CN110885070B - 一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料及其制备方法与应用 - Google Patents
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料及其制备方法与应用 Download PDFInfo
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- CN110885070B CN110885070B CN201911180579.3A CN201911180579A CN110885070B CN 110885070 B CN110885070 B CN 110885070B CN 201911180579 A CN201911180579 A CN 201911180579A CN 110885070 B CN110885070 B CN 110885070B
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- hydroxyapatite
- porous microsphere
- anhydrous calcium
- calcium
- mixed solution
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- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 118
- 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 118
- 239000004005 microsphere Substances 0.000 title claims abstract description 106
- 239000000463 material Substances 0.000 title claims abstract description 76
- 239000011575 calcium Substances 0.000 title claims abstract description 68
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229910052791 calcium Inorganic materials 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000002245 particle Substances 0.000 claims abstract description 7
- 239000011259 mixed solution Substances 0.000 claims description 66
- 230000002051 biphasic effect Effects 0.000 claims description 41
- 159000000007 calcium salts Chemical class 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 34
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 25
- 238000010899 nucleation Methods 0.000 claims description 25
- 230000006911 nucleation Effects 0.000 claims description 25
- 239000012716 precipitator Substances 0.000 claims description 23
- 150000003017 phosphorus Chemical class 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 19
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 16
- 238000001027 hydrothermal synthesis Methods 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 11
- 239000004202 carbamide Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 9
- 229910019142 PO4 Inorganic materials 0.000 claims description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 9
- 239000010452 phosphate Substances 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 claims description 6
- 229910001866 strontium hydroxide Inorganic materials 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 5
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 5
- 239000004254 Ammonium phosphate Substances 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims description 4
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 claims description 4
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 4
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 4
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 4
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 claims description 4
- 235000019837 monoammonium phosphate Nutrition 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 4
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 4
- DHEQXMRUPNDRPG-UHFFFAOYSA-N strontium nitrate Chemical compound [Sr+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O DHEQXMRUPNDRPG-UHFFFAOYSA-N 0.000 claims description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
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- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- -1 diamine hydrogen phosphate Chemical class 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 239000002667 nucleating agent Substances 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 229910001631 strontium chloride Inorganic materials 0.000 claims description 2
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 abstract description 18
- 230000015556 catabolic process Effects 0.000 abstract description 17
- 238000006731 degradation reaction Methods 0.000 abstract description 17
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- LFULEKSKNZEWOE-UHFFFAOYSA-N propanil Chemical compound CCC(=O)NC1=CC=C(Cl)C(Cl)=C1 LFULEKSKNZEWOE-UHFFFAOYSA-N 0.000 description 30
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- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 10
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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
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- C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
- A61L27/425—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of phosphorus containing material, e.g. apatite
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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
- A61L27/50—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
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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
- C01P2002/00—Crystal-structural characteristics
- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/82—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
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Abstract
本发明公开一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料及其制备方法与应用,由质量分数10%~90%的无水磷酸氢钙和质量分数90%~10%羟基磷灰石以共存的形式构成的颗粒微球,颗粒直径为15~65μm,表面多孔,孔径尺寸范围为1~50μm,孔隙率为33%~65.34%,由水热沉淀法制成;本发明无水磷酸氢钙/羟基磷灰石双相多孔微球材料具有较好的生物相容性、生物矿化能力以及较短的降解周期,较高的孔隙尺寸及孔隙率,是较为理想的生物医用材料,用于构建骨组织工程支架或作为作抗生素、抗结核化合物、生长因子、抗肿瘤剂等的缓释载体。
Description
技术领域
本发明涉及一种具有良好的生物相容性和生物矿化能力,较高的孔隙尺寸及孔隙率,由无水磷酸氢钙(DCPA)和羟基磷灰石(HAP)双相共存形成的表面呈多孔结构的类球形微球材料及其制备方法与应用,本发明制备的双相多孔微球可广泛用作制备骨组织工程支架的原料,或用作抗生素、抗结核化合物、生长因子、抗肿瘤剂等的缓释载体,属于生物材料领域。
背景技术
生物医用陶瓷中的典型材料是羟基磷灰石(HAP),其化学式为Ca10(PO4)6(OH)2,属于六方晶系,空间群P63/m。由于其成分接近人骨中的无机质,在临床上表现出良好的生物活性和骨传导性,因而常用于骨组织创伤、缺损、感染等的修复。但HAP本身的晶型结构稳定、结晶程度高反而导致人体对其的降解吸收过慢,骨组织修复的周期延长,特别是材料在移植早期表现出较差的生物矿化能力。相比于HAP,无水磷酸氢钙(CaHPO4,DCPA)表现出良好的生物相容性和生物矿化能力,能够被人体快速吸收,是可降解类的新型生物陶瓷。但同样也是由于其降解较快,不利于维持固有的形貌及强度优势,因而很少将DCPA单独使用,DCPA同时也是固相合成HAP的原料,液相沉淀法能通过水解反应转变为HAP,为制备DCPA/HAP共存的双相晶须提供了可行性,利用其共存结构能够互补DCPA、HAP两相的缺点,使双相材料具有更优异的生物学性能。HAP一般为纳米棒、晶须或无规粉体,DCPA多为片层状结构。
依据水解反应原理,制备DCPA/HAP双相陶瓷的方法主要为均相沉淀法,均相沉淀法合成的多为双相晶须以及晶须组装成的“束串”而非微球,另外均相沉淀法的可调控温度范围低且反应时间过长,导致工艺重复性和产品形貌稳定性都较差。
发明内容
本发明提供一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料及其制备方法与应用,为骨组织修复用支架以及细胞或药物缓释提供一种原料或载体;DCPA/HAP双相多孔微球所具备的优势是DCPA、HAP综合表现出的良好生物相容性、生物矿化能力和较短的降解周期,微球表面的多孔结构及其可调控的特色形貌;通过调控钙盐/磷盐的摩尔浓度比、沉淀剂及促形核剂用量、水热反应温度和时间等调控双相多孔微球的相组成、颗粒尺寸、表面形貌、孔隙大小以及孔隙率,制成的DCPA/HAP双相多孔微球的生物学表现及物理结构能够满足甚至优于骨组织工程支架对原料以及细胞或药物缓释对载体的要求。
本发明提供一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,由质量分数10%~90%的无水磷酸氢钙(DCPA)和质量分数90%~10%羟基磷灰石(HAP)以共存的形式构成的颗粒微球,微球呈类球形,颗粒直径为15~65μm,表面多孔,孔径尺寸范围为1~50μm,孔隙率为33%~65.34%。
本发明还提供所述无水磷酸氢钙/羟基磷灰石双相多孔微球材料的制备方法,具体步骤如下:配置钙盐、磷盐、沉积剂的混合液,调节混合液的pH值为2~4.5,将混合溶液装入反应釜进行水热反应,水热反应产物进行洗清及干燥后得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料。
所述混合液中钙盐的浓度为0.01~2 mol/L,磷盐的浓度为0.01~1.85 mol/L,沉淀剂的浓度为0.2~3.5mol/L。
所述钙盐为氯化钙、硝酸钙、氢氧化钙、磷酸氢钙、碳酸钙中的一种或几种任意比例混合;磷盐为磷酸二氢类(如磷酸二氢钠、磷酸二氢钾、磷酸二氢铵)、磷酸氢类(如磷酸氢二钠、磷酸氢二钾、磷酸氢二胺)、磷酸类(如磷酸钠、磷酸钾、磷酸铵、磷酸)中的一种或几种任意比例混合;沉淀剂为尿素、乙酰胺、质量分数25~28%的浓氨水中的一种或几种任意比例混合。
所述混合液中还加入促形核剂,促形核剂为钙盐摩尔量的0.04%~30%,促形核剂为锶、镁的硝酸盐、氯化盐、氢氧化盐几种任意比例混合。
所述混合液的pH值使用质量分数86~97.5%的浓硝酸、质量分数36~38%的浓盐酸或质量分数25~28%的浓氨水进行调节。
所述混合溶液加入量为反应釜有效容积的40%~85%。
所述水热反应温度为50~150ºC,反应时间为6~72h,反应釜内自压为0.01~3MPa。
本发明还提供所述无水磷酸氢钙/羟基磷灰石双相多孔微球材料在作为骨组织修复用支架胞或药物缓释载体上的应用。
本发明的有益效果:
1、本发明无水磷酸氢钙/羟基磷灰石双相多孔微球在37±1℃、pH = 7.40±0.02的模拟人体体液(simulated body fluid)中浸泡7天即可诱导磷灰石形核沉积,与HAP单相长达28天的诱导沉积期相比,DCPA相有助于改善材料的的生物矿化能力;
2、本发明无水磷酸氢钙/羟基磷灰石双相多孔微球在37±1℃、pH = 7.00±0.02的生理盐水中降解期为8~15周;在37±1℃、pH = 7.40±0.02的模拟人体体液(simulatedbody fluid)环境下的降解周为10~17周;表现出较好的降解性;
3、人胚胎肾上皮细胞(HEK293T)、小鼠胚胎成骨细胞前体细胞(MC3T3-E1细胞)以及猴骨髓间充质干细胞(mBMSC)在浓度为0.05~0.3g/mL的无水磷酸氢钙/羟基磷灰石双相多孔微球的浸提液浸泡后,其相应细胞相对增值度(RGR)均大于90%,双相多孔微球无细胞毒性,部分样品对细胞增殖有一定的促进作用;
4、本发明无水磷酸氢钙/羟基磷灰石双相多孔微球在浓度为2μg/mL到20μg/mL的庆大霉素、盐酸阿霉素、异烟肼、骨形态发生蛋白(BMP)、贝利司他等药物溶液中的载药量为22%~95%,包封率为92%~26%;同时,相应药物在192h的水浴震荡下其累计释放量为82%~93%;前期突释的时间节点为:20~120h,释放量达40%~85%;药物缓慢释放后的平均释放速度速率为:0.5~ 3.5μg/h;
5、本发明无水磷酸氢钙/羟基磷灰石双相多孔微球具有较高的振实密度,相比于HAP或DCPA单相,作为骨组织工程支架的原料能提供额外的强度支持,更重要的是,微球表面呈多孔结构,这些由针刺状、片层状DCPA/HAP双相堆叠、组装形成孔隙具有以下作用或优势:(1)增加与体液的接触面积,从而缩短磷灰石沉积期,进而加快生物矿化过程及降解吸收速率;(2)便于骨组织工程中种子细胞、生长因子及营养物质的储存、传输与排放;(3)可调控的孔径尺寸及孔隙率使其能作为载药材料,实现缓释的目的。
6、本发明采用水热沉淀法反应快速、低成本以及低能耗等优点,且自生压力对DCPA/HAP双相形核沉淀有促进作用,更为重要的是,水热沉淀合成时的反应温度和反应时间可调控范围广,使得双相多孔微球的表面能呈现“花瓣状”、“海胆状”、“针刺状”的特色形貌结构;水热沉淀制备的双相多孔微球陶瓷表现出良好的生物相容性、较快的生物矿化能力以及较短的降解周期,是构建骨组织工程支架的理想材料,同时具有的高孔隙率、宽孔径范围的孔隙结构,能作为作抗生素、抗结核化合物、生长因子、抗肿瘤剂等的载体,未来能在骨修复、抗菌缓释以及癌症治疗方面广泛应用。
附图说明
图1为实施例1的无水磷酸氢钙/羟基磷灰石双相多孔微球材料的XRD图谱;
图2为实施例1的无水磷酸氢钙/羟基磷灰石双相多孔微球材料的SEM;
图3为实施例2的无水磷酸氢钙/羟基磷灰石双相多孔微球材料的XRD图谱;
图4为实施例2的无水磷酸氢钙/羟基磷灰石双相多孔微球材料的SEM;
图5为实施例3的无水磷酸氢钙/羟基磷灰石双相多孔微球材料的FT-IR图谱;
图6为实施例3的无水磷酸氢钙/羟基磷灰石双相多孔微球材料的SEM;
图7为HEK293T细胞、MC3T3-E1细胞以及mBMSC细胞在浓度为0.05~0.3g/mL实施例4的无水磷酸氢钙/羟基磷灰石双相多孔微球材料浸提液中培养24h后的细胞相对增值度;
图8为将实施例5的无水磷酸氢钙/羟基磷灰石双相多孔微球材料镶嵌于牙托树脂并置于模拟人体体液(SBF)浸泡后的表面SEM形貌以及磷灰石沉积物的EDS能谱;
图9为实施例6的无水磷酸氢钙/羟基磷灰石双相多孔微球材料在37±1℃、pH=7.40±0.02的SBF和在37±1℃、pH=7.00±0.02的生理盐水(NS)中的降解失重曲线;
图10为以实施例7的无水磷酸氢钙/羟基磷灰石双相多孔微球为原料制备的骨组织工程支架的宏观形貌;
图11为实施例8的无水磷酸氢钙/羟基磷灰石双相多孔微球材料的SEM;
图12为实施例8的无水磷酸氢钙/羟基磷灰石双相多孔微球材料分别在庆大霉素、盐酸阿霉素溶液不同浓度下的载药量和包封率;
图13为实施例9的无水磷酸氢钙/羟基磷灰石双相多孔微球材料分别装载庆大霉素、异烟肼、盐酸阿霉素后在PBS缓冲液下的累积释放曲线。
具体实施方式
以下实施例是针对本发明的制备方法和特征所展开的一系列详细描述,不能凭此理解为是对本发明权利要求的限制。还需指出的是,在不脱离本发明构思的前提下所做出的若干替换和改进,都属于本发明的保护范围。
实施例1
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,具体制备步骤如下:
(1)配置钙盐、磷盐、沉积剂及促形核剂的混合液;选用的钙盐为硝酸钙和氯化钙按照质量比1:1混合,混合液中钙盐的浓度为0.05mol/L;磷盐为磷酸二氢钾和磷酸二氢钠按照质量比1:1混合,混合液中磷盐的浓度为0.03mol/L;沉淀剂为质量分数25~28%的浓氨水,混合液中氨的浓度0.2mol/L;
(2)选用质量分数86~97.5%的浓硝酸将步骤(1)的混合液pH值调至2.5;
(3)将步骤(2)的混合液装入反应釜中,混合液占反应釜有效容积的70%,进行水热反应,水热反应温度为75ºC,反应时间为12h,反应釜自压为0.05 MPa;
(4)步骤(3)合成产物用去离子水在室温下多次洗涤至中性,60℃烘干,得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料。
图1为实施例1的无水磷酸氢钙/羟基磷灰石双相多孔微球材料的XRD图谱;从图中可以看出,双相多孔微球材料的主相为羟基磷灰石(HAP),第二相为无水磷酸氢钙(DCPA),半定量分析表明双相多孔微球中HAP的质量分数为81.04%,无水磷酸氢钙的质量分数为18.96%。
图2为实施例1的无水磷酸氢钙/羟基磷灰石双相多孔微球材料的SEM;从图中可知双相多孔微球的微球尺寸的典型尺寸为35μm,表面结构具有“花瓣状”特殊形貌,花瓣间的孔隙尺寸范围为1~10μm。
实施例2
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,具体制备步骤如下:
(1)配置钙盐、磷盐、沉积剂及促形核剂的混合液;选用的钙盐为硝酸钙,混合液中钙盐的浓度为0.167mol/L;磷盐为磷酸氢二胺,混合液中磷盐的浓度为0.1mol/L;沉淀剂为尿素,混合液中尿素的浓度0.7mol/L,促形核剂为硝酸锶,添加量为钙盐摩尔量的20%;
(2)选用质量分数25~28%的浓氨水将步骤(1)的混合液pH值调至3;
(3)将步骤(2)的混合液装入反应釜中,混合液占反应釜有效容积的40%,进行水热反应,水热反应温度为95ºC,反应时间为24h,反应釜自压为0.01MPa;
(4)步骤(3)合成产物用去离子水在室温下多次洗涤至中性,60℃烘干,得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料。
图3为实施例2的无水磷酸氢钙/羟基磷灰石双相多孔微球的XRD图谱;从图中可以看出,双相多孔微球材料的主相为羟基磷灰石(HAP),第二相为无水磷酸氢钙(DCPA),半定量分析表明双相多孔微球中HAP的质量分数为80.92%,无水磷酸氢钙的质量分数为19.08%,促形核剂的的加入导致XRD衍射峰嘲小角度方向移动且峰型宽化。
图4为实施例2的无水磷酸氢钙/羟基磷灰石双相多孔微球的SEM;从图中可知双相多孔微球的微球尺寸的尺寸范围为15~25μm,表面结构具有“花瓣状”特殊形貌,花瓣间的孔隙尺寸范围为5~10μm;悬重法测量的孔隙率为33.45%。
实施例3
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,具体制备步骤如下:
(1)配置钙盐、磷盐、沉积剂及促形核剂的混合液;选用的钙盐为氢氧化钙和磷酸氢钙质量比1:1混合,混合液中钙盐的浓度为2mol/L;磷盐为磷酸和磷酸铵质量比1:1混合,混合液中磷盐的浓度为1.25mol/L;沉淀剂为尿素,混合液中尿素的浓度2.5mol/L,促形核剂为氯化镁和氯化锶,添加量分别为钙盐摩尔量的0.01%和0.03%;
(2)选用质量分数86~97.5%的浓硝酸将步骤(1)的混合液pH值调至2;
(3)将步骤(2)的混合液装入反应釜中,混合液占反应釜有效容积的50%,进行水热反应,水热反应温度为50ºC,反应时间为72h,反应釜自压为1.25MPa;
(4)步骤(3)合成产物用去离子水在室温下多次洗涤至中性,70℃烘干,得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料,由质量分数90%的无水磷酸氢钙(DCPA)和质量分数10%的羟基磷灰石(HAP)以共存的形式构成。
图5为实施例3的无水磷酸氢钙/羟基磷灰石双相多孔微球的FT-IR图谱;从图中可知,双相多孔微球材料主要具有OH-基团、PO4 3-基团、HPO4-基团以及CO3 2-基团的特征峰,HPO4-基团特征峰间接证实合成材料含有DCPA相,存在CO3 2-基团则表明HAP相中部分OH-被取代,它源于尿素分解产物CO2的局部溶解,引入CO3 2-基团使得DCPA/HAP双相表面多孔微球的阴离子端更接近人体骨组织中的无机成分。
图6为实施例3的无水磷酸氢钙/羟基磷灰石双相多孔微球的SEM;从图中可知双相多孔微球的微球尺寸的特征形貌为“刺球”,微球尺寸约35~65μm,表面孔隙是针刺状的DCPA/HAP双相以“发射状”自主装而成,孔隙尺寸为5~50μm;悬重法测量的孔隙率为65.34%。
实施例4
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,具体制备步骤如下:
(1)配置钙盐、磷盐、沉积剂及促形核剂的混合液;选用的钙盐为磷酸氢钙和碳酸钙质量比1:1混合,混合液中钙盐的浓度为0.01mol/L;磷盐为磷酸氢二钾、磷酸二氢钠和磷酸质量比1:1:1混合,混合液中磷盐的浓度为0.01mol/L;沉淀剂为乙酰胺,混合液中乙酰胺的浓度1.15mol/L,促形核剂为氢氧化锶,添加量为钙盐摩尔量的10%;
(2)选用质量分数25~28%的浓氨水将步骤(1)的混合液pH值调至4.5;
(3)将步骤(2)的混合液装入反应釜中,混合液占反应釜有效容积的85%,进行水热反应,水热反应温度为130ºC,反应时间为20h,反应釜自压为3MPa;
(4)步骤(3)合成产物用去离子水在室温下多次洗涤至中性,80℃烘干,得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料,由质量分数10%的无水磷酸氢钙(DCPA)和质量分数90%的羟基磷灰石(HAP)以共存的形式构成。
实施例4制备的无水磷酸氢钙/羟基磷灰石双相多孔微球材料分别采用人胚胎肾上皮细胞(HEK293T)、小鼠胚胎成骨细胞前体细胞(MC3T3-E1细胞)以及猴骨髓间充质干细胞(mBMSC)测试其的细胞毒性,双相多孔微球的浸提液浓度为0.05、0.1、0.2和0.3g/mL,上述细胞在浸提液中的培养时间为24h,相对增殖度(RGR)结果见图7,由图可知,HEK293T、MC3T3-E1和mBMSC三种细胞的细胞增殖度为83%~112%,整体上均大于80%,根据国家标准GB/T14233.2-2005,双相多孔微球材料的细胞毒性反应等级均为0或1级,可视为无毒,材料具有良好的生物相容性。
实施例5
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,具体制备步骤如下:
(1)配置钙盐、磷盐、沉积剂及促形核剂的混合液;选用的钙盐为氯化钙,混合液中钙盐的浓度为0.167mol/L;磷盐为磷酸氢二钾和磷酸氢二钠质量比1:1混合,混合液中磷盐的浓度为0.1mol/L;沉淀剂为尿素,混合液中尿素的浓度1mol/L,促形核剂氢氧化锶和硝酸镁,添加量分别为钙盐摩尔量的20%和5%;
(2)选用质量分数86~97.5%的浓硝酸将步骤(1)的混合液pH值调至3.55;
(3)将步骤(2)的混合液装入反应釜中,混合液占反应釜有效容积的80%,进行水热反应,水热反应温度为110ºC,反应时间为36h,反应釜自压为1.55MPa;
(4)步骤(3)合成产物用去离子水在室温下多次洗涤至中性,75℃烘干,得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料,由质量分数20%的无水磷酸氢钙(DCPA)和质量分数80%的羟基磷灰石(HAP)以共存的形式构成。
将实施例5制备的无水磷酸氢钙/羟基磷灰石双相多孔微球材料镶嵌于牙托树脂中,并用1000# SiC砂纸打磨多余粉体,再将其置于37±1℃、pH = 7.40±0.02的模拟人体体液(SBF)中浸泡,样品浸泡3天、7天后和14天后的表面形貌见图8,由图可知,双相多孔微球材料在SBF浸泡7天后表面开始出现明显的磷灰石沉积物,沉积的磷灰石为类球形颗粒,尺寸约5~15μm,浸泡到14天时,沉积物明显增多且覆盖于整个双相多孔微球材料表面,经EDS检测,浸泡7天和14天后沉积的磷灰石其Ca/P摩尔比分别为1.48和1.55,小于1.67,为钙不足型碳酸羟基磷灰石,双相多孔微球陶瓷材料能在7天内快速诱导磷灰石形核沉积,表现出较好的生物矿化能力。
实施例6
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,具体制备步骤如下:
(1)配置钙盐、磷盐、沉积剂及促形核剂的混合液;选用的钙盐为硝酸钙,混合液中钙盐的浓度为1.67mol/L;磷盐为磷酸和磷酸二氢钾质量比1:1混合,混合液中磷盐的浓度为1mol/L;沉淀剂为质量分数25~28%的浓氨水,混合液中氨的浓度2mol/L,促形核剂为氢氧化镁,添加量为钙盐摩尔量的30%;
(2)选用质量分数86~97.5%的浓硝酸将步骤(1)的混合液pH值调至4.25;
(3)将步骤(2)的混合液装入反应釜中,混合液占反应釜有效容积的65%,进行水热反应,水热反应温度为85℃,反应时间为45h,反应釜自压为0.05MPa;
(4)步骤(3)合成产物用去离子水在室温下多次洗涤至中性,70℃烘干,得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料,由质量分数20%的无水磷酸氢钙(DCPA)和质量分数80%的羟基磷灰石(HAP)以共存的形式构成。
将实施例6制备的无水磷酸氢钙/羟基磷灰石双相多孔微球材料分别置于37±1℃、pH=7.40±0.02的SBF和在37±1℃、pH=7.00±0.02的生理盐水(NS)中作浸泡降解实验,粉末与选用浸泡液的比例为50/50mg/mL,浸泡到材料基本完全降解(95%以上),其降解趋势见图9,由图9的降解曲线可知:双相多孔微球材料在生理盐水中的降解期约为13周,快速降解发生于第27~63天;在SBF中的降解期约为15周,快速降解发生于第35~77天,表现出较好的降解性。
实施例7
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,具体制备步骤如下:
(1)配置钙盐、磷盐、沉积剂及促形核剂的混合液;选用的钙盐为碳酸钙,混合液中钙盐的浓度为0.75mol/L;磷盐为磷酸二氢铵,混合液中磷盐的浓度为0.375mol/L;沉淀剂为乙酰胺,混合液中乙酰胺的浓度1.35mol/L,促形核剂为氢氧化锶和氯化镁,添加量分别为钙盐摩尔量的2.5%和4.5%;
(2)选用质量分数86~97.5%的浓硝酸将步骤(1)的混合液pH值调至4;
(3)将步骤(2)的混合液装入反应釜中,混合液占反应釜有效容积的85%,进行水热反应,水热反应温度为150℃,反应时间为6h,反应釜自压为0.01MPa;
(4)步骤(3)合成产物用去离子水在室温下多次洗涤至中性,75℃烘干,得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料,由质量分数18%的无水磷酸氢钙(DCPA)和质量分数82%的羟基磷灰石(HAP)以共存的形式构成。
将实施例7将硅胶、去离子水、酒精按体积比4:3:3配制成混合液,制备好的无水磷酸氢钙/羟基磷灰石双相多孔微球材料与混合液按质量比2:1配制成混合成浆料,采用自主设计的模具将浆料经模具塑形、酒精浸泡、冷冻干燥、中温煅烧(650℃/10h)等步骤制成直通孔规则排列的骨组织工程支架,其宏观形貌如图10所示,将此骨组织工程支架置于0.2KN十字头下,按0.1mm/min的下移速度进行抗压、抗弯试验,测得的抗压强度为5.13±1.42MPa,三点抗弯强度为2.16±0.38Pa。
实施例8
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,具体制备步骤如下:
(1)配置钙盐、磷盐、沉积剂的混合液;选用的钙盐为硝酸钙,混合液中钙盐的浓度为1.25mol/L;磷盐为磷酸二氢铵,混合液中磷盐的浓度为1.85mol/L;沉淀剂为尿素,混合液中尿素的浓度3.5mol/L;
(2)选用质量分数86~97.5%的浓硝酸将步骤(1)的混合液pH值调至2.25;
(3)将步骤(2)的混合液装入反应釜中,混合液占反应釜有效容积的85%,进行水热反应,水热反应温度为65℃,反应时间为30h,反应釜自压为1.75MPa;
(4)步骤(3)合成产物用去离子水在室温下多次洗涤至中性,80℃烘干,得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料,由质量分数10%的无水磷酸氢钙(DCPA)和质量分数90%的羟基磷灰石(HAP)以共存的形式构成。
图11为实施例8的无水磷酸氢钙/羟基磷灰石双相多孔微球的SEM;从图中可知,双相多孔微球的微球尺寸的尺寸范围为15~35μm,表面为“花瓣状”特殊形貌结构,花瓣间的孔隙尺寸范围为3~12μm,平均孔径为8.4μm,悬重法测量的孔隙率为53.38%,BET比表面积为220.37m2/g。
将预先准备好的浓度为100μg/mL的庆大霉素(Gentamicin)、盐酸阿霉素(DOXHCl)溶液分别稀释至2~20μg/mL的浓度梯度,浓度间隔为2μg/mL,每一浓度取20mL与10mg本实施例制备的无水磷酸氢钙/羟基磷灰石双相多孔微球材料混合,在37℃、100rpm速率下水浴震荡24h完成负载,离心后,利用紫外可见分光光度计对上清液进行药物量检测,计算负载量和包封率,其载药结果趋势见图12,由图12可知:DCPA/HAP双相多孔微球对庆大霉素的载药量为30.4%~88.7%,包封率为35.8%~93.2%;对盐酸阿霉素的载药量为47.6%~94.3%,包封率为53.2%~93.4%。
实施例9
一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,具体制备步骤如下:
(1)配置钙盐、磷盐、沉积剂及促形核剂的混合液;选用的钙盐为磷酸氢钙,混合液中钙盐的浓度为1mol/L;磷盐为磷酸铵,混合液中磷盐的浓度为1mol/L;沉淀剂为乙酰胺,混合液中乙酰胺的浓度1.15mol/L,促形核剂为氢氧化锶,添加量为钙盐摩尔量的10%;
(2)选用质量分数25~28%的浓氨水将步骤(1)的混合液pH值调至4.5;
(3)将步骤(2)的混合液装入反应釜中,混合液占反应釜有效容积的68%,进行水热反应,水热反应温度为83ºC,反应时间为7h,反应釜自压为0.05MPa;
(4)步骤(3)合成产物用去离子水在室温下多次洗涤至中性,80℃烘干,得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料,由质量分数80%的无水磷酸氢钙(DCPA)和质量分数20%的羟基磷灰石(HAP)以共存的形式构成。
将实施例9制备的无水磷酸氢钙/羟基磷灰石双相多孔微球材料按照实施例8的方法分别装载庆大霉素(Gentamicin)、异烟肼(Isonizide)、盐酸阿霉素(DOX HCl)药物后,将20mg装载不同药物的无水磷酸氢钙/羟基磷灰石双相多孔微球材料分散于40mL浓度为0.01mol/L的PBS缓冲液中,在37℃、100rpm速率下水浴震荡,按时间节点取样并离心,吸取0.6mL上清液并用紫外分光光度计测其含量,庆大霉素、异烟肼、盐酸阿霉素三种药物在PBS溶液中按时间节点的释放量见图13,由图可知,庆大霉素的前期突释时间节点为:48h,释放量达67.68%,从36h开始到 192h,药物缓慢释放,平均释放速度速率为:2.62μg/h,最终释放量为88.17%;异烟肼的前期突释时间节点为:96h,释放量达80.22%,从96h开始到 192h,药物缓慢释放,平均释放速度速率为:1.92μg/h,最终释放量为89.46%;盐酸阿霉素的前期突释时间节点为:36h,释放量达83.33%,从36h开始到 192h,药物缓慢释放,平均释放速度速率为:0.85μg/h,最终释放量为89.46%。
Claims (6)
1.一种无水磷酸氢钙/羟基磷灰石双相多孔微球材料,由质量分数10%~90%的无水磷酸氢钙和质量分数90%~10%羟基磷灰石以共存的形式构成的颗粒微球,表面多孔;
所述无水磷酸氢钙/羟基磷灰石双相多孔微球材料的制备方法的具体步骤如下:配置钙盐、磷盐、沉积剂、促形核剂的混合液,调节混合液的pH值为2~4.5,将混合溶液装入反应釜进行水热反应,水热反应产物进行洗清、干燥后得到无水磷酸氢钙/羟基磷灰石双相多孔微球材料;
混合液中还加入促形核剂,促形核剂为钙盐摩尔量的0.04%~30%,促形核剂为硝酸锶、硝酸镁、氯化锶、氯化镁、氢氧化锶、氢氧化镁中的一种或几种任意比例混合;
水热反应温度为50~150℃,反应时间为6~72h,压力为0.01~3MPa。
2.根据权利要求1所述无水磷酸氢钙/羟基磷灰石双相多孔微球材料,其特征在于,混合液中钙盐的浓度为0.01~2mol/L,磷盐的浓度为0.01~1.85mol/L,沉淀剂的浓度为0.2~3.5mol/L。
3.根据权利要求1所述无水磷酸氢钙/羟基磷灰石双相多孔微球材料,其特征在于,钙盐为氯化钙、硝酸钙、氢氧化钙、磷酸氢钙、碳酸钙中的一种或几种任意比例混合;磷盐为磷酸二氢钠、磷酸二氢钾、磷酸二氢铵、磷酸氢二钠、磷酸氢二钾、磷酸氢二胺、磷酸钠、磷酸钾、磷酸铵、磷酸中的一种或几种任意比例混合;沉淀剂为尿素、乙酰胺、质量分数25~28%的浓氨水中的一种或几种任意比例混合。
4.根据权利要求1所述无水磷酸氢钙/羟基磷灰石双相多孔微球材料,其特征在于,混合液的pH值使用质量分数86~97.5%的浓硝酸、质量分数36~38%的浓盐酸或质量分数25~28%的浓氨水进行调节。
5.根据权利要求1所述无水磷酸氢钙/羟基磷灰石双相多孔微球材料,其特征在于,混合溶液加入量为反应釜有效容积的40%~85%。
6.权利要求1所述无水磷酸氢钙/羟基磷灰石双相多孔微球材料在作为药物缓释载体上的应用。
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