CN106310374B - 一种可降解含镁磷灰石多孔生物支架 - Google Patents

一种可降解含镁磷灰石多孔生物支架 Download PDF

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CN106310374B
CN106310374B CN201610525626.3A CN201610525626A CN106310374B CN 106310374 B CN106310374 B CN 106310374B CN 201610525626 A CN201610525626 A CN 201610525626A CN 106310374 B CN106310374 B CN 106310374B
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bone
phosphorite
magnesium
multiporous biological
calcining
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CN106310374A (zh
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彭兆祥
蒋国强
汤亭亭
陆继业
李桑
傅俊
毛海蛟
熊汉锋
聂磊
李亚屏
郑建民
张国锋
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Abstract

本发明公开了一种可降解含镁磷灰石多孔生物支架，其材料组成为如下成分中的一种：Ca2.89Mg0.11(PO4)2、Ca2.71Mg0.29(PO4)2、Ca2.589Mg0.411(PO4)2。本发明将磷、镁有效掺入具备自然骨矿复杂精妙的三维互通网孔结构的牛煅烧松质骨骨矿多孔支架中，将煅烧牛松质单质的羟基磷灰石转化可降解含镁磷灰石多孔生物支架。本发明的可降解含镁磷灰石多孔生物支架兼具良好维互通网孔结构与骨传导性、可降解性、较好机械强度，动物骨缺损区移植实验发现其良好的生物相容性及良好的骨修复效果。

Description

一种可降解含镁磷灰石多孔生物支架
技术领域
本发明涉及医用材料领域，特别涉及一种可降解含镁磷灰石多孔生物支架。
背景技术
骨移植是仅少于输血的组织移植，骨替代材料的研究、开发是目前医学研究的重点之一。
构成人骨骨矿有Ca、P、C、O、H、S、Fe、Mg、Cu、Si、Zn、Mn、Na、K等元素，在人骨矿化过程中这些元素存在广泛的同质替换行为，人骨具有复杂的组成及结构。在骨组织工程支架或人工骨的设计过程中，关键要考虑人骨这种严重矿化组织的复杂组成及结构；人骨不能被单一材料所提供的有限特性所完全替代，更为重要的是，支架还必须为骨组织的再生提供三维多孔微结构以引导细胞的分化增殖，而且要能维持或较快取得足够的力学强度来满足被替代材料的力学要求。理想的骨移植替代材料或骨组织工程支架材料应具有以下条件:1)具有良好的骨传导性，材料具有孔径理想的三维互通网孔结构，尽可能高的孔隙率及比表面积2)具有骨诱导性即有良好的成骨活性；3)具有良好的生物相容性以及支持骨细胞生长和功能分化的表面化学性质与微结构；4)具有良好的生物降解性；5)材料中承担骨传导作用的部分必须有足够的力学强度及承载能力；6)易加工等。
Johan等2010年在一篇综述中把新西兰临床可得到的骨移植替代材料归纳为四类：1、单相钙磷材料包括羟基磷灰石转化生物陶瓷三种、合成羟基磷灰石水泥一种，β-磷酸三钙人工陶瓷两种；2、复合材料包括磷酸四钙/磷酸氢钙、62.5％α-磷酸三钙/26.8％无水磷酸氢钙/8.9％碳酸钙/1.8％羟基磷灰石、60％羟基磷灰石/40％b-磷酸三钙、73％b-磷酸三钙/21％磷酸二氢钙/5％磷酸氢镁、磷酸四钙/磷酸氢钙/无定形磷酸钙、α-磷酸三钙/碳酸钙/磷酸二氢钙等配方的合成水泥6种，配方为80％磷酸三钙/20％磷酸氢钙的人工陶瓷一种；3、单相硫酸钙制备的泥膏或颗粒共四种；4、含硅生物玻璃一种。磷灰石、硫酸钙是目前临床上最为常见的骨移植替代材料或构成成分。目前临床缺少理想的骨移植替代材料，主要表现在理想三维互通网孔结构、极大的孔隙率及比表面积、可降解性、骨传导性、骨诱导性及力学强度等特性多不能兼而有之。
临床已经应用的具有较为理想三维互通网孔微结构的人工骨均为动物材料转化而来：其中两个来源于牛松质骨经过高温烧结工序制备的多孔羟基磷灰石陶瓷骨，特点是保留了牛松质骨自然骨矿的三维互通网孔微结构且成分接近人骨骨矿成分，具有良好的生物相容性、良好的骨传导性及较好抗压缩强度，因高温烧结程序而免却异种骨免疫排斥反应及病原体导入之可能，且易于加工。来自牛骨的多孔羟基磷灰石具有60-90％的良好孔隙率且牛骨资源丰富，其孔径为390-1360μm，稍大于150-400μm的骨移植替代材料及骨组织工程支架的理想孔径；具备1-20MPa的良好的抗压缩强度；植入机体内有利于骨修复细胞募集、血管的进入、氧气及组织液的交换，为骨修复细胞提供良好的生理活动空间与黏附支持；其巨大的缺点是高温烧结牛松质骨得到的骨矿—羟基磷灰石太过稳定，在体内降解太过慢长【无孔块状羟基磷灰石在体内10年都不能完全降解】，在钙磷类植骨材料中溶解度最低，降解速度远远不能与新骨形成速度匹配，亦不能持续释放较高浓度钙等成骨有益离子、因此缺乏良好的成骨活性，不利于骨的修复及改造。近20年来，有科学工作者试图将煅烧牛松质骨多孔羟基磷灰石转化为磷酸三钙或含磷酸三钙的复相磷灰石陶瓷。
另外，磷酸钙及其他生物基材料的生物活性因掺入生物活性离子可能被提高。已有的研究表明，这些生物活性离子能有效的刺激蛋白活性，促进细胞生长和骨生长。人体约含有25g镁，镁在人体骨形成和所有生长过程、维护骨细胞结构与功能、骨代谢及重塑方面具有重要作用。低含镁量的磷酸镁钙基骨水泥能够显著提高细胞的粘附能力。掺镁磷酸钙骨水泥因为可促进植入材料与骨组织间界面生成成为日益受到重视的新型骨修复生物材料：掺镁骨水泥较容易配制，新西兰等西方国家已有73％b-磷酸三钙/21％磷酸二氢钙/5％磷酸氢镁配方的骨水泥在临床上应用。复合配方含镁的骨水泥具备降解性，可释放钙、磷、镁等骨形成有益元素，移植后在机体内能进行降解、离子交换，也不具备三维互通网孔结构而阻碍修复细胞及血管早期深入移植物内部，缺乏良好的骨传导性的三维互通网孔结构基础。
我们尝试将磷、镁掺入煅烧牛松质骨多孔骨矿支架，将煅烧牛松质骨单质的羟基磷灰石转变为一种可降解含镁磷灰石多孔生物支架。
发明内容
本发明的目的在于解决现有骨移植替代材料难以兼具良好三维互通网孔结构、机械强度、可降解性及生物活性等问题，提供一种可降解含镁磷灰石多孔生物支架，将磷、镁有效掺入具备自然骨矿复杂精妙的三维互通网孔结构的牛煅烧松质骨骨矿多孔支架中，将煅烧牛松质单质的羟基磷灰石转化可降解含镁磷灰石多孔生物支架。本发明的可降解含镁磷灰石多孔生物支架兼具良好三维互通网孔结构与骨传导性、可降解性、较好机械强度，动物骨缺损区移植实验发现其良好的生物相容性及良好的骨修复效果。该可降解含镁磷灰石多孔生物支架可能较多地满足了骨移植替代材料或骨组织工程支架材料的理想的条件。
本发明解决其技术问题所采用的技术方案是：
一种可降解含镁磷灰石多孔生物支架，其材料组成为如下成分中的一种：Ca2.89Mg0.11(PO4)2、Ca2.71Mg0.29(PO4)2、Ca2.589Mg0.411(PO4)2。
X线粉末衍射分析该可降解含镁磷灰石多孔生物支架材料为镁离子与总阳离子摩尔比在0.11-0.411:3的磷酸镁钙。可降解含镁磷灰石多孔生物支架材料可实现较好降解。我们通过改变复方配方中的反应物质量比及浓度改变支架材料的镁与总阳离子的质量比。该可降解含镁磷灰石多孔生物支架材料保留了牛自然骨骨矿精妙的三维互通网孔微结构及其良好的机械强度。可降解含镁磷灰石多孔生物支架材料的在模拟体液环境下多有较好溶降，有钙、镁离子持续释放。动物骨松质骨缺损区移植观察到骨修复细胞在支架内良好的黏附、增殖、分化、分泌骨基质，在支架内可见极早的血管形成，成骨过程类似生理状态的膜内成骨；观察期未见明显免疫排斥反应及炎性反应，提示可降解含镁磷灰石多孔生物支架具有良好的生物相容性，动物骨缺损区移植有快而良好的骨修复。
作为优选，所述可降解含镁磷灰石多孔生物支架的制备方法为：将牛煅烧松质骨骨矿多孔支架先在镁源溶液中浸渍并蒸干后，再进入磷源溶液中水热反应，取出干燥后，高温煅烧。
作为优选，牛煅烧松质骨骨矿多孔支架与镁源溶液的料液比为10g：50mL，牛煅烧松质骨骨矿多孔支架与磷源溶液的料液比为10g：100mL。
作为优选，所述镁源为硝酸镁；所述磷源为磷酸与磷酸二氢铵的组合。
作为优选，所述镁源溶液中的硝酸镁浓度为0.05-0.2mol/L，所述磷源溶液中磷酸浓度0.85wt％，磷酸二氢铵浓度为0.75mol/L。
作为优选，所述水热反应采用恒温水热方式；恒温水热方式控制温度70℃，反应时间24小时。
作为优选，所述高温煅烧的参数为900℃煅烧3小时。
作为优选，所述牛煅烧松质骨骨矿多孔支架的制备方法为：
(1)将牛松质骨切割成厚0.5-2cm的骨条或骨块得原料骨；
(2)原料骨置于蒸馏水内在高压锅内蒸煮40-60min，然后用40-60℃饮用水清洗干净，重复本步骤4-6次；
(3)将步骤(2)处理后的原料骨在恒温烘箱内80-120℃干燥12-24小时，然后置于煅烧炉内，900-1200℃煅烧8-12小时，冷却后得牛煅烧松质骨骨矿多孔支架。
作为优选，所述可降解含镁磷灰石多孔生物支架保持了牛煅烧松质骨骨矿多孔支架的三维互通网孔结构及机械强度，孔隙率70-85％，孔径400-1400μm。
本发明的有益效果是：
本发明可稳定有效地将磷、镁掺入牛煅烧松质骨骨矿多孔支架，将煅烧牛松质骨多孔羟基磷灰石单质支架转化为含镁质量比变化的可降解含镁磷灰石多孔生物支架，其成分为Ca2.89Mg0.11(PO4)2、Ca2.71Mg0.29(PO4)2、Ca2.589Mg0.411(PO4)2等。
可降解含镁磷灰石多孔生物支架保持了自然骨骨矿三维互通网孔微结构及其较好的机械强度，孔隙率70-85％，孔径400-1400μm。由于磷酸镁钙有较好的降解速度，材料可降解；材料在模拟体液中有较好溶降速度，溶降后仍可保持良好的机械强度及网孔结构，电镜下可见磷酸镁钙支架的溶降与重新沉积。本发明的可降解含镁磷灰石多孔生物支架材料在动物松质骨骨缺损区移植时，可见修复细胞良好的募集、黏附、增殖分化、分泌基质及快速的血管网形成，有良好的骨修复效果，可能提示材料良好的骨传导性及生物活性；观察过程中未发现免疫排斥反应及明显的炎症，提示可降解含镁磷灰石多孔生物支架具备良好的生物相容性。
总之，可降解含镁磷灰石多孔生物支架兼具良好三维互通网孔结构与骨传导性、可降解性、较好机械强度。动物骨缺损区移植具有良好的生物相容性及骨修复效果。
附图说明
图1是本发明产品的一种的扫描电镜图。
图2是本发明产品在模拟体液溶降实验早期钙值(n＝3，人血清钙离子参考值2-2.67mmol/l)。
图3本发明产品的一种模拟体液溶降实验后材料的扫描电镜图。
图4是本发明产品的一种移植实验早期组织学图示。
图5是本发明产品的一种移植实验后期期组织学图示。
具体实施方式
下面通过具体实施例，对本发明的技术方案作进一步的具体说明。
本发明中，若非特指，所采用的原料和设备等均可从市场购得或是本领域常用的。下述实施例中的方法，如无特别说明，均为本领域的常规方法。
牛煅烧松质骨骨矿多孔支架的制备：
(1)将牛松质骨(牛股骨髁松质骨)切割成厚0.5-2cm的骨条得原料骨；
(2)原料骨置于蒸馏水内在高压锅内蒸煮40-60分钟，然后用40-60℃水清洗干净，重复本步骤4-6次；
(3)将步骤(2)处理后的原料骨在恒温烘箱内80-120℃干燥12-24小时，然后置于煅烧炉内，900-1200℃(升温速率10℃/分钟)煅烧8-12小时，随炉冷却后得牛煅烧松质骨骨矿多孔支架。
总实施方案：
A：配料：磷源为磷酸和磷酸二氢铵；镁源为硝酸镁。
所述镁源溶液中的硝酸镁浓度为0.05-0.2mol/L，所述磷源溶液中磷酸浓度0.85wt％，磷酸二氢铵浓度为0.75mol/L。
B：称取硝酸镁溶液，牛煅烧松质骨骨矿多孔支架与硝酸镁溶液的固液比为10g：50毫升；将牛煅烧松质骨骨矿多孔支架硝酸镁溶液中，浸渍15-30分钟后微波蒸干：微波输出功率300-700w，时间15-30分钟。
C：按牛煅烧松质骨骨矿多孔支架与磷源溶液的固液比为10g：100毫升，用磷源溶液浸没步骤B处理后的牛煅烧松质骨骨矿多孔支架进行浸渍及水热反应，水热反应在恒温条件下完成：恒温箱温度70℃，时间24小时。
D：取出步骤C处理完的牛煅烧松质骨骨矿多孔支架恒温烘箱内70℃干燥48小时。
E：将步骤D处理后的牛煅烧松质骨骨矿多孔支架在置于煅烧炉内，900℃(升温速率2.5℃/分钟)煅烧3小时，1小时降温至400℃后随炉冷却至得产品。
每一样品进行大体观察进行X射线粉末衍射(Xray diffraction,XRD)分析；选择部分样品进行用扫描电镜进行显微结构观察；进行模拟体液溶降实验、骨缺损修复的动物实验等。大体观察观察材料的大体形态、强度等，部分样品用INSTRON—5566测试压缩强度。模拟体液溶降实验用医用氯化钠注射液作为模拟体液，检测材料与模拟体液的固液质量体积比为2克：100毫升，置入有盖烧杯内，在37℃恒温条件下进行模拟体液溶降实验，溶降实验时30天，每隔3天用AU5800全自动生化分析仪检测模拟体液内钙、磷、镁离子测定；用国产电子天平测定溶降实验30天后样品的质量并计算降解率；进行溶降实验开始前、结束时材料的XRD分析与扫描电镜观察等。动物骨缺损修复试验选择4只健康新西兰白兔，在兔股骨髁造成直径8mm的骨缺损，采用多孔复合生物材料进行骨缺损修复，术后1、4周处死实验动物，进行骨缺损修复的组织学检查。
实施例1
60117
按镁源溶液中的硝酸镁浓度为0.05mol/L，磷源溶液中磷酸浓度0.85wt％，磷酸二氢铵浓度为0.75mol/L。先取硝酸镁0.64克配制0.05mol/L硝酸镁50毫升，将孔隙率约70-85％的牛煅烧松质骨骨矿多孔支架10克沉浸其中，微波输出功率700瓦12分钟，微波输出功率500瓦18分钟蒸干。取85w％磷酸1毫升、磷酸二氢铵8.62克配制0.85w％磷酸、0.75mol/L磷酸二氢铵复合溶液100毫升，取蒸干的牛煅烧松质骨骨矿多孔支架沉浸其中，70℃恒温浸泡24小时取出；70℃干燥48小时；每分钟升温2.5℃至900℃，维持3小时后一小时降温至400℃，后随炉降至室温得601171A；
601171A成分如下：
Ca2.89Mg0.11(PO4)2 100％。
实施例2
601172
按镁源溶液中的硝酸镁浓度为0.1mol/L，磷源溶液中磷酸浓度0.85wt％，磷酸二氢铵浓度为0.75mol/L。先取硝酸镁1.28克配制0.1mol/L硝酸镁溶液50毫升，将孔隙率约85％的牛煅烧松质骨骨矿多孔支架10克沉浸其中，微波干燥；取85w％磷酸1毫升、磷酸二氢铵8.62克配制0.85w％磷酸、0.75mol/L磷酸二氢铵复合溶液100毫升，用复合溶液浸没蒸干的牛煅烧松质骨骨矿多孔支架，烧杯反罩下70℃恒温浸泡24小时取出；70℃干燥48小时；每分钟升温2.5℃至900℃，维持3小时后一小时降温至400℃，后随炉降至室温得601172A；
601172A成分如下：Ca2.71Mg0.29(PO4)2 100％。
实施例3
60117
按镁源溶液中的硝酸镁浓度为0.2mol/L，磷源溶液中磷酸浓度0.85wt％，磷酸二氢铵浓度为0.75mol/L。先取硝酸镁2.56克配制0.2mol/L硝酸镁溶液50毫升，将孔隙率约85％的牛煅烧松质骨骨矿多孔支架10克沉浸其中，微波干燥；取85w％磷酸1毫升、磷酸二氢铵8.62克配制0.85w％磷酸、0.75mol/L磷酸二氢铵复合溶液100毫升，用复合溶液浸没蒸干的牛煅烧松质骨骨矿多孔支架，烧杯反罩下70℃恒温浸泡24小时取出；70℃干燥48小时；每分钟升温2.5℃至900℃，维持3小时后一小时降温至400℃，后随炉降至室温得60117A；
60117A成分如下：Ca2.589Mg0.411(PO4)2 100％。
检测结果：
材料大体观察、强度测定、XRD成分分析及扫描电镜观察
各种产品完好保持牛松质骨的预制形态，无碎裂、崩塌或粉末化等，具有较好的机械强度；10×10×10mm的1-3号标本用INSTRON—5566松质骨测试压缩强度见表1。X线衍射(XRD)检测证实牛煅烧松质骨骨矿多孔支架经沉浸镁源及磷源溶液中的水热反应，干燥后经煅烧可转化为含磷灰石多孔生物支架材料如Ca2.89Mg0.11(PO4)2、Ca2.71Mg0.29(PO4)2、Ca2.589Mg0.411(PO4)2等，其镁离子与总阳离子的摩尔比为0.11-0.411:3。电镜扫描发现(参照图1)，产品保持了牛松质骨自然骨骨矿的三维互通网孔微结构的主体结构，微孔直径400-1400μm。
表1压缩强度
2、材料的体外溶降实验
模拟体液溶降实验用医用氯化钠注射作为模拟体液，检测材料与模拟体液的固液质量体积比为1-2克：100毫升，置入有盖烧杯内，在37℃恒温条件下进行模拟体液溶降实验，溶降实验时间4周，用AU5800全自动生化分析仪检测模拟体液内钙、磷、镁等离子测定，用国产电子天平测定4周时材料的质量并计算降解率；进行溶降实验开始前、结束时材料的XRD分析与扫描电镜观察等。实验发现材料有较好的降解率(表2)，模拟体液实验的早期(半月内)多数样品模拟体液中有较高的钙离子浓度即接近人血清正常参考值(2-2.67mmol/l)(图2)；亦有活性离子镁释放。溶降实验结束时支架网孔变大、机械强度良好(表3)。扫描电镜可发现材料的溶降及矿物成分的重新沉积(图3)。
表2材料在模拟体液内浸泡4周的降解率(n＝3)
表3溶降实验后压缩强度
3、动物骨缺损修复试验
多孔生物支架材料组的移植早期(1周)即可见细胞、血管进入支架的整个空间，可见修复细胞增殖、分化、分泌骨基质(图4)；四周即有骨小梁形成，新生骨组织与支架有完美的结合(图5)。观察过程中未发现免疫排斥反应及明显的炎症，材料具备良好的生物相容性。
以上所述的实施例只是本发明的一种较佳的方案，并非对本发明作任何形式上的限制，在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。

Claims (6)

1.一种可降解含镁磷灰石多孔生物支架，其特征在于：其材料组成为如下成分中的一种：Ca2.89Mg0.11(PO4)2、Ca2.71Mg0.29(PO4)2、Ca2.589Mg0.411(PO4)2；
所述可降解含镁磷灰石多孔生物支架的制备方法为：将牛煅烧松质骨骨矿多孔支架先在镁源溶液中浸渍并蒸干后，再进入磷源溶液中水热反应，取出干燥后，高温煅烧；
所述镁源为硝酸镁；所述磷源为磷酸与磷酸二氢铵的组合；所述硝酸镁浓度为0.05-0.2mol/L，所述磷酸浓度0.85wt％，磷酸二氢铵浓度为0.75mol/L。
2.根据权利要求1所述的一种可降解含镁磷灰石多孔生物支架，其特征在于：牛煅烧松质骨骨矿多孔支架与镁源溶液的料液比为10g∶50mL，牛煅烧松质骨骨矿多孔支架与磷源溶液的料液比为10g∶100mL。
3.根据权利要求1所述的一种可降解含镁磷灰石多孔生物支架，其特征在于：所述水热反应采用恒温水热方式；恒温水热方式控制温度70℃，反应时间24小时。
4.根据权利要求1所述的一种可降解含镁磷灰石多孔生物支架，其特征在于：所述高温煅烧的参数为900℃煅烧3小时。
5.根据权利要求1所述的一种可降解含镁磷灰石多孔生物支架，其特征在于，所述牛煅烧松质骨骨矿多孔支架的制备方法为：
(1)将牛松质骨切割成厚0.5-2cm的骨条或骨块得原料骨；
(2)原料骨置于蒸馏水内在高压锅内蒸煮40-60min，然后用40-60℃饮用水清洗干净，重复本步骤4-6次；
(3)将步骤(2)处理后的原料骨在恒温烘箱内80-120℃干燥12-24小时，然后置于煅烧炉内，900-1200℃煅烧8-12小时，冷却后得牛煅烧松质骨骨矿多孔支架。
6.根据权利要求1所述的一种可降解含镁磷灰石多孔生物支架，其特征在于：所述可降解含镁磷灰石多孔生物支架保持了牛煅烧松质骨骨矿多孔支架的三维互通网孔结构及机械强度，孔隙率70-85％，孔径400-1400μm。
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