CN116440322A - 一种添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥及其制备方法 - Google Patents
一种添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥及其制备方法 Download PDFInfo
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 title claims abstract description 81
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- ZOMBKNNSYQHRCA-UHFFFAOYSA-J calcium sulfate hemihydrate Chemical compound O.[Ca+2].[Ca+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O ZOMBKNNSYQHRCA-UHFFFAOYSA-J 0.000 description 1
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Abstract
本发明公开了一种添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥及其制备方法，该骨水泥由固相组成物和液相组成物构成，其中固相组成物为α‑磷酸三钙和β‑磷酸三钙，并添加分别由Mg2+、Zn2+、Sr2+、Cu2+和Si4+无机离子掺杂的羟基磷灰石，液相组成物为一水合柠檬酸和十二水合磷酸氢二钠混合水溶液。本发明依据人骨所含微量元素选择五种掺杂羟基磷灰石加入骨水泥，在临床应用中，无机离子随骨水泥的降解释放，能显著促进细胞增殖和新骨生成，缩短治疗时间。
Description
技术领域
本发明涉及一种添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥及其制备方法，属于生物医用材料技术领域。
背景技术
磷酸钙骨水泥的固相由一种或多种磷酸钙粉末组成，这些粉末在与液相混合后形成具有一定粘度的浆体，填入骨缺损部位后能够自凝固并原位硬化，具有生物活性，骨传导性，可注射性和可成型性等优异性能，在骨缺损修复领域具有很大的应用潜力。
磷酸钙骨水泥常见的固相组分是二水合磷酸氢钙(DCPD)、α-磷酸三钙(α-TCP)、β-磷酸三钙(β-TCP)、磷酸四钙(TTCP)和羟基磷灰石(HA)等，常以多种磷酸钙粉末组成固相体系。
目前已经认识到，人骨的正常代谢需要多种微量元素的参与：镁调节骨矿化和骨代谢，促进骨组织生长；锌具有良好的骨诱导性，微量锌还具有一定的抗菌性；锶增强成骨细胞的活性，并抑制破骨细胞的骨吸收作用；铜诱导血管形成，并可促进骨髓间充质干细胞分化；硅可诱导血管形成，并可调控生物矿化过程。若在骨水泥中引入天然人骨所含无机离子，将有助于新骨生成。
在骨修复材料中引入无机离子，近年来的研究主要集中于羟基磷灰石的掺杂。在羟基磷灰石引入微量无机离子，如Mg2+、Zn2+、Sr2+和Cu2+等，可取代羟基磷灰石晶体中的Ca2 +，不影响材料的生物相容性。但是目前的研究多聚焦于单一离子掺杂，如CN202210201997.1公开了一种一步合成铁掺杂羟基磷灰石及其制备方法和应用；也有部分双离子掺杂的研究，如CN202111075908.5涉及一种胶原模板仿生矿化锌锶掺杂羟基磷灰石及其制备方法；多种离子掺杂的研究很少见，专利CN201610127407.X将Si、Sr、F、Mg、Zn、Na、K、Al和C九种元素引入羟基磷灰石中，制备了多元离子共掺杂羟基磷灰石粉体材料。此外，将掺杂羟基磷灰石用作骨水泥固相成分的研究较少，如CN201611036752.9涉及一种具有生物活性和抑菌性的复合骨水泥及制备方法和应用，固相组分由半水硫酸钙和银锶掺杂羟基磷灰石混合组成；Dai J,Fu Y,Chen D,et al.A novel and injectable strontium-containing hydroxyapatite bone cement for bone substitution:A systematicevaluation[J].Materials Science&Engineering C:Materials for BiologicalApplications,2021,124:112052.以α-磷酸三钙和锶掺杂羟基磷灰石为固相制备了一种新型可注射骨水泥。目前现有研究存在以下不足：(1)将掺杂羟基磷灰石应用于骨水泥的研究较少；(2)骨水泥中掺杂离子的种类相对较少，掺杂多种离子主要通过在纯羟基磷灰石中同时引入多种离子源。
发明内容
发明目的：针对上述所述问题，本发明的第一目的是提供一种添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥，本发明的第二目的是提供一种该添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥的制备方法，在骨水泥中引入多种具有促进成骨性能的无机离子，缩短骨缺损修复时间；采用多种无机离子掺杂的羟基磷灰石，有利于维持骨缺损部位的微碱性环境，促进骨缺损修复。
技术方案：本发明所述一种添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥，其特征在于，所述磷酸三钙骨水泥包含固相组成物和液相组成物混合制得；其中，所述固相组成物为α-磷酸三钙(α-TCP)、β-磷酸三钙(β-TCP)和多种掺杂无机离子的羟基磷灰石，所述液相组成物为一水合柠檬酸与十二水合磷酸氢二钠混合水溶液，所述多种掺杂无机离子的羟基磷灰石包括掺杂Mg2+的羟基磷灰石、掺杂Zn2+的羟基磷灰石、掺杂Sr2+的羟基磷灰石、掺杂Cu2+的羟基磷灰石和掺杂Si4+的羟基磷灰石。
进一步地，所述α-磷酸三钙、β-磷酸三钙和多种掺杂无机离子的羟基磷灰石的质量百分比6～3:3～1:1～6，优选3:1:6。
进一步地，所述Mg2+的羟基磷灰石、掺杂Zn2+的羟基磷灰石、掺杂Sr2+的羟基磷灰石、掺杂Cu2+的羟基磷灰石和掺杂Si4+的羟基磷灰石的质量比为83～85:2～4:3～5:1～3:9～11。
进一步地，所述掺杂Mg2+的羟基磷灰石中Mg2+的掺杂摩尔分数为4.5～5.5％，优选5％。
进一步地，所述掺杂Zn2+的羟基磷灰石中Zn2+的掺杂摩尔分数为4.5～5.5％，优选5％。
进一步地，所述掺杂Sr2+的羟基磷灰石中Sr2+的掺杂摩尔分数为3～4％，优选3.2％。
进一步地，所述掺杂Cu2+的羟基磷灰石中Cu2+的掺杂摩尔分数为0.5～1.5％，优选1％。
进一步地，所述掺杂Si4+的羟基磷灰石中Si4+的掺杂摩尔分数为2.5～3.5，优选3％。
进一步地，所述液相组成物中一水合柠檬酸的质量百分比为6～8％，优选7％，十二水合磷酸氢二钠的质量百分比为7～9％，优选8％，余量为水。
进一步地，所述液相组成物和固相组成物的液固比为0.35～0.45mL/g。
本发明所述磷酸三钙骨水泥的制备方法，包括以下步骤：
(1)将α-磷酸三钙、β-磷酸三钙和五种无机离子掺杂羟基磷灰石混合均匀，得到骨水泥固相组成物；
(2)配制一水合柠檬酸与十二水合磷酸氢二钠的混合水溶液，得到骨水泥液相组成物；
(3)将固相组成物与液相组成物混合，调和均匀，得到所述添加多种无机离子掺杂羟基磷灰石的磷酸三钙水泥。
进一步地，步骤(1)中，所述α-磷酸三钙、β-磷酸三钙和五种无机离子掺杂羟基磷灰石通过研磨混合均匀。
进一步地，步骤(2)中，所述混合水溶液的配制方法为室温搅拌溶解。
人骨的无机成分中含有镁、钠、钾、锶、硅、氟、锌、铜等多种不同的微量元素，因此可依据人骨所含微量元素将无机离子引入羟基磷灰石，制备掺杂羟基磷灰石，再将掺杂羟基磷灰石添加到骨水泥中。本发明依据人骨所含微量元素选择五种掺杂羟基磷灰石加入骨水泥，在临床应用中，无机离子随骨水泥的降解释放，能显著促进细胞增殖和新骨生成，缩短治疗时间。
有益效果：与现有技术相比，本发明具有以下显著优点：
(1)本发明依据人骨所含微量元素选择多种掺杂羟基磷灰石加入磷酸三钙骨水泥，既引入多种无机离子，又使掺杂含量更加可控。
(2)本发明制备的添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥能显著促进细胞增殖和成骨分化，有望应用于骨缺损的临床治疗。
附图说明
图1为实施例1～6、对比例1和对比例2的浸提液和骨髓间充质干细胞共培养3天后被5-乙炔基-2'-脱氧尿苷(EdU)标记的细胞百分比图；
图2为实施例1～6、对比例1和对比例2的浸提液和骨髓间充质干细胞共培养7天后碱性磷酸酶(ALP)基因的表达水平图。
具体实施方式
下面结合附图对本发明的技术方案作进一步说明。
实施例1：
(1)称取6gα-TCP、3gβ-TCP、0.83g掺杂摩尔分数5％Mg2+的羟基磷灰石(记为5Mg-HA)、0.02g掺杂摩尔分数5％ Zn2+的羟基磷灰石(记为5Zn-HA)、0.03g掺杂摩尔分数3.2％Sr2+的羟基磷灰石(记为3.2Sr-HA)、0.01g掺杂摩尔分数1％Cu2+的羟基磷灰石(记为1Cu-HA)和0.11g掺杂摩尔分数3％Si4+的羟基磷灰石(记为3Si-HA)，研磨混合均匀作为骨水泥固相组成物。
(2)称取0.82g一水合柠檬酸和0.94g十二水合磷酸氢二钠，加入10mL去离子水，搅拌溶解制得骨水泥液相组成物。
(3)取0.7mL液相组成物与2g固相组成物混合，调和均匀，得到添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥。
实施例2：
制备过程同实施例1：
(1)称取6gα-TCP、2gβ-TCP、1.68g 5Mg-HA、0.04g 5Zn-HA、0.06g3.2Sr-HA、0.02g1Cu-HA和0.2g 3Si-HA，研磨混合均匀作为骨水泥固相组成物。
(2)称取0.82g一水合柠檬酸和0.94g十二水合磷酸氢二钠，加入10mL去离子水，搅拌溶解制得骨水泥液相组成物。
(3)取0.8mL液相组成物与2g固相组成物混合，调和均匀，得到添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥。
实施例3：
制备过程同实施例1：
(1)称取6gα-TCP、1gβ-TCP、2.49g 5Mg-HA、0.08g 5Zn-HA、0.07g3.2Sr-HA、0.03g1Cu-HA和0.33g 3Si-HA，研磨混合均匀作为骨水泥固相组成物。
(2)称取0.82g一水合柠檬酸和0.94g十二水合磷酸氢二钠，加入10mL去离子水，搅拌溶解制得骨水泥液相组成物。
(3)取0.9mL液相组成物与2g固相组成物混合，调和均匀，得到添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥。
实施例4：
制备过程同实施例1：
(1)称取5gα-TCP、1gβ-TCP、3.32g 5Mg-HA、0.08g 5Zn-HA、0.12g3.2Sr-HA、0.06g1Cu-HA和0.42g 3Si-HA，研磨混合均匀作为骨水泥固相组成物。
(2)称取0.82g一水合柠檬酸和0.94g十二水合磷酸氢二钠，加入10mL去离子水，搅拌溶解制得骨水泥液相组成物。
(3)取0.7mL液相组成物与2g固相组成物混合，调和均匀，得到添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥。
实施例5：
制备过程同实施例1：
(1)称取4gα-TCP、1gβ-TCP、4.15g 5Mg-HA、0.1g 5Zn-HA、0.13g3.2Sr-HA、0.07g1Cu-HA和0.55g 3Si-HA，研磨混合均匀作为骨水泥固相组成物。
(2)称取0.82g一水合柠檬酸和0.94g十二水合磷酸氢二钠，加入10mL去离子水，搅拌溶解制得骨水泥液相组成物。
(3)取0.8mL液相组成物与2g固相组成物混合，调和均匀，得到添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥。
实施例6：
制备过程同实施例1：
(1)称取3gα-TCP、1gβ-TCP、4.98g 5Mg-HA、0.12g 5Zn-HA、0.18g3.2Sr-HA、0.06g1Cu-HA和0.66g 3Si-HA，研磨混合均匀作为骨水泥固相组成物。
(2)称取0.82g一水合柠檬酸和0.94g十二水合磷酸氢二钠，加入10mL去离子水，搅拌溶解制得骨水泥液相组成物。
(3)取0.9mL液相组成物与2g固相组成物混合，调和均匀，得到添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥。
对比例1：
(1)称取3gα-TCP、1gβ-TCP和6g无掺杂的羟基磷灰石，研磨混合均匀作为骨水泥固相组成物。
(2)称取0.82g一水合柠檬酸和0.94g十二水合磷酸氢二钠，加入10mL去离子水，搅拌溶解制得骨水泥液相组成物。
(3)取0.9mL液相组成物与2g固相组成物混合，调和均匀，得到磷酸三钙/无掺杂的羟基磷灰石骨水泥。
对比例2：
(1)称取4gα-TCP、4.98g 5Mg-HA、0.12g 5Zn-HA、0.18g 3.2Sr-HA、0.06g 1Cu-HA和0.66g 3Si-HA，研磨混合均匀作为骨水泥固相组成物。
(2)称取0.82g一水合柠檬酸和0.94g十二水合磷酸氢二钠，加入10mL去离子水，搅拌溶解制得骨水泥液相组成物。
(3)取0.9mL液相组成物与2g固相组成物混合，调和均匀，得到α-磷酸三钙/添加多种无机离子掺杂羟基磷灰石骨水泥。
分别将实施例1～6、对比例1和对比例2制得的骨水泥填入模具中固化成形，在37℃、100％湿度环境下养护48h。将上述8种骨水泥的浸提液分别和骨髓间充质干细胞(BMSC)在24孔板中共培养3天并染色，统计被5-乙炔基-2'-脱氧尿苷(EdU)标记的骨髓间充质干细胞的百分比，如图1所示，图1为实施例1～6、对比例1和对比例2的浸提液和骨髓间充质干细胞共培养3天后被5-乙炔基-2'-脱氧尿苷(EdU)标记的细胞百分比图；共培养7天后测试成骨蛋白碱性磷酸酶(ALP)基因的表达水平，如图2所示，图2为实施例1～6、对比例1和对比例2的浸提液和骨髓间充质干细胞共培养7天后碱性磷酸酶(ALP)基因的表达水平图。由图1和图2可见，实施例6制备的添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥组被EdU标记的细胞比例和ALP基因表达水平明显高于对比例2制备的α-磷酸三钙/添加多种无机离子掺杂羟基磷灰石骨水泥组，说明添加两种磷酸三钙的效果要远远好于添加一种磷酸三钙的效果。同时实施例6制备的添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥组被EdU标记的细胞比例和ALP基因表达水平也显著高于对比例1制备的磷酸三钙/无掺杂的羟基磷灰石骨水泥组，说明添加多种无机离子掺杂羟基磷灰石的效果要远好于无掺杂的羟基磷灰石，因此添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥能显著促进细胞增殖和成骨分化，有望应用于骨缺损的临床治疗。
Claims (10)
1.一种添加多种无机离子掺杂羟基磷灰石的磷酸三钙骨水泥，其特征在于，所述磷酸三钙骨水泥包含固相组成物和液相组成物混合制得；其中，所述固相组成物为α-磷酸三钙、β-磷酸三钙和多种掺杂无机离子的羟基磷灰石，所述液相组成物为一水合柠檬酸与十二水合磷酸氢二钠混合水溶液，所述多种掺杂无机离子的羟基磷灰石包括掺杂Mg2+的羟基磷灰石、掺杂Zn2+的羟基磷灰石、掺杂Sr2+的羟基磷灰石、掺杂Cu2+的羟基磷灰石和掺杂Si4+的羟基磷灰石。
2.根据权利要求1所述的磷酸三钙骨水泥，其特征在于，所述α-磷酸三钙、β-磷酸三钙和多种掺杂无机离子的羟基磷灰石的质量百分比6～3:3～1:1～6。
3.根据权利要求1所述的磷酸三钙骨水泥，其特征在于，所述Mg2+的羟基磷灰石、掺杂Zn2+的羟基磷灰石、掺杂Sr2+的羟基磷灰石、掺杂Cu2+的羟基磷灰石和掺杂Si4+的羟基磷灰石的质量比为83～85:2～4:3～5:1～3:9～11。
4.根据权利要求1所述的磷酸三钙骨水泥，其特征在于，所述掺杂Mg2+的羟基磷灰石中Mg2+的掺杂摩尔分数为4.5～5.5％，所述掺杂Zn2+的羟基磷灰石中Zn2+的掺杂摩尔分数为4.5～5.5％。
5.根据权利要求1所述的磷酸三钙骨水泥，其特征在于，所述掺杂Sr2+的羟基磷灰石中Sr2+的掺杂摩尔分数为3～4％，所述掺杂Cu2+的羟基磷灰石中Cu2+的掺杂摩尔分数为0.5～1.5％，所述掺杂Si4+的羟基磷灰石中Si4+的掺杂摩尔分数为2.5～3.5％。
6.根据权利要求1所述的磷酸三钙骨水泥，其特征在于，所述液相组成物中一水合柠檬酸的质量百分比为6～8％，十二水合磷酸氢二钠质量百分比为7～9％，余量为水。
7.根据权利要求1所述的磷酸三钙骨水泥，其特征在于，所述液相组成物与固相组成物的液固比为0.35～0.45mL/g。
8.权利要求1～7任一项所述磷酸三钙骨水泥的制备方法，其特征在于，包括以下步骤：
(1)将α-磷酸三钙、β-磷酸三钙和五种无机离子掺杂羟基磷灰石混合均匀，得到骨水泥固相组成物；
(2)配制一水合柠檬酸与十二水合磷酸氢二钠的混合水溶液，得到骨水泥液相组成物；
(3)将固相组成物与液相组成物混合，调和均匀，得到所述添加多种无机离子掺杂羟基磷灰石的磷酸三钙水泥。
9.根据权利要求8所述的制备方法，其特征在于，步骤(1)中，所述α-磷酸三钙、β-磷酸三钙和五种无机离子掺杂羟基磷灰石通过研磨混合均匀。
10.根据权利要求8所述的制备方法，其特征在于，步骤(2)中，所述混合水溶液的配制方法为室温搅拌溶解。
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