French (fr)
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张兴
崔嵬
杨锐
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中国科学院金属研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic materials
    • A61L27/32—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • C01B25/325—Preparation by double decomposition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
    • C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/01—Particle morphology depicted by an image
    • C01P2004/03—Particle morphology depicted by an image obtained by SEM

Definitions

  • the invention relates to the technical field of biomedical materials, in particular to a method for preparing degradable artificial bone material by using natural magnesium-containing calcite (starfish and sea urchin shell skeleton) ( ⁇ -phase tricalcium phosphate, ⁇ -phase tricalcium phosphate and hydroxyapatite) A method of mixing or a mixture of a beta phase tricalcium phosphate and calcite.
  • natural magnesium-containing calcite starfish and sea urchin shell skeleton
  • ⁇ -phase tricalcium phosphate, ⁇ -phase tricalcium phosphate and hydroxyapatite A method of mixing or a mixture of a beta phase tricalcium phosphate and calcite.
  • bioceramics are mainly composed of hydroxyapatite and ⁇ -phase tricalcium phosphate. They are mainly used for filling and repairing various bone defects in clinical practice. Among them, hydroxyapatite materials are difficult to degrade in vivo, while ⁇ -phase tricalcium phosphate can be degraded and absorbed in vivo. . In recent years, the preparation of calcium phosphate by hydrothermal synthesis using calcium carbonate as a raw material has become a research hotspot.
  • the invention mainly uses calcium carbonate materials (corals, shells and squid bones) and phosphate to react in hydrothermal conditions to prepare in vivo degradation. Hydroxyapatite; how to use natural materials to prepare degradable artificial bone materials through a reasonable process has become a research hotspot.
  • the invention mainly uses a natural magnesium-containing calcite material (starfish, sea urchin shell) to prepare a degradable artificial bone material ( ⁇ -phase tricalcium phosphate, ⁇ -phase tricalcium phosphate and hydroxyapatite mixture or ⁇ -phase tricalcium phosphate) a mixture of calcite).
  • the invention aims to provide a method for preparing a degradable artificial bone material by using natural magnesium-containing calcite, which mainly utilizes the excellent through-hole structure of sea stars and sea urchin shells to prepare degradable artificial bone materials, including in vivo degradable materials.
  • the degradable ⁇ -phase tricalcium phosphate artificial bone scaffold prepared by starfish and sea urchin shell has a connected porous structure, and the material has moderate mechanical strength, and is suitable for bone defect repair.
  • a method for preparing a degradable artificial bone material by using natural magnesium-containing calcite wherein the natural magnesium-containing calcite is used as a raw material to prepare a degradable artificial bone material by hydrothermal synthesis reaction;
  • the natural magnesium-containing material Calcite is a starfish and/or sea urchin shell skeleton having a three-dimensional through-hole, wherein the starfish has a magnesium content of 17-21%, the sea urchin shell has a magnesium content of 8-15%, and the degradable artificial bone material is a beta phase phosphate.
  • the method of the invention specifically comprises the following steps:
  • the natural magnesium-containing calcite treated by the step (1) is processed into a micron-sized fine powder, granule or block sample as needed, and mixed with a diammonium hydrogen phosphate solution.
  • the micron-sized fine powder sample particle size is less than 100 ⁇ m; the granular sample size is 0.4-2 mm; the block sample size 2mm x 2mm x 2mm ⁇ 5mm x 5mm x 5mm; the weight ratio of the natural magnesium-containing calcite to diammonium hydrogen phosphate (calculated as diammonium hydrogen phosphate in the diammonium hydrogen phosphate solution) is 1: (1-5) ), the concentration of the diammonium hydrogen phosphate solution used is 0.1-0.5 g/mL.
  • the reaction product of the step (2) is taken out and washed three times with deionized water, then once with absolute ethanol, and then dried at 70 ° C for 6 hours to obtain the above-mentioned Degraded artificial bone material.
  • the hydrothermal synthesis reaction is carried out with a diammonium hydrogen phosphate solution at 150-250 ° C for a reaction time of 24-144 hours, and the reaction product is a ⁇ -phase phosphoric acid III. a mixture of calcium and hydroxyapatite, a two-phase calcium phosphate material.
  • the granular sample when selected, it is hydrothermally synthesized with diammonium hydrogen phosphate solution at 200-250 ° C for a reaction time of 24-144 hours, and the reaction product is ⁇ -phase tricalcium phosphate.
  • the hydrothermal synthesis reaction is carried out with a diammonium hydrogen phosphate solution at 200-250 ° C for a reaction time of 24-144 hours, and the reaction product is a ⁇ -phase tricalcium phosphate;
  • the reaction product is a mixture of ⁇ -calcium tricalcium phosphate and calcite.
  • the artificial bone material prepared by using the starfish as raw material has a porosity of 20%-40% and a pore diameter of 10-30 ⁇ m; and the artificial bone material prepared by using the sea urchin shell as a raw material has a porosity of 40%-60%,
  • the pore size is 10-30 ⁇ m.
  • the prepared ⁇ -phase tricalcium phosphate artificial bone material retains the three-dimensional connected porous structure of the raw material, and the mechanical strength of the material is moderate (the compression strength of the ⁇ -phase tricalcium phosphate artificial bone prepared by the starfish is 3.8- 5.6 MPa, the ⁇ -phase tricalcium phosphate artificial bone prepared from sea urchin shell has a compressive strength of 8.4-11.2 MPa), which is suitable for bone defect repair.
  • the present invention proposes to utilize the unique microstructure of natural starfish and sea urchin shells to directly convert the particles and blocks of sea stars and sea urchin shells into three-dimensional connected porous ⁇ -TCP artificial bone scaffolds by hydrothermal reaction, and the special microstructure is in the bone defect. Repair is beneficial to new bone regeneration.
  • the invention can mechanically process artificial bone supports of specific shape and size, and prepare artificial bone materials capable of different strengths and degradation speeds through raw material size and control of hydrothermal reaction process parameters, which can meet the needs of patients with different bone defects. Individual needs. Compared with the existing porous ⁇ -TCP ceramic firing method, the process of the invention is obviously simplified and has important clinical application value.
  • the invention proposes to directly synthesize a two-phase calcium phosphate material (a mixture of ⁇ -TCP and HA) by using a micro-scale fine powder of a starfish and a sea urchin shell (mainly containing magnesium calcite) by hydrothermal reaction, and can develop a two-phase calcium phosphate.
  • Bioceramic suitable for bone filling materials.
  • Figure 1 is a photograph of a 5 mm x 5 mm x 5 mm starfish block sample; where: (A) before hydrothermal reaction; (B) after hydrothermal reaction at 250 °C for 24 hours.
  • Figure 3 is a Micro-CT image of a starfish sample after 24 hours of hydrothermal reaction at 250 °C; where: the left panel is a side view of the sample and the right panel is a top view of the sample.
  • Figure 4 is an X-ray diffraction spectrum of a product with a particle size of 5 mm x 5 mm x 5 mm starfish at various temperatures for a certain period of time; wherein: (A) hydrothermal reaction at 250 ° C for 24 hours, hydrothermal reaction Completely, the product component is ⁇ -phase tricalcium phosphate; (B) hydrothermal reaction at 200 ° C for 72 hours, hydrothermal reaction is complete, product component ⁇ phase tricalcium phosphate; (C) hydrothermal reaction at 150 ° C for 144 hours The raw material is partially reacted, and the product is a mixture of ⁇ -phase tricalcium phosphate and magnesium-containing calcite.
  • the letter T represents ⁇ -phase tricalcium phosphate
  • the letter C represents calcite.
  • Figure 5 is an infrared spectrum of a starfish sample; wherein: (A) the spectrum after removing the organic matter; (B) the spectrum of the sample after 24 hours of hydrothermal reaction at 200 °C.
  • Figure 6 is an X-ray diffraction spectrum of the sample; wherein: (A) 20-40 mesh starfish particles (magnesium calcite) obtained by hydrothermal reaction at 200 ° C for 24 hours, ⁇ phase of tricalcium phosphate; (B) ball milled starfish powder 200 A mixture of ⁇ -phase tricalcium phosphate and hydroxyapatite obtained after 24 hours of hydrothermal reaction at °C.
  • A 20-40 mesh starfish particles (magnesium calcite) obtained by hydrothermal reaction at 200 ° C for 24 hours, ⁇ phase of tricalcium phosphate
  • B ball milled starfish powder 200 A mixture of ⁇ -phase tricalcium phosphate and hydroxyapatite obtained after 24 hours of hydrothermal reaction at °C.
  • Figure 7 is a sample of a starfish sample; wherein: (A) a scanning electron micrograph of the original starfish sample; (B) a microstructure diagram of the hydrothermal reaction at 200 ° C for 24 hours.
  • Figure 8 is a 5 mm x 5 mm x 5 mm sea urchin shell-like sample; wherein: (A) photograph of the original sample; (B) photograph after 24 hours of hydrothermal reaction at 250 °C.
  • Fig. 9 is an X-ray diffraction spectrum of the sample; wherein: (A) natural sea material (magnesium-containing calcite), (B) ⁇ -phase tricalcium phosphate obtained after hydrothermal reaction of sea urchin shell at 250 ° C for 24 hours.
  • Fig. 10 is a Micro-CT image of a sea urchin shell sample after hydrothermal reaction at 250 ° C for 24 hours; wherein: the left side is a side view of the sample, and the right side is a top view of the sample.
  • Figure 11 is an X-ray diffraction spectrum of a 5 mm x 5 mm x 5 mm sea urchin shell after reacting at different temperatures for a certain period of time; wherein: (A) hydrothermal reaction at 250 ° C for 24 hours, product composition ⁇ phase tricalcium phosphate; B) 200 ° C hydrothermal reaction for 72 hours, the product composition ⁇ phase tricalcium phosphate; (C) 150 ° C hydrothermal reaction for 144 hours, the raw material part of the reaction, the product is a mixture of ⁇ phase tricalcium phosphate and magnesium calcite, (C) The middle letter T stands for ⁇ -phase tricalcium phosphate, and the letter C stands for calcite.
  • Figure 12 is an infrared spectrum of sea urchin shell samples; (A) infrared spectrum of sea urchin shell samples after removal of organic matter; (B) sample spectrum after 200 hours of hydrothermal reaction at 200 °C.
  • Figure 13 is a sample of sea urchin shell samples; wherein: (A) scanning electron micrograph of the original sea urchin shell sample; (B) microstructure of the sample after 200 hours of hydrothermal reaction at 200 °C.
  • Figure 14 is a photograph of a two-phase calcium phosphate artificial bone ceramic; wherein: (A) an artificial bone ceramic having a density of 1 g/cm 3 ; (B) an artificial bone ceramic having a density of 0.8 g/cm 3 .
  • the raw materials of the invention are: ordinary starfish, sea urchin shell, analytical pure diammonium hydrogen phosphate, deionized water.
  • the invention relates to a natural magnesium-containing calcite material (starfish and sea urchin shell) which is made into a degradable artificial bone material by hydrothermal synthesis, including a ⁇ -phase tricalcium phosphate artificial bone material and a two-phase calcium phosphate material ( ⁇ -phase phosphoric acid three) a mixture of calcium and hydroxyapatite) or a mixture of beta phase tricalcium phosphate and calcite.
  • the invention is characterized in that: natural starfish and sea urchin shell (magnesium calcite material) having micron through holes are used as raw materials, and degradable artificial bone materials with different particle sizes are prepared at different temperatures by hydrothermal synthesis reaction; part of artificial bone samples are prepared. The original connected porous structure of the natural material is retained.
  • Raw materials ordinary starfish, analysis of pure diammonium hydrogen phosphate, deionized water.
  • the starfish was placed in boiling water for 30 minutes, and ultrasonically shaken for 40 minutes in a 10% by mass sodium hypochlorite solution to remove organic matter. After washing with deionized water, it was placed in a constant temperature drying oven and dried at 120 ° C for 6 hours to obtain a three-dimensionally connected porous starfish sample (magnesium-containing calcite) (Fig. 2(A)).
  • Hydrothermal reaction The starfish sample was placed in a hydrothermal reaction kettle in a ratio of 1 g: 20 ml to a 0.1 g/ml diammonium hydrogen phosphate solution. The mixture was hydrothermally reacted at 250 ° C for 24 hours in a blast drying oven.
  • Example 2 The sample was hydrothermally reacted at 200 ° C for 72 hours, and the rest was the same as in Example 1. A ⁇ -phase tricalcium phosphate artificial bone material was obtained (Fig. 4(B)).
  • the sample was hydrothermally reacted at 150 ° C for 144 hours, and the rest was the same as in Example 1.
  • the resulting artificial bone material product was a mixture of ⁇ -phase tricalcium phosphate and calcite (Fig. 4(C)).
  • the starfish is ground into small particles with a mortar, and the milled small particles are passed through a 20 and 40 mesh sieve to obtain 20-40 mesh (430-900 ⁇ m) starfish small particles (magnesium containing calcite, Fig. 5 (A), 7 ( A)), then the organic matter was removed, and further hydrothermal reaction was carried out at 200 ° C for 24 hours, and the rest was the same as in Example 1.
  • a ⁇ -phase tricalcium phosphate artificial bone material was obtained (Fig. 5 (B), 6 (A), 7 (B)).
  • the starfish was ground into small particles by a mortar, and then the organic matter was removed, and then ball-milled at 190 rpm for 24 hours using a planetary ball mill to obtain a micron-sized fine powder, and further hydrothermally reacted at 200 ° C for 24 hours, and the rest was the same as in Example 1.
  • a mixture of ⁇ -phase tricalcium phosphate and hydroxyapatite was obtained (Fig. 6(B)).
  • Raw materials common sea urchin shell, analysis of pure diammonium hydrogen phosphate, deionized water.
  • the sea urchin shell was placed in boiling water for 30 minutes, and ultrasonically shaken for 40 minutes in a 10% by mass sodium hypochlorite solution to remove organic matter. After washing with deionized water, it was placed in a constant temperature drying oven and dried at 120 ° C for 6 hours to obtain a three-dimensionally connected porous sea urchin sample (magnesium-containing calcite) (Fig. 9(A)).
  • Hydrothermal reaction The sea urchin shell sample was mixed with a 0.1 g/ml diammonium hydrogen phosphate solution in a ratio of 1 g: 20 ml in a hydrothermal reaction vessel. The mixture was hydrothermally reacted at 250 ° C for 24 hours in a blast drying oven.
  • the sea urchin shell was processed into cubes having a size of 5 mm x 5 mm x 5 mm, and the sample was hydrothermally reacted at 200 ° C for 72 hours, and the rest was the same as in Example 6.
  • a ⁇ -phase tricalcium phosphate artificial bone material was obtained (Fig. 11(B)).
  • the sea urchin shell was processed into cubes having a size of 5 mm x 5 mm x 5 mm, and the sample was hydrothermally reacted at 150 ° C for 144 hours, and the rest was the same as in Example 6.
  • the obtained artificial bone material product was a mixture of ⁇ -phase tricalcium phosphate and calcite (Fig. 11(C)).
  • the sea urchin shell is ground into small particles with a mortar, and the milled small particles are passed through a 20 and 40 mesh sieve to obtain 20-40 mesh (430-900 ⁇ m) sea urchin shell small particles (magnesium containing calcite, Fig. 12 (A), 13 (A)), then the organic matter was removed, and further hydrothermal reaction was carried out at 200 ° C for 24 hours, and the rest was the same as in Example 6.
  • a ⁇ -phase tricalcium phosphate artificial bone material was obtained (Fig. 12 (B), 13 (B)).
  • a two-phase calcium phosphate material is prepared from a starfish (or sea urchin shell) powder and further used to prepare an artificial bone ceramic. Proceed as follows:
  • Preparation of polyvinyl alcohol solution 10 g of polyvinyl alcohol was added to 200 ml of water. The heated solution was stirred at 70 ° C using a magnetic stirrer at 400 rpm to dissolve the polyvinyl alcohol completely to obtain a 5% by mass solution of polyvinyl alcohol.
  • Ceramic preparation 60 ppi porous sponge (1 cm x 1 cm x 1 cm) was squeezed to adsorb 1 ml of 1 g/ml ceramic slurry, taken out, placed in a high temperature furnace, and heated to 600 ° C at a rate of 4 ° C per minute for 3 hours. The temperature was raised to 1000 ° C at a rate of 10 ° C per minute, and the temperature was maintained for 2 hours. After that, the power was turned off with the furnace to obtain a two-phase calcium phosphate artificial bone ceramic, as shown in Fig. 14(A).
  • Example 5 4 g of the two-phase calcium phosphate material obtained in Example 5 was weighed, mixed with 5 ml of a 5% by mass solution of polyvinyl alcohol, and stirred uniformly to obtain a 0.8 g/ml ceramic slurry for preparing a two-phase calcium phosphate artificially.
  • the bone ceramics were the same as in Example 10.
  • a two-phase calcium phosphate artificial bone ceramic is obtained as shown in Fig. 14(B).

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Abstract

利用天然含镁方解石制备可降解的人工骨材料的方法，该方法以天然含镁的方解石材料海星和/或海胆壳骨架为原材料，通过水热合成反应制备可降解的人工骨材料β相磷酸三钙人工骨材料、两相磷酸钙材料或者β相磷酸三钙与方解石的混合物，部分人工骨材料保持了海星和海胆壳原始的连通多孔结构。

Description

利用天然含镁的方解石制备可降解的人工骨材料的方法 技术领域
本发明涉及生物医用材料技术领域，具体涉及一种利用天然含镁的方解石(海星和海胆壳骨架)制备可降解的人工骨材料(β相磷酸三钙、β相磷酸三钙与羟基磷灰石混合物或者β相磷酸三钙与方解石的混合物)的方法。
背景技术
从二十世纪后半叶开始，人工骨技术研究领域进入快速发展期，从自体骨移植发展出生物陶瓷、活性玻璃、医用金属材料等一系列人工骨材料。其中生物陶瓷以羟基磷灰石和β相磷酸三钙为主，在临床上主要用于各种骨缺损填充修复，其中羟基磷灰石材料体内难降解，而β相磷酸三钙体内可以降解吸收。近年来以碳酸钙为原材料通过水热合成制备磷酸钙盐成为一项研究热点，主要是利用碳酸钙材料(珊瑚，贝壳和乌贼骨等)与磷酸盐在水热条件下反应制备体内不能降解的羟基磷灰石；而如何利用天然材料通过合理的工艺制备可降解的人工骨材料成为研究热点。本发明主要是利用天然含镁的方解石材料(海星、海胆壳)，制备可降解的人工骨材料(β相磷酸三钙、β相磷酸三钙与羟基磷灰石混合物或者β相磷酸三钙与方解石的混合物)。
发明内容
本发明目的在于提供一种利用天然含镁的方解石制备可降解的人工骨材料的方法，主要是利用海星与海胆壳优异的贯通孔结构，制备出可降解的人工骨材料，包括体内可降解的β相磷酸三钙人工骨支架、两相磷酸钙材料(β相磷酸三钙与羟基磷灰石混合物)以及β相磷酸三钙与方解石的混合物。其中由海星和海胆壳制备的可降解的β相磷酸三钙人工骨支架，具有连通多孔结构，材料机械强度适中，适合于骨缺损修复。
为实现上述目的，本发明所采用的技术方案如下：
一种利用天然含镁的方解石制备可降解的人工骨材料的方法，该方法是以天然含镁的方解石为原材料，通过水热合成反应制得可降解的人工骨材料；所述天然含镁的方解石为海星和/或海胆壳骨架，其具有三维贯通孔，其中海星的镁含量为17-21％，海胆壳的镁含量为8-15％；所述可降解的人工骨材料为β相磷酸三钙人工骨材料、两相磷酸钙材料(β相磷酸三钙与羟基磷灰石混合物)或者β相磷酸三钙与方解石的混合物。
本发明方法具体包括如下步骤：
(1)天然含镁的方解石的清洁处理：将海星和/或海胆壳在去离子水中煮沸30分钟，然后在浓度为10wt.％的次氯酸钠溶液中超声清洗40分钟，以去离子水清洗三遍后，再在120℃条件下烘干6小时，以去除海星和/或海胆壳上的有机质和其他杂质；
(2)水热合成反应：将经步骤(1)处理后的天然含镁的方解石根据需要加工成微米级细粉状、颗粒状或块状样品，将其与磷酸氢二铵溶液混合置于水热反应釜中，在150-250℃反应24-144小时；该步骤中，所述微米级细粉状样品粒度小于100μm；所述颗粒状样品尺寸为0.4-2mm；所述块状样品尺寸为2mm x 2mm x 2mm～5mm x5mm x 5mm；所述天然含镁的方解石与磷酸氢二铵(按磷酸氢二铵溶液中所含磷酸氢二铵计算)的重量比例为1:(1-5)，所采用的磷酸氢二铵溶液的浓度范围为 0.1-0.5g/mL。
(3)反应后清洗：将步骤(2)的反应产物取出后先使用去离子水清洗三遍，然后用无水乙醇清洗一次，再在70℃条件下烘干6小时，即获得所述可降解的人工骨材料。
本发明上述方法中：当选取微米级细粉状样品时，其与磷酸氢二铵溶液在150-250℃条件下进行水热合成反应，反应时间24-144小时，反应产物为β相磷酸三钙与羟基磷灰石的混合物，即两相磷酸钙材料。
本发明上述方法中：当选取颗粒状样品时，其与磷酸氢二铵溶液在200-250℃条件下进行水热合成反应，反应时间24-144小时，反应产物为β相磷酸三钙。
本发明上述方法中：当选取块状样品时，其与磷酸氢二铵溶液在200-250℃条件下进行水热合成反应，反应时间24-144小时，反应产物为β相磷酸三钙；选取块状样品时，其与磷酸氢二铵溶液在150-小于200℃条件下进行水热合成反应，反应时间24-144小时，反应产物为β相磷酸三钙与方解石的混合物。
采用本发明方法，以海星为原材料制备的人工骨材料的孔隙率为20％-40％，孔径为10-30μm；以海胆壳为原材料制备的人工骨材料的孔隙率为40％-60％，孔径为10-30μm。
采用本发明制备的人工骨材料中，制备的β相磷酸三钙人工骨材料保留了原材料的三维连通多孔结构，材料机械强度适中(由海星制备的β相磷酸三钙人工骨压缩强度为3.8-5.6MPa，由海胆壳制备的β相磷酸三钙人工骨压缩强度为8.4-11.2MPa)，适合于骨缺损修复。
与现有技术相比，本发明的有益效果体现在：
1、本发明提出利用天然海星、海胆壳独特的微观结构，通过水热反应将海星、海胆壳的颗粒和块材直接转化成三维连通多孔β-TCP人工骨支架，其特殊微观结构在骨缺损修复中有利于新骨再生。
2、本发明可以通过机械加工出特定形状和尺寸的人工骨支架，并通过原材料尺寸及控制水热反应工艺参数制备出能够具有不同强度及降解速度的人工骨材料，能够满足不同骨缺损患者的个体需求。与现有的多孔β-TCP陶瓷烧制方法相比，本发明工艺明显简化，具有重要的临床应用价值。
3、本发明提出使用海星、海胆壳(主要成分为含镁方解石)微米级细粉经水热反应可以直接合成出两相磷酸钙材料(β-TCP与HA混合物)，可以开发两相磷酸钙生物陶瓷，适合用于骨填充材料。
附图说明
图1为5mm x 5mm x 5mm海星块状样品的照片；其中：(A)水热反应前；(B)250℃水热反应24小时之后。
图2为样品的X射线衍射谱图：(A)天然海星材料(含镁方解石)，(B)海星250℃水热反应24小时后得到的β相磷酸三钙。
图3为250℃水热反应24小时后海星样品的Micro-CT图像；其中：左图为样品侧视图，右图为样品俯视图。
图4为颗粒尺寸为5mm x 5mm x 5mm海星块体在不同温度下反应一定时间后的产物的X射线衍射谱图；其中：(A)在250℃的条件下水热反应24小时，水热反应 完全，产物成分β相磷酸三钙；(B)在200℃的条件下水热反应72小时，水热反应完全，产物成分β相磷酸三钙；(C)在150℃的条件下水热反应144小时，原材料部分反应，产物为β相磷酸三钙与含镁方解石的混合物，(C)中字母T代表β相磷酸三钙，字母C代表方解石。
图5为海星样品的红外光谱图；其中：(A)去除有机质后谱图；(B)200℃水热反应24小时后样品谱图。
图6为样品的X射线衍射谱图；其中：(A)20-40目海星颗粒(含镁方解石)200℃水热反应24小时后得到的β相磷酸三钙；(B)球磨海星粉200℃水热反应24小时后得到的β相磷酸三钙和羟基磷灰石的混合物。
图7为海星样品图；其中：(A)原始海星样品的扫描电镜照片；(B)200℃水热反应24小时后的微观结构图。
图8为5mm x 5mm x 5mm海胆壳块状样品；其中：(A)原始样品照片；(B)250℃水热反应24小时之后的照片。
图9为样品的X射线衍射谱图；其中：(A)天然海材料(含镁方解石)，(B)海胆壳250℃水热反应24小时后得到的β相磷酸三钙。
图10为250℃水热反应24小时后海胆壳样品的Micro-CT图像；其中：左图为样品侧视图，右图为样品俯视图。
图11为5mm x 5mm x 5mm海胆壳块体在不同温度下反应一定时间后产物的X射线衍射谱图；其中：(A)250℃水热反应24小时，产物成分β相磷酸三钙；(B)200℃水热反应72小时，产物成分β相磷酸三钙；(C)150℃水热反应144小时，原材料部分反应，产物为β相磷酸三钙与含镁方解石的混合物，(C)中字母T代表β相磷酸三钙，字母C代表方解石。
图12为海胆壳样品的红外光谱图；其中：(A)去除有机质后海胆壳样品的红外光谱图；(B)200℃水热反应24小时后样品谱图。
图13为海胆壳样品图；其中：(A)原始海胆壳样品的扫描电镜照片；(B)200℃水热反应24小时后样品的微观结构图。
图14为两相磷酸钙人工骨陶瓷照片；其中：(A)密度1g/cm3的人工骨陶瓷；(B)密度0.8g/cm3的人工骨陶瓷。
具体实施方式
下面结合实施例对本发明的技术方案做进一步说明：
本发明原料为：普通海星，海胆壳，分析纯磷酸氢二铵，去离子水。
本发明涉及将天然含镁的方解石材料(海星和海胆壳)通过水热合成方法制成可降解的人工骨材料，包括β相磷酸三钙人工骨材料、两相磷酸钙材料(β相磷酸三钙与羟基磷灰石混合物)或者β相磷酸三钙与方解石的混合物。其特征在于：以具有微米贯通孔的天然海星和海胆壳(含镁方解石材料)为原料，通过水热合成反应在不同温度下，制备出不同颗粒尺寸的可降解人工骨材料；部分人工骨样品保留了天然材料原有的连通多孔结构。
实施例1
原材料：普通海星，分析纯磷酸氢二铵，去离子水。
样品加工：将海星加工成尺寸为5mm x 5mm x 5mm的方块(图1(A))。
去除有机质：将海星置于沸水中煮30分钟，在质量百分比为10％的次氯酸钠溶液中超声振荡40分钟以去除有机质。去离子水洗净后放入恒温干燥箱中，120℃下烘干6小时得到三维连通多孔的海星样品(含镁方解石)(图2(A))。
水热反应：将海星样品以1g:20ml的比例与0.1g/ml的磷酸氢二铵溶液混合置于水热反应釜内。在鼓风干燥箱中，250℃水热反应24小时。
清洗：水热反应的产物取出后加入去离子水，放入离心机中以2000转每分钟的转速离心清洗5分钟，重复3次。再在无水乙醇中离心清洗一次。
烘干：清洗后的产物放入恒温干燥箱中，70℃下烘干6小时，得到β相磷酸三钙人工骨材料(图1(B)、2(B)、4(A))，保持了海星原有的多孔结构(图3)。
实施例2
样品在200℃下水热反应72小时，其余同实施例1相同。得到β相磷酸三钙人工骨材料(图4(B))。
实施例3
样品在150℃下水热反应144小时，其余同实施例1相同。得到的人工骨材料产物为β相磷酸三钙与方解石的混合物(图4(C))。
实施例4
用研钵将海星研磨为小颗粒，并将研磨后的小颗粒过20和40目的筛子，得到20-40目(430-900μm)海星小颗粒(含镁方解石，图5(A)、7(A))，然后去除有机质，进一步200℃下水热反应24小时，其余同实施例1相同。得到β相磷酸三钙人工骨材料(图5(B)、6(A)、7(B))。
实施例5
用研钵将海星研磨为小颗粒，然后去除有机质，再使用行星球磨机190转/分钟球磨24小时获得微米级细粉，进一步200℃下水热反应24小时，其余同实施例1相同。得到β相磷酸三钙和羟基磷灰石混合物(图6(B))。
实施例6
原材料：普通海胆壳，分析纯磷酸氢二铵，去离子水。
样品加工：将海胆壳加工成尺寸为5mm x 5mm x 5mm的方块(图8(A))。
去除有机质：将海胆壳置于沸水中煮30分钟，在质量百分比为10％的次氯酸钠溶液中超声振荡40分钟以去除有机质。去离子水洗净后放入恒温干燥箱中，120℃下烘干6小时得到三维连通多孔的海胆壳样品(含镁方解石)(图9(A))。
水热反应：将海胆壳样品以1g:20ml的比例与0.1g/ml的磷酸氢二铵溶液混合置于水热反应釜内。在鼓风干燥箱中，250℃水热反应24小时。
清洗：水热反应的产物取出后加入去离子水，放入离心机中以2000转每分钟的转速离心清洗5分钟，重复3次。再在无水乙醇中离心清洗一次。
烘干：清洗后的产物放入恒温干燥箱中，70℃下烘干6小时，得到β相磷酸三钙人工骨材料(图9(B)、11(A))。反应后的微观Micro-CT图像表明得到的β相磷酸三钙人工骨材料保持了原始海星的三维连通孔结构(图10)。
实施例7
将海胆壳加工成尺寸为5mm x 5mm x 5mm的方块，该样品在200℃下水热反应72小时，其余同实施例6相同。得到β相磷酸三钙人工骨材料(图11(B))。
实施例8
将海胆壳加工成尺寸为5mm x 5mm x 5mm的方块，该样品在150℃下水热反应144小时，其余同实施例6相同。得到的人工骨材料产物为β相磷酸三钙与方解石的混合物(图11(C))。
实施例9
用研钵将海胆壳研磨为小颗粒，并将研磨后的小颗粒过20和40目的筛子，得到20-40目(430-900μm)海胆壳小颗粒(含镁方解石，图12(A)、13(A))，然后去除有机质，进一步200℃下水热反应24小时，其余同实施例6相同。得到β相磷酸三钙人工骨材料(图12(B)、13(B))。
实施例10
从海星(或海胆壳)粉体制备两相磷酸钙材料，进一步用于制备人工骨陶瓷。步骤如下：
聚乙烯醇溶液的制备：将10g聚乙烯醇加入200ml水中。在70℃下，使用磁力搅拌器以每分钟400转的转速搅拌加热溶液至聚乙烯醇溶解完全，得到质量百分比为5％的聚乙烯醇溶液。
陶瓷浆料制备：称取5g的实施例5中得到的两相磷酸钙材料，与5ml质量百分比为5％的聚乙烯醇溶液混合，搅拌均匀，得到1g/ml陶瓷浆料。
陶瓷制备：将60ppi的多孔海绵(1cm x 1cm x 1cm)挤压吸附1ml 1g/ml陶瓷浆料，取出后放于高温炉内，以每分钟4℃的速度升温至600℃，恒温3小时。以每分钟10℃的速度升温至1000℃，恒温2小时。之后断电随炉冷却，得到两相磷酸钙人工骨陶瓷，如附图14(A)。
实施例11
称取4g的实施例5中得到的两相磷酸钙材料，与5ml质量百分比为5％的聚乙烯醇溶液混合，搅拌均匀，得到0.8g/ml陶瓷浆料，用于制备两相磷酸钙人工骨陶瓷，其余同实施例10。得到两相磷酸钙人工骨陶瓷如附图14(B)。

Claims (10)

  1. 利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：该方法是以天然含镁的方解石为原材料，通过水热合成反应制得可降解的人工骨材料；所述天然含镁的方解石为海星和/或海胆壳骨架；所述可降解的人工骨材料为β相磷酸三钙人工骨材料、两相磷酸钙材料或者β相磷酸三钙与方解石的混合物。
  2. 根据权利要求1所述的利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：所述天然含镁的方解石具有三维贯通孔，其中海星的镁含量为17-21％，海胆壳的镁含量为8-15％。
  3. 根据权利要求1或2所述的利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：该方法具体包括如下步骤：
    (1)天然含镁的方解石的清洁处理：将海星和/或海胆壳在去离子水中煮沸30分钟，然后在浓度为10wt.％的次氯酸钠溶液中超声清洗40分钟，以去离子水清洗三遍后，再在120℃条件下烘干6小时，以去除海星和/或海胆壳上的有机质和其他杂质；
    (2)水热合成反应：将经步骤(1)处理后的天然含镁的方解石根据需要加工成微米级细粉状、颗粒状或块状样品，将其与磷酸氢二铵溶液混合置于水热反应釜中，在150-250℃反应24-144小时；
    (3)反应后清洗：将步骤(2)的反应产物取出后先使用去离子水清洗三遍，然后用无水乙醇清洗一次，再在70℃条件下烘干6小时，即获得所述可降解的人工骨材料。
  4. 根据权利要求3所述的利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：步骤(2)中，所述微米级细粉状样品粒度小于100μm；所述颗粒状样品尺寸为0.4-2mm；所述块状样品尺寸为2mm x 2mm x 2mm～5mm x 5mm x 5mm。
  5. 根据权利要求4所述的利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：选取微米级细粉状样品时，其与磷酸氢二铵溶液在150-250℃条件下进行水热合成反应，反应时间24-144小时，反应产物为β相磷酸三钙与羟基磷灰石的混合物，即两相磷酸钙材料。
  6. 根据权利要求4所述的利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：选取颗粒状样品时，其与磷酸氢二铵溶液在200-250℃条件下进行水热合成反应，反应时间24-144小时，反应产物为β相磷酸三钙。
  7. 根据权利要求4所述的利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：选取块状样品时，其与磷酸氢二铵溶液在200-250℃条件下进行水热合成反应，反应时间24-144小时，反应产物为β相磷酸三钙；选取块状样品时，其与磷酸氢二铵溶液在150-小于200℃条件下进行水热合成反应，反应时间24-144小时，反应产物为β相磷酸三钙与方解石的混合物。
  8. 根据权利要求3所述的利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：步骤(2)中，所述天然含镁的方解石与磷酸氢二铵的重量比例为1:(1-5)，所采用的磷酸氢二铵溶液的浓度范围为0.1-0.5g/mL。
  9. 根据权利要求3所述的利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：该方法中，以海星为原材料制备的人工骨材料的孔隙率为20％-40％，孔径为10-30μm；以海胆壳为原材料制备的人工骨材料的孔隙率为40％-60％，孔径为10-30μm。
  10. 根据权利要求3所述的利用天然含镁的方解石制备可降解的人工骨材料的方法，其特征在于：该方法所制备的β相磷酸三钙人工骨、β相磷酸三钙与方解石混合物人工骨保留了原材料的三维连通多孔结构。
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