CN107140617A - 一种单分散多孔羟基磷灰石微球、制备方法及其应用 - Google Patents
一种单分散多孔羟基磷灰石微球、制备方法及其应用 Download PDFInfo
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- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 84
- 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 65
- 239000004005 microsphere Substances 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000011575 calcium Substances 0.000 claims abstract description 28
- 229920000642 polymer Polymers 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002131 composite material Substances 0.000 claims abstract description 21
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 8
- 239000011574 phosphorus Substances 0.000 claims abstract description 8
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 10
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- JSAIENUMNDAGTD-UHFFFAOYSA-N benzene ethene styrene Chemical compound C1=CC=CC=C1.C=C.C=C.C=CC1=CC=CC=C1 JSAIENUMNDAGTD-UHFFFAOYSA-N 0.000 claims description 5
- 229920001577 copolymer Polymers 0.000 claims description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000090 biomarker Substances 0.000 claims description 3
- 229920001519 homopolymer Polymers 0.000 claims description 3
- 238000001354 calcination Methods 0.000 claims description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical group [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 39
- 239000002245 particle Substances 0.000 description 33
- 239000011148 porous material Substances 0.000 description 17
- 238000000034 method Methods 0.000 description 12
- 238000009826 distribution Methods 0.000 description 10
- 229920000620 organic polymer Polymers 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229920002454 poly(glycidyl methacrylate) polymer Polymers 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
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- 239000011805 ball Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical compound CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011806 microball Substances 0.000 description 1
- 238000000593 microemulsion method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000278 osteoconductive effect Effects 0.000 description 1
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[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 VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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Abstract
本发明公开了一种单分散多孔羟基磷灰石微球、制备方法及其应用,其中制备方法包括步骤:包括以下步骤:(1)在水中引入多孔高分子微球,均匀分散后,边搅拌边加入碱,调节PH=10‑11,得溶液A;(2)在水中引入钙源和磷源,得溶液B;(3)向溶液A中逐步滴加溶液B,滴加完后继续反应,得溶液C;(4)过滤溶液C,洗涤、干燥后得高分子‑羟基磷灰石复合微球;(5)将所述高分子‑羟基磷灰石复合微球煅烧,得多孔羟基磷灰石微球。该羟基磷灰石微球粒径可控,粒径尺寸均一,孔径可控,制备工艺简单,反应条件容易控制。适于大规模生产,能够广泛应用于生物分离和组织工程等领域。
Description
技术领域
本发明涉及羟基磷灰石微球技术领域,具体涉及一种单分散多孔羟基磷灰石微球、制备方法及其应用。
背景技术
羟基磷灰石作为一种理想的骨修复材料,主要存在于人体骨骼、牙齿等硬组织当中,是其重要的无机组成部分,具有良好的骨传导性、生物活性以及生物相容性等优点。多孔结构的羟基磷灰石微球由于具有相对密度低、比表面积高、重量轻等特点而在组织工程和药物分离等领域有着广泛的应用。
目前制备羟基磷灰石微球的方法主要有微乳液法和喷雾干燥法。中国专利(申请号200910104114.x)公开了一种纳米羟基磷灰石/聚乳酸复合微球的制备方法,采用超声波共混复合工艺和乳化-溶剂挥发法制备纳米羟基磷灰石微球。中国专利(申请号201580022238.7)公开了一种球形多孔羟基磷灰石吸附剂及其方法,其方法为先制备羟基磷灰石初级颗粒的悬浮液,然后将羟基磷灰石初级颗粒的悬浮液进行喷雾干燥,获得羟基磷灰石微球,最后进行复杂的筛分方法进行分级处理得到球形羟基磷灰石。
当前制备羟基磷灰石微球的方法存在很多问题,如:微球的粒径分布不均、产率低和制备工艺复杂等。因此,开发新型的、能工业化生产的羟基磷灰石微球的制备方法是当今研究急需解决的问题。
发明内容
本发明要解决的技术问题是克服现有技术的缺陷,提供一种单分散多孔羟基磷灰石微球、制备方法及其应用,根据本发明实施例中的单分散多孔羟基磷灰石微球粒径可控,粒径尺寸均一,孔径可控。
为解决上述技术问题,本发明采用的技术方案是:
根据本发明第一方面实施例的一种单分散多孔羟基磷灰石微球制备方法,包括以下步骤:
(1)在水中引入多孔高分子微球,均匀分散后,边搅拌边加入碱,调节PH=10-11,得溶液A;
(2)在水中引入钙源和磷源,得溶液B;
(3)向溶液A中逐步滴加溶液B,滴加完后继续反应,得溶液C;
(4)过滤溶液C,洗涤、干燥后得高分子-羟基磷灰石复合微球;
(5)将所述高分子-羟基磷灰石复合微球煅烧,得多孔羟基磷灰石微球。
优选地,所述钙源为Ca(NO3)2·4H2O,所述磷源为(NH4)2HPO4。
优选地,所述钙源和磷源中,Ca:P=1-3。进一步优选地,所述Ca:P=1.67。
优选地,所述碱选自氨水、氢氧化钠、氢氧化钾、三乙胺或三甲胺中的一种或多种。进一步优选地,所述碱为氨水。
优选地,所述多孔高分子微球选自苯乙烯-二乙烯基苯共聚物、苯乙烯均聚物或聚甲基丙烯酸缩水甘油酯中的一种。
优选地,步骤(3)中继续反应的温度为25-100℃,继续反应时间为10h以上。
优选地,步骤(5)中煅烧温度为500-1000℃。
根据本发明第二方面实施例的一种单分散多孔羟基磷灰石微球,所述微球由上述单分散多孔羟基磷灰石微球制备方法制备而得。
本发明的还包括单分散多孔羟基磷灰石微球在生物分离、生物标记和组织工程中的应用。
本发明上述技术方案的有益效果如下:
根据本发明实施例方法,其制备工艺简单,反应条件容易控制。适于大规模生产,且制得的单分散多孔羟基磷灰石微球的粒径可控,粒径尺寸均一,孔径灵活可控,孔径尺寸范围为0.5-800nm,且孔分布均匀,孔道结构有序。本发明实施例的单分散多孔羟基磷灰石微球在生物分离、生物标记和组织工程中有广泛应用。
附图说明
图1为本发明实施例的单分散多孔羟基磷灰石微球的电镜照片。
具体实施方式
下面结合具体实施例对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案,而不能以此来限制本发明的保护范围。
根据本发明实施例的单分散多孔羟基磷灰石微球制备方法,若无特别说明,所使用的“水”包括蒸馏水或去离子水,所述使用的多孔高分子微球可由商业手段购买的到,或由本领域技术人员所熟知的方法制备而得。对于本发明实施例所使用的其他试剂,如氨水、钙源、磷源等,若无特殊说明均指本领域常用规格的试剂类别。
此外,根据本发明实施例的方法制备的单分散多孔羟基磷灰石微球在生物分离中的应用包括但不限于药物分离、蛋白质等生物大分子分离。
如图1所示,由本发明实施例的方法制备的单分散多孔羟基磷灰石微球的粒径均一。
实施例一
一种单分散多孔羟基磷灰石微球,包括以下步骤:
(1)制备粒径为5μm,CV=3.2%的多孔高分子微球;
(2)将100克多孔高分子微球置于120克水中,边搅拌边加入氨水,使体系调到pH=10-11得溶液A;
(3)称量Ca(NO3)2.4H2O和(NH4)2HPO4溶解在80克水中,按配比Ca:P=1.67,得溶液B;
(4)向A中滴加B,滴加完后继续反应24h,得溶液C;
(5)过滤C,洗涤、干燥后得高分子-羟基磷灰石复合微球;
(6)将高分子-羟基磷灰石复合微球升温至650℃煅烧6小时,去除有机高分子,得多孔羟基磷灰石微球。
步骤(1)中多孔高分子微球为苯乙烯-二乙烯基苯共聚物。
采用Beckman Counter测定其粒径及粒径分布得:粒径大小5μm,CV(coefficientof variation)为3.0%,微球平均孔径孔体积1.0ml/g。
实施例二
一种单分散多孔羟基磷灰石微球,包括以下步骤:
(1)制备粒径为2μm,CV=3.1%的多孔高分子微球;
(2)将50克多孔高分子微球置于70克水中,边搅拌边加入氨水,使体系调到pH=10-11得溶液A;
(3)称量Ca(NO3)2.4H2O和(NH4)2HPO4溶解在50克水中,按配比Ca:P=2.37,得溶液B;
(4)向溶液A中滴加溶液B,滴加完后在70-80℃下,继续反应24h,得溶液C;
(5)过滤溶液C,洗涤、干燥后得高分子-羟基磷灰石复合微球;
(6)将高分子-羟基磷灰石复合微球升温至550℃煅烧6小时,去除有机高分子,得多孔羟基磷灰石微球。
步骤(1)中多孔高分子微球为苯乙烯均聚物。
采用Beckman Counter测定其粒径及粒径分布得:粒径大小2μm,CV(coefficientof variation)为3.0%,微球平均孔径孔体积2.3ml/g。
实施例三
一种单分散多孔羟基磷灰石微球,包括以下步骤:
(1)制备粒径为500μm,CV=3.2%的多孔高分子微球;
(2)将100克多孔高分子微球置于120克水中,边搅拌边加入氨水,使体系调到pH=10-11得溶液A;
(3)称量Ca(NO3)2.4H2O和(NH4)2HPO4溶解在80克水中,按配比Ca:P=1.67,得溶液B;
(4)向溶液A中滴加溶液B,滴加完后在50℃下继续反应24h,得溶液C;
(5)过滤溶液C,洗涤、干燥后得高分子-羟基磷灰石复合微球;
(6)将高分子-羟基磷灰石复合微球升温至800℃煅烧6小时,去除有机高分子,得多孔羟基磷灰石微球。
步骤(1)中多孔高分子微球为苯乙烯-二乙烯基苯共聚物。
采用Beckman Counter测定其粒径及粒径分布得:粒径大小500μm,CV(coefficient of variation)为3.0%,微球平均孔径孔体积2.3ml/g。
将本实施例所制备的单分散多孔羟基磷灰石微球用于吸附蛋白,其生物相容性好,无毒性,且吸附能力强。
实施例四
一种单分散多孔羟基磷灰石微球,包括以下步骤:
(1)制备粒径为800μm,CV=3.8%的多孔高分子微球;
(2)将100克多孔高分子微球置于120克水中,边搅拌边加入氢氧化钠水溶液,使体系调到pH=10-11得溶液A;
(3)称量Ca(NO3)2.4H2O和(NH4)2HPO4溶解在80克水中,按配比Ca:P=1.67,得溶液B;
(4)向溶液A中滴加溶液B,滴加完后在100℃下继续反应24h,得溶液C;
(5)过滤溶液C,洗涤、干燥后得高分子-羟基磷灰石复合微球;
(6)将高分子-羟基磷灰石复合微球升温至650℃煅烧6小时,去除有机高分子,得多孔羟基磷灰石微球。
步骤(1)中多孔高分子微球为苯乙烯-二乙烯基苯共聚物。
采用Beckman Counter测定其粒径及粒径分布得:粒径大小800μm,CV(coefficient of variation)为3.6%,微球平均孔径孔体积1.8ml/g。
实施例五
一种单分散多孔羟基磷灰石微球,包括以下步骤:
(1)制备粒径为10μm,CV=3.0%的多孔高分子微球;
(2)将90克多孔高分子微球置于110克水中,边搅拌边加入氨水,使体系调到pH=10-11得溶液A;
(3)称量Ca(NO3)2.4H2O和(NH4)2HPO4溶解在70克水中,按配比Ca:P=1.67,得溶液B;
(4)向A中滴加B,滴加完后继续反应24h,得溶液C;
(5)过滤C,洗涤、干燥后得高分子-羟基磷灰石复合微球;
(6)将高分子-羟基磷灰石复合微球升温至650℃煅烧6小时,去除有机高分子,得多孔羟基磷灰石微球。
步骤(1)中多孔高分子微球为聚甲基丙烯酸缩水甘油酯。
采用Beckman Counter测定其粒径及粒径分布得:粒径大小10μm,CV(coefficientof variation)为2.9%,微球平均孔径孔体积1.1ml/g。
实施例六
一种单分散多孔羟基磷灰石微球,包括以下步骤:
(1)制备粒径为50μm,CV=2.9%的多孔高分子微球;
(2)将110克多孔高分子微球置于150克水中,边搅拌边加入氨水,使体系调到pH=10-11得溶液A;
(3)称量Ca(NO3)2.4H2O和(NH4)2HPO4溶解在70克水中,按配比Ca:P=1.67,得溶液B;
(4)向A中滴加B,滴加完后继续反应24h,得溶液C;
(5)过滤C,洗涤、干燥后得高分子-羟基磷灰石复合微球;
(6)将高分子-羟基磷灰石复合微球升温至650℃煅烧6小时,去除有机高分子,得多孔羟基磷灰石微球。
步骤(1)中多孔高分子微球为聚甲基丙烯酸缩水甘油酯。
采用Beckman Counter测定其粒径及粒径分布得:粒径大小50μm,CV(coefficientof variation)为3.0%,微球平均孔径孔体积1.0ml/g。
实施例七
一种单分散多孔羟基磷灰石微球,包括以下步骤:
(1)制备粒径为30μm,CV=3.0%的多孔高分子微球;
(2)将90克多孔高分子微球置于110克水中,边搅拌边加入氨水,使体系调到pH=10-11得溶液A;
(3)称量Ca(NO3)2.4H2O和(NH4)2HPO4溶解在70克水中,按配比Ca:P=1.67,得溶液B;
(4)向A中滴加B,滴加完后继续反应20h,得溶液C;
(5)过滤C,洗涤、干燥后得高分子-羟基磷灰石复合微球;
(6)将高分子-羟基磷灰石复合微球升温至650℃煅烧6小时,去除有机高分子,得多孔羟基磷灰石微球。
步骤(1)中多孔高分子微球为聚甲基丙烯酸缩水甘油酯。
采用Beckman Counter测定其粒径及粒径分布得:粒径大小30μm,CV(coefficientof variation)为2.9%,微球平均孔径孔体积1.1ml/g。
实施例八
多孔羟基磷灰石微球对BSA静态吸附载量测试:
取上述实施例六制备的粒径为50um的单分散多孔羟基磷灰石微球40mg,加入6mgBSA以及1.5mL去离子水,在摇床中旋转孵育12小时进行吸附,用紫外分光光度计测试280nm上清液的吸光度。最终获得120mg/g的蛋白吸附载量。
实施例九
多孔羟基磷灰石微球的抗体纯化:
取上述实施例六制备的50um多孔羟基磷灰石微球100mg,装填小柱,将20ml羊血清过柱,先用20mM磷酸盐溶液清洗,然后用200mM磷酸盐溶液洗脱,可以将8mg的抗体和蛋白质完全分离,纯度达98%,收率达96%。
总而言之,本发明实施例的多孔羟基磷灰石微球粒径大小、粒径分布情况及孔径大小受工艺参数:反应温度、搅拌速度、试剂浓度等影响较小,反应调节容易控制,因此本发明方法适于大规模生产,且制得的单分散多孔羟基磷灰石微球的粒径灵活可控,均一度高。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原理的前提下,还可以作出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
1.一种单分散多孔羟基磷灰石微球制备方法,其特征在于,包括以下步骤:
(1)在水中引入多孔高分子微球,均匀分散后,边搅拌边加入碱,调节PH=10-11,得溶液A;
(2)在水中引入钙源和磷源,得溶液B;
(3)向溶液A中逐步滴加溶液B,滴加完后继续反应,得溶液C;
(4)过滤溶液C,洗涤、干燥后得高分子-羟基磷灰石复合微球;
(5)将所述高分子-羟基磷灰石复合微球煅烧,得多孔羟基磷灰石微球。
2.根据权利要求1所述的一种单分散多孔羟基磷灰石微球制备方法,其特征在于,所述钙源为Ca(NO3)2·4H2O,所述磷源为(NH4)2HPO4。
3.根据权利要求1或2所述的一种单分散多孔羟基磷灰石微球制备方法,其特征在于,所述钙源和磷源中,Ca:P=1-3。
4.根据权利要求3所述的一种单分散多孔羟基磷灰石微球制备方法,其特征在于,所述Ca:P=1.67。
5.根据权利要求1所述的一种单分散多孔羟基磷灰石微球制备方法,其特征在于,所述碱选自氨水、氢氧化钠、氢氧化钾、三乙胺或三甲胺中的一种或多种。
6.根据权利要求1所述的一种单分散多孔羟基磷灰石微球制备方法,其特征在于,所述多孔高分子微球选自苯乙烯-二乙烯基苯共聚物、苯乙烯均聚物或聚甲基丙烯酸缩水甘油酯中的一种。
7.根据权利要求1所述的一种单分散多孔羟基磷灰石微球制备方法,其特征在于,步骤(3)中继续反应的温度为25-100℃,继续反应时间为10h以上。
8.根据权利要求1所述的一种单分散多孔羟基磷灰石微球制备方法,其特征在于,步骤(5)中煅烧温度为500-1000℃。
9.一种单分散多孔羟基磷灰石微球,其特征在于,所述微球由权利要求1-8任一项所述的单分散多孔羟基磷灰石微球制备方法制备而得。
10.如权利要求9所述单分散多孔羟基磷灰石微球在生物分离、生物标记和组织工程中的应用。
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