CN118206089B - A kind of hydroxyapatite microsphere and its preparation method and application - Google Patents
A kind of hydroxyapatite microsphere and its preparation method and application Download PDFInfo
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- CN118206089B CN118206089B CN202410320397.6A CN202410320397A CN118206089B CN 118206089 B CN118206089 B CN 118206089B CN 202410320397 A CN202410320397 A CN 202410320397A CN 118206089 B CN118206089 B CN 118206089B
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- 239000004005 microsphere Substances 0.000 title claims abstract description 54
- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 34
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- CGMRCMMOCQYHAD-UHFFFAOYSA-J dicalcium hydroxide phosphate Chemical compound [OH-].[Ca++].[Ca++].[O-]P([O-])([O-])=O CGMRCMMOCQYHAD-UHFFFAOYSA-J 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 21
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 13
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 12
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000011575 calcium Substances 0.000 claims abstract description 12
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 12
- 239000004202 carbamide Substances 0.000 claims abstract description 12
- 239000002738 chelating agent Substances 0.000 claims abstract description 12
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000001509 sodium citrate Substances 0.000 claims abstract description 11
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000463 material Substances 0.000 claims abstract description 10
- 239000011574 phosphorus Substances 0.000 claims abstract description 10
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 10
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000004220 glutamic acid Substances 0.000 claims abstract description 8
- 235000013922 glutamic acid Nutrition 0.000 claims abstract description 8
- 239000002244 precipitate Substances 0.000 claims abstract description 7
- 229940009098 aspartate Drugs 0.000 claims abstract description 6
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 6
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229930195712 glutamate Natural products 0.000 claims abstract description 6
- 230000001172 regenerating effect Effects 0.000 claims abstract description 5
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 17
- 238000001027 hydrothermal synthesis Methods 0.000 claims description 11
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 10
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 10
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 8
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 8
- 239000001110 calcium chloride Substances 0.000 claims description 8
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 8
- 229920002674 hyaluronan Polymers 0.000 claims description 8
- 229960003160 hyaluronic acid Drugs 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 6
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 159000000007 calcium salts Chemical class 0.000 claims description 4
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 229910019670 (NH4)H2PO4 Inorganic materials 0.000 claims description 2
- 239000007836 KH2PO4 Substances 0.000 claims description 2
- 238000004140 cleaning Methods 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 238000005406 washing Methods 0.000 abstract description 6
- 102000008186 Collagen Human genes 0.000 abstract description 4
- 108010035532 Collagen Proteins 0.000 abstract description 4
- 229920001436 collagen Polymers 0.000 abstract description 4
- 238000011049 filling Methods 0.000 abstract description 4
- 230000008929 regeneration Effects 0.000 abstract description 3
- 238000011069 regeneration method Methods 0.000 abstract description 3
- BDOYKFSQFYNPKF-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;sodium Chemical compound [Na].[Na].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O BDOYKFSQFYNPKF-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 16
- 239000002245 particle Substances 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 14
- 239000011148 porous material Substances 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 7
- 238000009826 distribution Methods 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 235000019838 diammonium phosphate Nutrition 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000005696 Diammonium phosphate Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940049906 glutamate Drugs 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 238000001000 micrograph Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 229960003707 glutamic acid hydrochloride Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
Classifications
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- 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
- 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
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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- 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
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- 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
- C01P2004/02—Particle morphology depicted by an image obtained by optical microscopy
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- 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
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- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/30—Particle morphology extending in three dimensions
- C01P2004/32—Spheres
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- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/51—Particles with a specific particle size distribution
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/61—Micrometer sized, i.e. from 1-100 micrometer
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
本发明涉及生物医用材料技术领域，尤其是涉及一种羟基磷灰石微球及其制备方法和应用，其制备方法包括如下步骤：S1、将螯合剂、钙源、磷源、尿素溶于水中，得到反应液；其中，所述螯合剂包括：谷氨酸、谷氨酸盐、天冬氨酸、天冬氨酸盐中的一种或多种，以及乙二胺四乙酸二钠、柠檬酸钠中的一种或多种；S2、调节反应液的pH值至1.00～4.00；S3、将pH调节后的反应液转移至水热反应釜中，置于90～250℃的温度下进行反应；S4、反应结束后，收集沉淀物并将其清洗至中性，干燥后得到羟基磷灰石微球。本发明的方法能够制备形貌可调控的多孔羟基磷灰石微球，用于再生填充材料领域，能够很好的刺激胶原的再生。
The present invention relates to the technical field of biomedical materials, and in particular to a hydroxyapatite microsphere and a preparation method and application thereof, wherein the preparation method comprises the following steps: S1, dissolving a chelating agent, a calcium source, a phosphorus source, and urea in water to obtain a reaction solution; wherein the chelating agent comprises: one or more of glutamic acid, glutamate, aspartic acid, and aspartate, and one or more of disodium ethylenediaminetetraacetic acid and sodium citrate; S2, adjusting the pH value of the reaction solution to 1.00-4.00; S3, transferring the pH-adjusted reaction solution to a hydrothermal reactor, and placing it at a temperature of 90-250°C for reaction; S4, after the reaction is completed, collecting the precipitate and washing it to neutrality, and drying it to obtain hydroxyapatite microspheres. The method of the present invention can prepare porous hydroxyapatite microspheres with adjustable morphology, which are used in the field of regenerative filling materials and can well stimulate the regeneration of collagen.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a hydroxyapatite microsphere, a preparation method and application thereof.
Background
Hydroxyapatite (Hydroxyapatite, HAP) is the main inorganic component of human hard tissue. In the field of biomedical materials, the composite material is widely applied to the fields of bone implantation, wound repair, regenerative filling, medicine carrying and the like. Aiming at the requirements of different fields, the HAP with different morphological structural characteristics is designed to have important significance for exerting the functions of the HAP. The porous HAP microsphere has high specific surface area, high adsorption characteristic, high interaction between protein and cell, and other advantages. Therefore, developing HAP microsphere materials with specific porous morphology is of great significance.
Methods for preparing porous HAP microspheres include spray drying, emulsion, hydrothermal synthesis, and the like. Although porous HAP microspheres can be obtained by both spray drying and emulsion methods, the preparation method is relatively cumbersome. For example, the spray drying method needs to be subjected to the processes of synthesis, collection, washing, drying, crushing and grinding, slurry preparation, spraying, drying, sintering and the like, and meanwhile, the spray slurry needs to be adjusted according to the different microsphere morphologies, so that the process is complicated; emulsion process, which is similar to spray drying process for preparing HAP microsphere, requires a great amount of organic oil phase reagent and also needs to adjust dispersed phase of HAP for microsphere with different morphology. Meanwhile, the HAP microsphere with the nanometer self-assembled structure is difficult to obtain in the two preparation modes. Compared with the two preparation methods, the hydrothermal synthesis method has simple preparation process and is easy to realize the nano assembly structure. In addition, the HAP microsphere prepared by the hydrothermal method has more similar composition with natural HAP. Although there are many reports at present that HAP microspheres with a certain particle size can be obtained by a hydrothermal synthesis method, the HAP microspheres with continuously controllable particle size are difficult to obtain by the method, and the adjustment of the pore structure of the HAP microspheres is still difficult. Therefore, developing a novel hydrothermal synthesis process and obtaining a preparation method of HAP microspheres with controllable and adjustable structures still has a need of solving the problem.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a hydroxyapatite microsphere, a preparation method and application thereof, wherein the method can be used for preparing the porous hydroxyapatite microsphere with adjustable morphology.
In a first aspect of the present invention, there is provided a method for preparing hydroxyapatite microspheres, comprising the steps of:
S1, dissolving a chelating agent, a calcium source, a phosphorus source and urea in water to obtain a reaction solution;
Wherein the chelating agent comprises: one or more of glutamic acid, glutamate, aspartic acid and aspartate, and one or more of disodium edetate and sodium citrate;
s2, regulating the pH value of the reaction solution to 1.00-4.00;
S3, transferring the reaction solution with the pH value adjusted into a hydrothermal reaction kettle, and placing the reaction solution into a temperature of 90-250 ℃ for reaction;
and S4, after the reaction is finished, collecting a precipitate, cleaning the precipitate to be neutral, and drying the precipitate to obtain the hydroxyapatite microsphere.
Preferably, in step S1, the chelating agent is dissolved in deionized water, and then the calcium source, the phosphorus source and urea are added sequentially.
Preferably, in step S1, the chelating agent is any one of the following components:
glutamic acid and disodium ethylenediamine tetraacetate;
(ii) glutamate and disodium edetate;
(iii) glutamic acid and sodium citrate;
(iv) glutamate and sodium citrate;
(v) aspartic acid, disodium ethylenediamine tetraacetate;
(VI) aspartate and disodium ethylenediamine tetraacetate;
(vii) aspartic acid, sodium citrate;
(VIII) aspartate and sodium citrate.
Preferably, the molar ratio of the two chelating agents in any one of groups (I) to (VIII) is (1.0 to 1.5): 0.0 to 0.3.
In specific embodiments, the particle size and pore size of the hydroxyapatite microspheres can be effectively reduced by increasing the proportion of disodium ethylenediamine tetraacetate or sodium citrate.
Preferably, in step S1, the molar ratio of the chelating agent to the calcium source is (1.4 to 2.0): 1.
Preferably, in step S1, the molar ratio of the calcium source to the phosphorus source is 1.2 to 2.0.
Preferably, in step S1, the molar ratio of urea to calcium source is (0.67 to 1.67): (0.02-0.22).
In a specific embodiment, the particle size of the hydroxyapatite microspheres can be reduced from 70 μm to 5 μm and the pore size can be reduced from 2 μm to 0.1 μm by increasing the urea concentration.
Preferably, in step S1, the calcium source is a soluble calcium salt, and the phosphorus source is a soluble phosphate salt.
Preferably, the soluble calcium salt comprises: ca (one or more of NO 3)2·4H2O、CaCl2·2H2O、CaCl2), the soluble phosphate salt including one or more of ：(NH4)2HPO4、(NH4)H2PO4、Na2HPO4、NaH2PO4、K2HPO4、KH2PO4.
Preferably, in the step S1, the molar concentration of the calcium source is 0.02-0.22 mol/L, the molar concentration of the phosphorus source is 0.02-0.11 mol/L, and the molar concentration of the urea is 0.67-1.67 mol/L.
Preferably, in step S2, the acid used for adjusting the pH is one or more of nitric acid, hydrochloric acid or sulfuric acid, and the base used is one or more of ammonia water or caustic soda solution; more preferably, the acid used to adjust the pH is nitric acid and the base used is ammonia.
Preferably, in the step S3, the reaction temperature is 160-190 ℃ and the reaction time is 1-10 h; more preferably, the reaction temperature is 180 ℃ and the reaction time is 2 hours.
In a specific embodiment, the balling effect can be effectively improved by controlling the reaction temperature and the reaction time.
Preferably, in step S4, the mixture is oven dried to a constant weight at 80 ℃.
In a second aspect of the invention, there is provided a hydroxyapatite microsphere prepared by the above preparation method.
In a third aspect of the invention, there is provided the use of the hydroxyapatite microspheres described above in the field of regenerative filling.
Preferably, the hydroxyapatite microspheres are implanted subcutaneously in combination with hyaluronic acid gel.
Specifically, the hydroxyapatite microspheres are mixed with hyaluronic acid gel and injected subcutaneously.
In a fourth aspect of the present invention, there is provided a regenerative filler material comprising: the hydroxyapatite microsphere and hyaluronic acid.
Preferably, the mass ratio of the hydroxyapatite microsphere to the hyaluronic acid gel is (10-56) (10-25); more preferably 35:18.
The invention has the following beneficial effects:
(1) The method adopts specific chelating agent types, and can regulate and control the particle size and the pore diameter of the hydroxyapatite microsphere by controlling the proportion of the chelating agent;
(2) The method can adjust the particle size and the pore diameter of the hydroxyapatite microsphere by adjusting the proportion of reactants;
(3) The method can effectively improve the balling effect by adjusting the reaction temperature and the reaction time;
(4) The method can realize the preparation of porous hydroxyapatite microspheres with different morphological structures;
(5) The hydroxyapatite microsphere prepared by the invention is used in the field of regenerated filling materials, and can well stimulate the regeneration of collagen.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is an optical microscopic image of hydroxyapatite microspheres prepared in example 1 of the present invention;
FIG. 2 is an optical microscopic image of hydroxyapatite microspheres prepared in example 2 of the present invention;
FIG. 3 is an optical microscopic image of hydroxyapatite microspheres prepared in example 3 of the present invention;
FIGS. 4A-C are optical microscopic images of hydroxyapatite microspheres prepared in example 4 of the present invention;
FIG. 5A is an optical microscopic image of hydroxyapatite microspheres prepared in example 5 of the present invention;
FIG. 5B is a scanning electron microscope image of hydroxyapatite microspheres prepared in example 5 of the present invention;
FIG. 6A is an optical microscopic image of hydroxyapatite microspheres prepared in example 6 of the present invention;
FIG. 6B is a scanning electron microscope image of hydroxyapatite microspheres prepared in example 6 of the present invention;
FIG. 6C is an X-ray diffraction pattern of hydroxyapatite microspheres prepared in example 6 of the present invention;
FIG. 6D is a graph showing the particle size distribution of hydroxyapatite microspheres prepared in example 6 of the present invention;
FIG. 7A is an optical microscopic image of hydroxyapatite microspheres prepared in example 7 of the present invention;
FIG. 7B is a scanning electron microscope image of hydroxyapatite microspheres prepared in example 7 of the present invention;
FIG. 7C is an X-ray diffraction pattern of hydroxyapatite microspheres prepared in example 7 of the present invention;
FIG. 7D is a graph showing the particle size distribution of hydroxyapatite microspheres prepared in example 7 of the present invention;
FIG. 8A is a chart showing the results of Masson staining 4 weeks after subcutaneous implantation provided in example 8 of the present invention;
fig. 8B is an H & E staining result provided in example 8 of the present invention 4 weeks after subcutaneous implantation.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present application. As used herein, the singular forms also include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The embodiment provides a preparation method of hydroxyapatite microspheres, which comprises the following steps:
S1, 0.5297g of glutamic acid is dissolved in 60mL of deionized water, and then 0.2877g of calcium chloride, 0.205g of diammonium hydrogen phosphate and 3.00g of urea are sequentially added to obtain a reaction solution;
s2, adjusting the pH value of the reaction solution to 1.00-4.00 by HNO 3/ammonia water;
S3, continuously stirring the reaction solution with the pH value adjusted for 30min, then transferring the reaction solution into a hydrothermal reaction kettle, placing the reaction solution into a blast drying oven with the temperature raised to 160 ℃ for reaction for 2h, and naturally cooling the reaction solution to room temperature after the reaction is finished;
S4, filtering and collecting a precipitated product, repeatedly washing the product by adopting purified water until the product is neutral, and then drying the product in an oven at 80 ℃ until the weight is constant, thus obtaining the hydroxyapatite microsphere.
The optical microscopic image of the hydroxyapatite microsphere prepared in the embodiment is shown in fig. 1, and can be seen from the figure: the particles collected after the reaction have a certain non-balled cluster structure.
Example 2
In this example, the reaction temperature in step S3 in example 1 was changed to 180℃and the remaining operation steps were the same as in example 1.
The optical microscopic image of the hydroxyapatite microsphere prepared in the embodiment is shown in fig. 2, and can be seen from the figure: compared with example 1, under the condition of the same reaction time length, the balling effect can be improved by increasing the reaction temperature.
Example 3
In this example, the reaction temperature in step S3 in example 1 was changed to 190℃and the remaining operation steps were the same as in example 1.
The optical microscopic image of the hydroxyapatite microsphere prepared in the embodiment is shown in fig. 3, and can be seen from the figure: compared with example 2, under the condition of the same reaction time length, the further increase of the reaction temperature can lead to the increase of the non-balled cluster structure, which indicates that the reaction temperature and the reaction time length have an influence on the particle formation.
Example 4
The reaction conditions and the like of this example are the same as those of example 2, except that: 160mg/500mg/1000mg of disodium edetate was added to step S1, respectively, and the other steps were the same as in example 2.
The optical microscopic images of the hydroxyapatite microspheres prepared in the embodiment are shown in fig. 4A to C, and can be seen from the figures: the particle size decreases as the disodium edetate content increases.
Example 5
S1, 1.0594g of glutamic acid is dissolved in 60mL of deionized water, and then 0.5754g of calcium chloride, 0.4098g of diammonium phosphate, 3.60g of urea and 160mg of disodium ethylenediamine tetraacetate are sequentially added to obtain a reaction solution;
s2, adjusting the pH value of the reaction solution to 1.00-4.00 by HNO 3/ammonia water;
S3, continuously stirring the reaction solution with the pH value adjusted for 30min, then transferring the reaction solution into a hydrothermal reaction kettle, placing the reaction solution into a blast drying oven with the temperature raised to 180 ℃ for reaction for 2h, and naturally cooling the reaction solution to room temperature after the reaction is finished;
S4, filtering and collecting a precipitated product, repeatedly washing the product by adopting purified water until the product is neutral, and then drying the product in an oven at 80 ℃ until the weight is constant, thus obtaining the hydroxyapatite microsphere.
The optical microscopic image and the scanning electron microscopic image of the hydroxyapatite microsphere prepared in the embodiment are shown in fig. 5A to B, and can be seen from the figures: the microsphere pore size was reduced by increasing the reactant concentration compared to example 4.
Example 6
S1, 2.2461g of glutamic acid hydrochloride is dissolved in 60mL of deionized water, and then 1.264g of calcium chloride, 0.900g of diammonium phosphate, 3.60g of urea and 160mg of disodium ethylenediamine tetraacetate are sequentially added to obtain a reaction solution;
s2, adjusting the pH value of the reaction solution to 1.00-4.00 by HNO 3/ammonia water;
S3, continuously stirring the reaction solution with the pH value adjusted for 30min, then transferring the reaction solution into a hydrothermal reaction kettle, placing the reaction solution into a blast drying oven with the temperature raised to 180 ℃ for reaction for 2h, and naturally cooling the reaction solution to room temperature after the reaction is finished;
S4, filtering and collecting a precipitated product, repeatedly washing the product by adopting purified water until the product is neutral, and then drying the product in an oven at 80 ℃ until the weight is constant, thus obtaining the hydroxyapatite microsphere.
The optical microscopic image and the scanning electron microscopic image of the hydroxyapatite microsphere prepared in the embodiment are shown in fig. 6A to fig. B, and can be seen from the figures: the concentration of the reactant was further increased and the pore size of the microspheres was further decreased compared to example 5.
The X-ray diffraction diagram of the hydroxyapatite microsphere prepared in the embodiment is shown in fig. 6C, and can be seen from the figure: the obtained microspheres are in one-to-one correspondence with XRD diffraction characteristic peaks of HAP, which indicates that the synthesized microspheres are typical HAP phase materials.
The particle size distribution diagram of the hydroxyapatite microsphere prepared in the embodiment is shown in fig. 6D, and can be seen from the figure: the particle size distribution is normal, and the proportion of the microspheres with 10-45 um is about 82%.
Example 7
S1, 2.2461g of glutamic acid hydrochloride is dissolved in 60mL of deionized water, and then 1.264g of calcium chloride, 0.900g of diammonium phosphate, 3.60g of urea and 1600mg of disodium ethylenediamine tetraacetate are sequentially added to obtain a reaction solution;
s2, adjusting the pH value of the reaction solution to 1.00-4.00 by HNO 3/ammonia water;
S3, continuously stirring the reaction solution with the pH value adjusted for 30min, then transferring the reaction solution into a hydrothermal reaction kettle, placing the reaction solution into a blast drying oven with the temperature raised to 180 ℃ for reaction for 2h, and naturally cooling the reaction solution to room temperature after the reaction is finished;
S4, filtering and collecting a precipitated product, repeatedly washing the product by adopting purified water until the product is neutral, and then drying the product in an oven at 80 ℃ until the weight is constant, thus obtaining the hydroxyapatite microsphere.
The optical microscopic image and the scanning electron microscopic image of the hydroxyapatite microsphere prepared in the embodiment are shown in fig. 7A to B, and can be seen from the figures: the pore size of the microspheres was reduced by increasing the disodium edetate concentration compared to example 6.
The X-ray diffraction diagram of the hydroxyapatite microsphere prepared in this example is shown in fig. 7C, and it can be seen from the figure: the obtained microspheres are in one-to-one correspondence with XRD diffraction characteristic peaks of HAP, which indicates that the synthesized microspheres are typical HAP phase materials.
The particle size distribution diagram of the hydroxyapatite microsphere prepared in the embodiment is shown in fig. 7D, and can be seen from the figure: the particle size distribution is normal, and the proportion of the 2-20 um microsphere is about 96%.
Example 8
The hydroxyapatite microspheres prepared in example 6 were mixed with hyaluronic acid gel at a mass ratio of 35:18, injected into the rat subcutaneous, and samples were taken at 4 weeks for section staining.
The Masson staining results are shown in fig. 8A, from which it can be seen: collagen deposition increases.
The H & E staining results are shown in fig. 8B, from which it can be seen: local cell increase.
The above results indicate that: the porous hydroxyapatite microsphere prepared by the invention can be combined with hyaluronic acid gel to well stimulate the regeneration of collagen.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (9)
1. The preparation method of the hydroxyapatite microsphere is characterized by comprising the following steps:
S1, dissolving a chelating agent, a calcium source, a phosphorus source and urea in water to obtain a reaction solution;
wherein the chelating agent is any one of the following components:
glutamic acid and disodium ethylenediamine tetraacetate;
(ii) glutamate and disodium edetate;
(iii) glutamic acid and sodium citrate;
(iv) glutamate and sodium citrate;
(v) aspartic acid, disodium ethylenediamine tetraacetate;
(VI) aspartate and disodium ethylenediamine tetraacetate;
(vii) aspartic acid, sodium citrate;
(VIII) aspartate and sodium citrate
S2, regulating the pH value of the reaction solution to 1.00-4.00;
S3, transferring the reaction solution with the pH value adjusted into a hydrothermal reaction kettle, and placing the reaction solution into a temperature of 90-250 ℃ for reaction;
and S4, after the reaction is finished, collecting a precipitate, cleaning the precipitate to be neutral, and drying the precipitate to obtain the hydroxyapatite microsphere.
2. The method of claim 1, wherein in step S1, the molar ratio of the calcium source to the phosphorus source is 1.2-2:1.
3. The method of claim 1, wherein in step S1, the calcium source is a soluble calcium salt and the phosphorus source is a soluble phosphate salt.
4. A method of preparing hydroxyapatite microspheres according to claim 3, wherein the soluble calcium salt comprises: ca (one or more of NO 3)2·4H2O、CaCl2·2H2O、CaCl2), the soluble phosphate salt including one or more of ：(NH4)2HPO4、(NH4)H2PO4、Na2HPO4、NaH2PO4、K2HPO4、KH2PO4.
5. The method according to claim 1, wherein in the step S1, the molar concentration of the calcium source is 0.02 to 0.22mol/L, the molar concentration of the phosphorus source is 0.02 to 0.11mol/L, and the molar concentration of the urea is 0.67 to 1.67mol/L.
6. The method for preparing hydroxyapatite microspheres according to claim 1, wherein in step S2, the acid used for adjusting the pH is one or more of nitric acid, hydrochloric acid or sulfuric acid, and the base used is one or more of ammonia water or caustic soda solution.
7. A hydroxyapatite microsphere prepared by the method of any one of claims 1 to 6.
8. Use of hydroxyapatite microspheres according to claim 7 in the field of regenerative filler material, wherein said hydroxyapatite microspheres are implanted subcutaneously in combination with hyaluronic acid gel.
9. A reclaimed filler, comprising: the hydroxyapatite microsphere and hyaluronic acid gel of claim 7.
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