羟基磷灰石/氧化锆生物复合材料制备与性能研究
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摘要
羟基磷灰石作为生物陶瓷材料，在骨和牙的缺损修复以及骨组织工程替代方面有着非常重要的意义。从成分来看，人体骨骼的无机成分为骨磷灰石，通常，骨磷灰石里含有许多其他离子，例如K+、Na+、Mg+、CI一、F一和CO2一2+3等，这些离子会不同程度地取代磷灰石中的Ca或者OH-，在人体内的生物学过程中起到非常重要的作用。从结构来看，人体骨磷灰石的结构是长约40～60nm，宽约20nm，主要基本单元是针状或棒状磷灰石晶体，它们定向和卷排列构成多种织构，有利于营养物质的传递。目前，人工合成的羟基磷灰石尚不能达到骨磷灰石的成分和结构。另外，内部连通的三维多孔结构可以允许细胞附着、分化和增殖，为生物流体提供通道。新生骨组织可以沿着多孔结构的孔壁长入孔内，构成骨性结合。从性能上看，人工合成的单一组分羟基磷灰石强度低、韧性差，难以承受较大的负荷，限制了它作为骨组织工程材料的使用。
本文拟从成分和结构上模仿骨磷灰石，提高现有生物陶瓷材料的性能，设计和制备了一种玻璃改性的钛掺杂羟基磷灰石涂层/多孔氧化锆生物复合材料。采用化学沉淀法合成了羟基磷灰石纳米粉，通过钛掺杂改变羟基磷灰石的晶格结构来提高它的烧结稳定性，同时，添加吐温80来诱导形成纳米棒状羟基磷灰石。采用凝胶成型法制备了具有三维网状贯通结构的多孔氧化锆陶瓷，在其表面使用涂覆-烧结工艺制备了生物玻璃改性的钛掺杂羟基磷灰石涂层。对该复合材料的形貌、界面物相、截面形貌、力学性能和生物性能及相关机理等进行了系统研究。在以下几个方面获得了创造性成果：
（1）采用化学沉淀法，通过钛掺杂合成了具有良好烧结稳定性的羟基磷灰石纳米粉。研究发现，钛掺杂对羟基磷灰石的烧结稳定性、晶粒尺寸和形貌有显著影响。钛掺杂限制了羟基磷灰石的高温分解，在1000℃-1200℃烧结，不同钛掺杂量（0.2-2.4wt%）的羟基磷灰石均未发生分解，羟基磷灰石和钛之间未发生热反应，表明钛掺杂抑制了羟基磷灰石的高温分解，提高了它的烧结稳定性。同时，钛掺杂有效限制了烧结过程中羟基磷灰石晶粒的长大，0.8wt%钛掺杂的羟基磷灰石晶粒尺寸较纯羟基磷灰石晶粒尺寸明显细化。
（2）采用钛掺杂羟基磷灰石/氧化锆复合材料，抑制了羟基磷灰石与氧化锆之间的热反应。研究发现，钛离子进入了羟基磷灰石的晶格，在1000℃-1200℃烧结，0.8wt%钛掺杂羟基磷灰石/氧化锆复合材料的主晶相始终是羟基磷灰石和氧化锆，表现出良好的相稳定性。
（3）采用化学沉淀法，通过诱导剂吐温80的添加合成了棒状羟基磷灰石纳米粉。研究表明，吐温80对羟基磷灰石晶体生长和形貌有显著影响。不添加任何诱导剂，羟基磷灰石晶体是片层状形貌，晶粒尺寸分布范围较宽，在100~300nm之间。随着吐温80的加入，羟基磷灰石的形貌逐渐由片层状变为均匀棒状。当6.5g/ml吐温80加入后，羟基磷灰石几乎全部呈现棒状形貌，晶粒尺寸分布范围变窄，大约都在60nm左右。进一步增加吐温80添加量对合成的羟基磷灰石形貌没有更加显著的影响。
（4）采用羟基磷灰石在Na2O-CaO-SiO2玻璃基板上自组装的方法在其表面定期形成了羟基磷灰石层。研究发现，形成的羟基磷灰石的结晶度和形貌主要受浸泡溶液Na2HPO4的浓度、浸泡时间和Na2O-CaO-SiO2玻璃中CaO含量的影响，形成的羟基磷灰石总体呈现“松叶片状”多层结构形貌。
（5）采用凝胶成型法制备了具有三维网状开孔结构、孔与孔之间相互贯通、分布均匀的多孔氧化锆陶瓷支架，实现了对其孔径和孔隙率的可控。
（6）采用涂覆-烧结工艺在多孔氧化锆陶瓷表面制备了玻璃改性的钛掺杂羟基磷灰石涂层。研究发现，该复合材料依然具有孔径和孔隙率可控的三维连通孔结构。与单一多孔羟基磷灰石相比，该复合材料的力学性能得到了改善，抗压强度达到27MPa。玻璃改性的钛掺杂羟基磷灰石涂层与多孔氧化锆陶瓷支架之间结合紧密，没有出现分层和裂纹，结合强度达到了53MPa，是单一羟基磷灰石涂层的两倍。模拟体液研究表明，玻璃改性的0.8wt%钛掺杂羟基磷灰石涂层/多孔氧化锆生物复合材料表面快速的形成磷灰石层，具有良好的生物活性。细胞毒性试验表明，该复合材料对成骨细胞没有毒性，成骨细胞在其表面生长良好，呈现梭形形态。体外细胞培养研究表明，该复合材料可以支持成骨细胞的附着和生长。在培养的第七天，玻璃改性的0.8wt%钛掺杂羟基磷灰石涂层上的成骨细胞生物活性显著的高于纯羟基磷灰石涂层，表明该复合涂层可以促进成骨细胞的增殖。
Hydroxyapatite is one of the most extensively used synthetic calciumphosphates for restoring of defects of bone and teeth as well as bone tissueengineering materials. Human bone apatites are characterized by a variety ofionic substitutions, such as K+、Na+、Mg+、CI一、F一and CO2一3which replacesthe Ca2+and OH-in apatite and plays a very important role in the biologicalprocesses in the human body. Human bone apatite structure is about40-60nm inlength and20nm in width and the basic unit is a needle-like or rod-like boneapatite crystals, which consists of a variety of orientation and arrangement and ishelpful for transfer of nutrients. Furthermore, three-dimensional porous structureof interconnected can allow cell attachment and proliferation which providesaccess for biological fluids. New bone tissue can along the pore walls of theporous structure into the hole, constituting osseointegration. Applications ofsynthetic calcium phosphates using as bone tissue engineering materials arelimited because of their poor strength and toughness for the load-bearing parts.
The purpose of this study is to imitate bone apatite from the compositionand structure, so glass modified titanium-doped hydroxyapatite coating/porouszirconia composite was designed and fabricated to meet the demand of bonetissue engineering materials. Hydroxyapatite nanopowder was synthesized bychemical precipitation doped by tetrabutyl titanate which changed the latticestructure of hydroxyapatite and improved its thermal stability. Furthermore, theaddition of Tween80induced to obtain nanorods hydroxyapatite.Three-dimensional interconnected porous zirconia was fabricated by gel-formingmethod on which glass modified titanium-doped hydroxyapatite coating wascoated by coating-sintering. Morphology and phases on interface, mechanicaland biological properties were studied systematically. Some important andcreative conclusions were made as follows:
(1) Hydroxyapatite nanopowder was synthesized by chemical precipitationmethod doped by tetrabutyl titanate. The results showed that the addition of titanium to hydroxyapatite had a great influence on thermal stability、grain sizeand morphology. When sintered at1000℃-1200℃,0.8wt%titanium-dopedhydroxyapatite did not decompose and hydroxyapatite did not react withtitanium either, which demonstrated that titanium-doped hydroxyapatite didrestrain the decomposition and improved the thermal stability of hydroxyapatite.Titanium-doped hydroxyapatite restrained the grain growth during the sintering.The grain size of0.8wt%titanium-doped hydroxyapatite was much smaller thanthat of pure hydroxyapatite.
(2) Hydroxyapatite/zirconia doped by titanium restrained the thermalreaction between hydroxyapatite and zirconia. The results showed that with thetitanium doped to hydroxyapatite/zirconia composite, titanium iron entering thestructure of hydroxyapatite, when sintered at1000℃-1200℃, the main phases of0.8wt%titanium-doped hydroxyapatite/zirconia composite were alwayshydroxyapatite and zirconia which had the combination of good bioactive ofhydroxyapatite and high strength of zirconia.
(3) Nanorod hydroxyapatite was synthesized by chemical precipitationmethod induced by Tween80. The results showed that Tween80had asignificant effect on crystal growth and morphology of hydroxyapatite. Withoutaddition of Tween80, hydroxyapatite crystals were lamellar with a wide range ofgrain size distribution between100-300nm. With6.5g/ml addition of Tween80,hydroxyapatite was rod-like morphology and grain size distribution was narrowaround about60nm. More addition of Tween80had no more significant effecton the morphology of synthetic hydroxyapatite.
(4) Hydroxyapatite generated self-assembly on the surface of Na2O-CaO-SiO2glass. The results showed that the crystallinity and morphology ofhydroxyapatite depended on the concentration of Na2HPO4、 soaking time andthe content of CaO in the Na2O-CaO-SiO2glass. Morphology of synthetichydroxyapatite showed “pine leaf-shape” multilayer structure.
(5) Porous zirconia was fabricated by gel-forming method. Three-dimensional mesh interconnected structure was obtained with controlled porosityand pore size.
(6) The glass modified titanium-doped hydroxyapatite coating was coatedon porous zirconia by coating-sintering method. The results showed that this composite still had three-dimensional interconnected structure with controlledporosity and pore size. Compared with pure porous hydroxyapatite, thecompressive strength of this composite improved and the maximum valuereached27MPa. The glass modified titanium-doped hydroxyapatite coating andporous zirconia combined tightly and there were no lamination and cracksbetween them. The maximum bonding strength between them was about53MPa,which was twice of pure hydroxyapatite coating. Simulated body fluid showedthat the apatite layers generated quickly on the glass modified0.8wt%titanium-doped hydroxyapatite coating/porous zirconia composite, whichdemonstrated that this composite had good biological activity. Cytotoxicity testshowed that this composite was not toxic to osteoblasts and the morphology ofosteoblasts was spindle. In vitro test showed that this composite could supportthe attachment and growth of osteoblasts. On the seventh day culture, osteoblastscultured on the glass modified0.8wt%titanium-doped hydroxyapatite coatingwere more bioactive than that of pure hydroxyapatite coating, which indicatedthat the glass modified0.8wt%titanium-doped hydroxyapatite coating couldpromote cell proliferation.
本文拟从成分和结构上模仿骨磷灰石，提高现有生物陶瓷材料的性能，设计和制备了一种玻璃改性的钛掺杂羟基磷灰石涂层/多孔氧化锆生物复合材料。采用化学沉淀法合成了羟基磷灰石纳米粉，通过钛掺杂改变羟基磷灰石的晶格结构来提高它的烧结稳定性，同时，添加吐温80来诱导形成纳米棒状羟基磷灰石。采用凝胶成型法制备了具有三维网状贯通结构的多孔氧化锆陶瓷，在其表面使用涂覆-烧结工艺制备了生物玻璃改性的钛掺杂羟基磷灰石涂层。对该复合材料的形貌、界面物相、截面形貌、力学性能和生物性能及相关机理等进行了系统研究。在以下几个方面获得了创造性成果：
（1）采用化学沉淀法，通过钛掺杂合成了具有良好烧结稳定性的羟基磷灰石纳米粉。研究发现，钛掺杂对羟基磷灰石的烧结稳定性、晶粒尺寸和形貌有显著影响。钛掺杂限制了羟基磷灰石的高温分解，在1000℃-1200℃烧结，不同钛掺杂量（0.2-2.4wt%）的羟基磷灰石均未发生分解，羟基磷灰石和钛之间未发生热反应，表明钛掺杂抑制了羟基磷灰石的高温分解，提高了它的烧结稳定性。同时，钛掺杂有效限制了烧结过程中羟基磷灰石晶粒的长大，0.8wt%钛掺杂的羟基磷灰石晶粒尺寸较纯羟基磷灰石晶粒尺寸明显细化。
（2）采用钛掺杂羟基磷灰石/氧化锆复合材料，抑制了羟基磷灰石与氧化锆之间的热反应。研究发现，钛离子进入了羟基磷灰石的晶格，在1000℃-1200℃烧结，0.8wt%钛掺杂羟基磷灰石/氧化锆复合材料的主晶相始终是羟基磷灰石和氧化锆，表现出良好的相稳定性。
（3）采用化学沉淀法，通过诱导剂吐温80的添加合成了棒状羟基磷灰石纳米粉。研究表明，吐温80对羟基磷灰石晶体生长和形貌有显著影响。不添加任何诱导剂，羟基磷灰石晶体是片层状形貌，晶粒尺寸分布范围较宽，在100~300nm之间。随着吐温80的加入，羟基磷灰石的形貌逐渐由片层状变为均匀棒状。当6.5g/ml吐温80加入后，羟基磷灰石几乎全部呈现棒状形貌，晶粒尺寸分布范围变窄，大约都在60nm左右。进一步增加吐温80添加量对合成的羟基磷灰石形貌没有更加显著的影响。
（4）采用羟基磷灰石在Na2O-CaO-SiO2玻璃基板上自组装的方法在其表面定期形成了羟基磷灰石层。研究发现，形成的羟基磷灰石的结晶度和形貌主要受浸泡溶液Na2HPO4的浓度、浸泡时间和Na2O-CaO-SiO2玻璃中CaO含量的影响，形成的羟基磷灰石总体呈现“松叶片状”多层结构形貌。
（5）采用凝胶成型法制备了具有三维网状开孔结构、孔与孔之间相互贯通、分布均匀的多孔氧化锆陶瓷支架，实现了对其孔径和孔隙率的可控。
（6）采用涂覆-烧结工艺在多孔氧化锆陶瓷表面制备了玻璃改性的钛掺杂羟基磷灰石涂层。研究发现，该复合材料依然具有孔径和孔隙率可控的三维连通孔结构。与单一多孔羟基磷灰石相比，该复合材料的力学性能得到了改善，抗压强度达到27MPa。玻璃改性的钛掺杂羟基磷灰石涂层与多孔氧化锆陶瓷支架之间结合紧密，没有出现分层和裂纹，结合强度达到了53MPa，是单一羟基磷灰石涂层的两倍。模拟体液研究表明，玻璃改性的0.8wt%钛掺杂羟基磷灰石涂层/多孔氧化锆生物复合材料表面快速的形成磷灰石层，具有良好的生物活性。细胞毒性试验表明，该复合材料对成骨细胞没有毒性，成骨细胞在其表面生长良好，呈现梭形形态。体外细胞培养研究表明，该复合材料可以支持成骨细胞的附着和生长。在培养的第七天，玻璃改性的0.8wt%钛掺杂羟基磷灰石涂层上的成骨细胞生物活性显著的高于纯羟基磷灰石涂层，表明该复合涂层可以促进成骨细胞的增殖。
Hydroxyapatite is one of the most extensively used synthetic calciumphosphates for restoring of defects of bone and teeth as well as bone tissueengineering materials. Human bone apatites are characterized by a variety ofionic substitutions, such as K+、Na+、Mg+、CI一、F一and CO2一3which replacesthe Ca2+and OH-in apatite and plays a very important role in the biologicalprocesses in the human body. Human bone apatite structure is about40-60nm inlength and20nm in width and the basic unit is a needle-like or rod-like boneapatite crystals, which consists of a variety of orientation and arrangement and ishelpful for transfer of nutrients. Furthermore, three-dimensional porous structureof interconnected can allow cell attachment and proliferation which providesaccess for biological fluids. New bone tissue can along the pore walls of theporous structure into the hole, constituting osseointegration. Applications ofsynthetic calcium phosphates using as bone tissue engineering materials arelimited because of their poor strength and toughness for the load-bearing parts.
The purpose of this study is to imitate bone apatite from the compositionand structure, so glass modified titanium-doped hydroxyapatite coating/porouszirconia composite was designed and fabricated to meet the demand of bonetissue engineering materials. Hydroxyapatite nanopowder was synthesized bychemical precipitation doped by tetrabutyl titanate which changed the latticestructure of hydroxyapatite and improved its thermal stability. Furthermore, theaddition of Tween80induced to obtain nanorods hydroxyapatite.Three-dimensional interconnected porous zirconia was fabricated by gel-formingmethod on which glass modified titanium-doped hydroxyapatite coating wascoated by coating-sintering. Morphology and phases on interface, mechanicaland biological properties were studied systematically. Some important andcreative conclusions were made as follows:
(1) Hydroxyapatite nanopowder was synthesized by chemical precipitationmethod doped by tetrabutyl titanate. The results showed that the addition of titanium to hydroxyapatite had a great influence on thermal stability、grain sizeand morphology. When sintered at1000℃-1200℃,0.8wt%titanium-dopedhydroxyapatite did not decompose and hydroxyapatite did not react withtitanium either, which demonstrated that titanium-doped hydroxyapatite didrestrain the decomposition and improved the thermal stability of hydroxyapatite.Titanium-doped hydroxyapatite restrained the grain growth during the sintering.The grain size of0.8wt%titanium-doped hydroxyapatite was much smaller thanthat of pure hydroxyapatite.
(2) Hydroxyapatite/zirconia doped by titanium restrained the thermalreaction between hydroxyapatite and zirconia. The results showed that with thetitanium doped to hydroxyapatite/zirconia composite, titanium iron entering thestructure of hydroxyapatite, when sintered at1000℃-1200℃, the main phases of0.8wt%titanium-doped hydroxyapatite/zirconia composite were alwayshydroxyapatite and zirconia which had the combination of good bioactive ofhydroxyapatite and high strength of zirconia.
(3) Nanorod hydroxyapatite was synthesized by chemical precipitationmethod induced by Tween80. The results showed that Tween80had asignificant effect on crystal growth and morphology of hydroxyapatite. Withoutaddition of Tween80, hydroxyapatite crystals were lamellar with a wide range ofgrain size distribution between100-300nm. With6.5g/ml addition of Tween80,hydroxyapatite was rod-like morphology and grain size distribution was narrowaround about60nm. More addition of Tween80had no more significant effecton the morphology of synthetic hydroxyapatite.
(4) Hydroxyapatite generated self-assembly on the surface of Na2O-CaO-SiO2glass. The results showed that the crystallinity and morphology ofhydroxyapatite depended on the concentration of Na2HPO4、 soaking time andthe content of CaO in the Na2O-CaO-SiO2glass. Morphology of synthetichydroxyapatite showed “pine leaf-shape” multilayer structure.
(5) Porous zirconia was fabricated by gel-forming method. Three-dimensional mesh interconnected structure was obtained with controlled porosityand pore size.
(6) The glass modified titanium-doped hydroxyapatite coating was coatedon porous zirconia by coating-sintering method. The results showed that this composite still had three-dimensional interconnected structure with controlledporosity and pore size. Compared with pure porous hydroxyapatite, thecompressive strength of this composite improved and the maximum valuereached27MPa. The glass modified titanium-doped hydroxyapatite coating andporous zirconia combined tightly and there were no lamination and cracksbetween them. The maximum bonding strength between them was about53MPa,which was twice of pure hydroxyapatite coating. Simulated body fluid showedthat the apatite layers generated quickly on the glass modified0.8wt%titanium-doped hydroxyapatite coating/porous zirconia composite, whichdemonstrated that this composite had good biological activity. Cytotoxicity testshowed that this composite was not toxic to osteoblasts and the morphology ofosteoblasts was spindle. In vitro test showed that this composite could supportthe attachment and growth of osteoblasts. On the seventh day culture, osteoblastscultured on the glass modified0.8wt%titanium-doped hydroxyapatite coatingwere more bioactive than that of pure hydroxyapatite coating, which indicatedthat the glass modified0.8wt%titanium-doped hydroxyapatite coating couldpromote cell proliferation.
引文
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