基于缓释锌离子及仿细胞外基质的高生物响应性涂层制备和表征研究
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摘要
在医用金属基体表面设计、制备具有高生物学响应性的生物活性涂层是当前生物材料研究领域的热点之一。高生物响应性涂层应能从分子水平上调控生物材料与细胞间的相互作用,主动刺激成骨细胞活性,促进骨组织生长和修复。本研究根据植入体/骨组织界面作用机理,针对植入早期移植体表面羟基磷灰石(HA)涂层生物响应性不足、骨整合速率较慢以及涂层长期稳定性较差等问题,在钛金属基体表面设计并制备高生物响应性的生物活性涂层,达到加快植入体/骨组织整合速率的目的。
含氟羟基磷灰石(FHA)与HA相比,具有相当的生物活性性和更好的抗溶解性。本研究设计首先采用溶胶凝胶法在钛金属表面制备一层FHA薄涂层作为底层,保证涂层的长期稳定性。然后,结合微量元素锌促进成骨的药理学作用,构建具有促进移植体周围骨组织早期生长的生物活性功能层:可缓释锌离子的FHA涂层。最后,采用电化学沉积的方法组装磷酸钙/胶原多孔复合层,该层与自然骨组织成分类似,具有仿细胞外基质的作用,既有利于成骨细胞的粘附,又能作为生物活性因子如骨形态蛋白的理想载体。本文主要研究内容和结果如下:
(1)直接掺Zn的FHA(ZnFHA)涂层制备研究。采用Ca(NO_3)_2-P_2O_5-HPF_6-C_2H_5OH-Zn(NO_3)_2体系作为先驱体溶液,制备ZnFHA涂层。XRD谱图表明这种直接掺Zn的涂层为磷灰石相,Zn的掺入并没有改变涂层的晶相,但是掺Zn后涂层结晶度下降。涂层表面形貌致密且平整,厚度大约为2μm。ZnFHA涂层与基体界面结合牢固,划痕法测试结果显示涂层与基体的结合强度大约为480±13 mN。而且Zn的掺入对于涂层的结合强度并没有产生影响。XPS分析结果显示涂层表面Zn含量明显高于涂层内部20 nm处,即在涂层表面富集。Zn在ZnFHA涂层表面的富集以及涂层结晶度降低都有利于Zn离子的释放。
(2)ZnFHA涂层表征研究。通过体外(in vitro)检测研究ZnFHA涂层的生物活性、Zn离子释放行为及其细胞相容性。ZnFHA涂层在模拟体液(SBF)中能够诱导磷灰石层的沉积。在Tris缓冲溶液中浸泡初期,Zn离子浓度迅速增加,之后随着浸泡过程的进行无明显变化。尽管ZnFHA涂层的Zn离子呈现早期快速释放规律,由于涂层中Zn离子载入量低,溶液中的Zn离子浓度仍在安全范围内,并没有产生细胞毒性。细胞体外相容性测试结果显示,较纯钛金属和FHA涂层,成骨样细胞在ZnFHA涂层表面能更快的增殖和铺展,表明ZnFHA涂层具有更好的生物相容性。
(3)纳米含Zn的β-TCP(ZnTCP)粉末制备和表征研究。为了使涂层具有更好的Zn离子释放能力,本研究采用纳米ZnTCP粉末作为Zn离子载体,掺入到FHA涂层中。其纳米ZnTCP粉末采用水溶液共沉积方法制备,先形成含Zn无定形磷酸钙沉淀物为先驱体,然后在800℃下晶化可获得纳米含Zn的β-TCP(ZnTCP)粉末。XPS结果证明ZnTCP粉末中Zn离子进入β-TCP晶格中。SEM和TEM结果显示随着水溶液中Zn离子浓度的增加,合成的ZnTCP粉末中Zn含量随之增加,ZnTCP颗粒尺寸随之逐渐减小,尺寸范围为200～500 nm。
(4)掺纳米ZnTCP颗粒的FHA(ZnTCP/FHA)涂层制备和表征研究。本研究设计两种方式调节涂层中的Zn载入量,以期获得最佳的Zn离子释放行为:(系列1)将不同质量的ZnTCP颗粒加入到涂膜液中,调节涂层中Zn的载入量;(系列2)在ZnTCP添加量相同且合适的条件下,通过改变ZnTCP中Zn含量,调节涂层中Zn的载入量。SEM结果显示ZnTCP/FHA涂层表面形貌粗糙,由FHA基质及分散在其中的“岛状”的ZnTCP团聚体构成。系列2涂层样品中表现出具有更均匀的表面形貌。Zn在两种系列涂层中的分布并不均匀,只存在于“岛状”ZnTCP团聚体中。系列2涂层的Zn离子释放源于ZnTCP相的溶解,涂层样品浸泡275小时后仍能释放出Zn离子。因此,系列2涂层中的Zn离子释放是一个缓慢而持续的过程。通过改变涂层中ZnTCP含量或ZnTCP粉末中Zn含量这两种方式都可以调控涂层的Zn释放行为。
(5) ZnTCP/FHA涂层生物学评价研究。对系列2涂层样品进行体外细胞检测,结果表明可缓释Zn离子的ZnTCP/FHA双相复合涂层与不含Zn的TCP/FHA涂层或FHA涂层相比,能有效促进成骨样细胞的增殖和生长。涂膜液中ZnTCP(Zn含量6.1 wt%)添加量为67.21 mg/ml可获得均匀的、缺陷少的、具有持续缓释Zn离子能力的ZnTCP/FHA涂层(系列2)。选择该样品并植入兔子胫骨部位12周后组织切片显示,纯钛合金被纤维组织包裹,FHA涂层与骨组织形成不连续的整合界面,而可缓释Zn离子的ZnTCP/FHA双相复合涂层与骨组织形成完整的、连续的骨结合界面。四环素荧光标记图片中清晰的双标线也表明植入体表面通过接触成骨的方式形成新骨。动物体内实验结果表明ZnTCP/FHA涂层具有良好的生物响应性,能有效促进早期骨生长及骨整合。
(6)在钛金属表面电化学沉积磷酸钙/胶原多孔仿细胞外基质层研究。实验采用化学处理改变钛阴极表面氧化物层性质,系统地研究了不同电化学参数下获得涂层的形貌。结果显示存碱热处理后具有多孔氧化物表面的钛基体上能获得不同矿化程度的、均匀的磷酸钙/胶原多孔层。涂层中磷酸钙晶相随沉积条件的改变而变化,沉积电压为3.0 V,电解质溶液pH为3.6,离子浓度Ca~(2+):4.5 mM,PO_4~(3-):9 mM时,为OCP相;沉积电压为3.0 V,电解质溶液pH为3.6,离子浓度Ca~(2+):2.5 mM,PO_4~(3-):5 mM时,为无定型相。本研究还对电化学沉积磷酸钙/胶原层机理进行探讨,认为该复合层是磷酸钙相电解沉积和胶原分子束电泳沉积两种不同的电化学行为共同作用的结果。体外细胞测试结果表明磷酸钙/胶原层具有良好的细胞相容性。
The research on metallic implants surface modification using bioactive coatings and their cell and tissue response is one of the most attractive aspects of biomaterials.Bioactive coatings with high biological response should be able to modulate materials/cell interfical reactions at the molecular level and initiatively stimulate cell activity to promote bone growth.Hydroxyapatite(HA) coating has been widely used to improve implant/bone tissue bonding.However,the clinical application of HA coatings shows limited bioactivity and relatively large dissolution or resorption rates after implantation,which may result in slow osteointegration in the early stage and poor long-term effectiveness.In this dissertation,based on the interface reactions between implant and bone,we proposed one bioactive functional coating on titanium substrate.
Compared with HA,fluoridated hydroxyapatite(FHA) has comparable bioactivity and better dissolution resistance.In this study,a dense and stable bottom layer was first applied on titanium to promise the long-term stability.Then, based on this bottom layer,we designed one bioactive coating with zinc ions release ability to stimulate bone formation in the early stage.Finally,an extracellular matrix(ECM) mimicked layer composed of calcium phosphate/collagen was assembled,which might facilitate osteoblasts adhesion and also act as carrier of bioactive molecules such as bone morphogenetic proteins.The researches are summarized as followings:
(1) Ca(NO_3)_2-P_2O_5-HPF_6-C_2H_5OH system was selected as precursors and Zn(YO_3)_2 was added to prepare zinc containing FHA coating.The XRD results demonstrated the crystal phase was still apatite,but the crystalinity decreased after zinc incorporation.The coating was dense and the thickness was about 2μm.The scratch test demonstrated that the bonding strength between the coating and the substrate was strong,which was about 480±13 mN.The XPS results showed the content of zinc on the coating surface was obviously higher than that in the coating, indicating zinc enrichment on the coating surface.
(2) Characterization of ZnFHA coating.The ZnFHA coating could induce apatite layer formation on its surface when soaked in SBF solution,indicating the coating was bioactive.The samples were also soaked in Tris buffered solution to investigate their zinc release property.The zinc content tested in the solution increased dramatically in the first 12 hours and then tapered off.In vitro cell viability was tested in term of MTT absorbance.Comparatively,the cell counts on the zinc containing FHA coatings showed statistically significantly higher optical density value than those on titanium substrate and FHA coating.
(3) Preparation and characterization of Nano ZnTCP particles.In this study, ZnTCP particles were used as zinc carriers.ZnTCP were successfully synthesized through crystallization of zinc containing amorphous calcium phosphate(ACP) at 800℃.The structural analysis proved that zinc ions had entered the calcium sites in theβ-TCP lattice.The zinc content in ZnTCP increased with increasing zinc concentration in the Ca(NO_3)_2-Zn(NO_3)_2-(NH_4)_2HPO_4-PEG system.SEM and TEM results showed that the particle size of ZnTCP decreased with increasing zinc content in the particle,about 200～500 nm.
(4) Preparation and characterization of ZnTCP/FHA coating.The nano ZnTCP particles were added to prepare ZnTCP/FHA biphasic coating on titanium substrate.We used two ways to regulate the zinc content in the coating:add different amount of ZnTCP particles in the colloidal solution(Series 1);add the same amount of ZnTCP particles in the colloidal solution(Series 2).The obtained coating from the colloidal solution is composed of two phases:HA and TCP.All the coatings exhibited a heterogeneous surface with micro-scaled roughness.The EDX results showed that there existed an obvious amount of zinc in the agglomerated ZnTCP particles.The zinc release behavior of ZnTCP/FHA coating was slow and sustained for up to tens of days.Moreover,the zinc release process could be regulated by changing zinc content in the coating.
(5) In vitro and in vivo test of ZnTCP/FHA coating.The ZnTCP/FHA coating (Series 2) could support osteoblasts growth and showed statistically increase in cell viability in comparison with the TCP/FHA coating and FHA coating.In vivo results showed new bone formed in the gap created at the implantation site,and was in direct contact with the ZnTCP/FHA coating after 12 weeks implantation. These evaluations demonstrated that the ZnTCP/FHA coating had good cytocompatibility,the capability of accelerating bone formation and osteointegration with the implant.
(6) Electrochemical deposition of calcium phosphate/collagen extracellular matrix(ECM) mimicked layer composed of calcium phosphate/collagen was assembled on titanium substrates using electrolytic deposition method.The oxidized titanium substrates were used to simulate those with FHA bottom layers in this research.We systematically investigated the micro-structure of the layer under different parameters and the ECM mimicked layer formation mechanisms were discussed.The crystal phase of Calcium phosphate changed with the deposition parameters:at 3.0 V,pH:3.6,Ca~(2+):4.5 mM,pO_4~(3-):9 mM,the crystal was OCP;at 3.0 V,pH:3.6,Ca~(2+):4.5 mM,PO_4~(3-):9 mM,forming amorphous phase. The formation of the calcium phosphate/collagen layer involved two different electro-chemical behaviors:electrolytic deposition of Ca-P and electrophoretic deposition of collagen molecules.It is believed that the simultaneously occurrence of these two kinds of deposition was crucial to form a homogenous layer.The calcium phosphate/collagen coating showed good osetoblast cells biocompatibility.
含氟羟基磷灰石(FHA)与HA相比,具有相当的生物活性性和更好的抗溶解性。本研究设计首先采用溶胶凝胶法在钛金属表面制备一层FHA薄涂层作为底层,保证涂层的长期稳定性。然后,结合微量元素锌促进成骨的药理学作用,构建具有促进移植体周围骨组织早期生长的生物活性功能层:可缓释锌离子的FHA涂层。最后,采用电化学沉积的方法组装磷酸钙/胶原多孔复合层,该层与自然骨组织成分类似,具有仿细胞外基质的作用,既有利于成骨细胞的粘附,又能作为生物活性因子如骨形态蛋白的理想载体。本文主要研究内容和结果如下:
(1)直接掺Zn的FHA(ZnFHA)涂层制备研究。采用Ca(NO_3)_2-P_2O_5-HPF_6-C_2H_5OH-Zn(NO_3)_2体系作为先驱体溶液,制备ZnFHA涂层。XRD谱图表明这种直接掺Zn的涂层为磷灰石相,Zn的掺入并没有改变涂层的晶相,但是掺Zn后涂层结晶度下降。涂层表面形貌致密且平整,厚度大约为2μm。ZnFHA涂层与基体界面结合牢固,划痕法测试结果显示涂层与基体的结合强度大约为480±13 mN。而且Zn的掺入对于涂层的结合强度并没有产生影响。XPS分析结果显示涂层表面Zn含量明显高于涂层内部20 nm处,即在涂层表面富集。Zn在ZnFHA涂层表面的富集以及涂层结晶度降低都有利于Zn离子的释放。
(2)ZnFHA涂层表征研究。通过体外(in vitro)检测研究ZnFHA涂层的生物活性、Zn离子释放行为及其细胞相容性。ZnFHA涂层在模拟体液(SBF)中能够诱导磷灰石层的沉积。在Tris缓冲溶液中浸泡初期,Zn离子浓度迅速增加,之后随着浸泡过程的进行无明显变化。尽管ZnFHA涂层的Zn离子呈现早期快速释放规律,由于涂层中Zn离子载入量低,溶液中的Zn离子浓度仍在安全范围内,并没有产生细胞毒性。细胞体外相容性测试结果显示,较纯钛金属和FHA涂层,成骨样细胞在ZnFHA涂层表面能更快的增殖和铺展,表明ZnFHA涂层具有更好的生物相容性。
(3)纳米含Zn的β-TCP(ZnTCP)粉末制备和表征研究。为了使涂层具有更好的Zn离子释放能力,本研究采用纳米ZnTCP粉末作为Zn离子载体,掺入到FHA涂层中。其纳米ZnTCP粉末采用水溶液共沉积方法制备,先形成含Zn无定形磷酸钙沉淀物为先驱体,然后在800℃下晶化可获得纳米含Zn的β-TCP(ZnTCP)粉末。XPS结果证明ZnTCP粉末中Zn离子进入β-TCP晶格中。SEM和TEM结果显示随着水溶液中Zn离子浓度的增加,合成的ZnTCP粉末中Zn含量随之增加,ZnTCP颗粒尺寸随之逐渐减小,尺寸范围为200～500 nm。
(4)掺纳米ZnTCP颗粒的FHA(ZnTCP/FHA)涂层制备和表征研究。本研究设计两种方式调节涂层中的Zn载入量,以期获得最佳的Zn离子释放行为:(系列1)将不同质量的ZnTCP颗粒加入到涂膜液中,调节涂层中Zn的载入量;(系列2)在ZnTCP添加量相同且合适的条件下,通过改变ZnTCP中Zn含量,调节涂层中Zn的载入量。SEM结果显示ZnTCP/FHA涂层表面形貌粗糙,由FHA基质及分散在其中的“岛状”的ZnTCP团聚体构成。系列2涂层样品中表现出具有更均匀的表面形貌。Zn在两种系列涂层中的分布并不均匀,只存在于“岛状”ZnTCP团聚体中。系列2涂层的Zn离子释放源于ZnTCP相的溶解,涂层样品浸泡275小时后仍能释放出Zn离子。因此,系列2涂层中的Zn离子释放是一个缓慢而持续的过程。通过改变涂层中ZnTCP含量或ZnTCP粉末中Zn含量这两种方式都可以调控涂层的Zn释放行为。
(5) ZnTCP/FHA涂层生物学评价研究。对系列2涂层样品进行体外细胞检测,结果表明可缓释Zn离子的ZnTCP/FHA双相复合涂层与不含Zn的TCP/FHA涂层或FHA涂层相比,能有效促进成骨样细胞的增殖和生长。涂膜液中ZnTCP(Zn含量6.1 wt%)添加量为67.21 mg/ml可获得均匀的、缺陷少的、具有持续缓释Zn离子能力的ZnTCP/FHA涂层(系列2)。选择该样品并植入兔子胫骨部位12周后组织切片显示,纯钛合金被纤维组织包裹,FHA涂层与骨组织形成不连续的整合界面,而可缓释Zn离子的ZnTCP/FHA双相复合涂层与骨组织形成完整的、连续的骨结合界面。四环素荧光标记图片中清晰的双标线也表明植入体表面通过接触成骨的方式形成新骨。动物体内实验结果表明ZnTCP/FHA涂层具有良好的生物响应性,能有效促进早期骨生长及骨整合。
(6)在钛金属表面电化学沉积磷酸钙/胶原多孔仿细胞外基质层研究。实验采用化学处理改变钛阴极表面氧化物层性质,系统地研究了不同电化学参数下获得涂层的形貌。结果显示存碱热处理后具有多孔氧化物表面的钛基体上能获得不同矿化程度的、均匀的磷酸钙/胶原多孔层。涂层中磷酸钙晶相随沉积条件的改变而变化,沉积电压为3.0 V,电解质溶液pH为3.6,离子浓度Ca~(2+):4.5 mM,PO_4~(3-):9 mM时,为OCP相;沉积电压为3.0 V,电解质溶液pH为3.6,离子浓度Ca~(2+):2.5 mM,PO_4~(3-):5 mM时,为无定型相。本研究还对电化学沉积磷酸钙/胶原层机理进行探讨,认为该复合层是磷酸钙相电解沉积和胶原分子束电泳沉积两种不同的电化学行为共同作用的结果。体外细胞测试结果表明磷酸钙/胶原层具有良好的细胞相容性。
The research on metallic implants surface modification using bioactive coatings and their cell and tissue response is one of the most attractive aspects of biomaterials.Bioactive coatings with high biological response should be able to modulate materials/cell interfical reactions at the molecular level and initiatively stimulate cell activity to promote bone growth.Hydroxyapatite(HA) coating has been widely used to improve implant/bone tissue bonding.However,the clinical application of HA coatings shows limited bioactivity and relatively large dissolution or resorption rates after implantation,which may result in slow osteointegration in the early stage and poor long-term effectiveness.In this dissertation,based on the interface reactions between implant and bone,we proposed one bioactive functional coating on titanium substrate.
Compared with HA,fluoridated hydroxyapatite(FHA) has comparable bioactivity and better dissolution resistance.In this study,a dense and stable bottom layer was first applied on titanium to promise the long-term stability.Then, based on this bottom layer,we designed one bioactive coating with zinc ions release ability to stimulate bone formation in the early stage.Finally,an extracellular matrix(ECM) mimicked layer composed of calcium phosphate/collagen was assembled,which might facilitate osteoblasts adhesion and also act as carrier of bioactive molecules such as bone morphogenetic proteins.The researches are summarized as followings:
(1) Ca(NO_3)_2-P_2O_5-HPF_6-C_2H_5OH system was selected as precursors and Zn(YO_3)_2 was added to prepare zinc containing FHA coating.The XRD results demonstrated the crystal phase was still apatite,but the crystalinity decreased after zinc incorporation.The coating was dense and the thickness was about 2μm.The scratch test demonstrated that the bonding strength between the coating and the substrate was strong,which was about 480±13 mN.The XPS results showed the content of zinc on the coating surface was obviously higher than that in the coating, indicating zinc enrichment on the coating surface.
(2) Characterization of ZnFHA coating.The ZnFHA coating could induce apatite layer formation on its surface when soaked in SBF solution,indicating the coating was bioactive.The samples were also soaked in Tris buffered solution to investigate their zinc release property.The zinc content tested in the solution increased dramatically in the first 12 hours and then tapered off.In vitro cell viability was tested in term of MTT absorbance.Comparatively,the cell counts on the zinc containing FHA coatings showed statistically significantly higher optical density value than those on titanium substrate and FHA coating.
(3) Preparation and characterization of Nano ZnTCP particles.In this study, ZnTCP particles were used as zinc carriers.ZnTCP were successfully synthesized through crystallization of zinc containing amorphous calcium phosphate(ACP) at 800℃.The structural analysis proved that zinc ions had entered the calcium sites in theβ-TCP lattice.The zinc content in ZnTCP increased with increasing zinc concentration in the Ca(NO_3)_2-Zn(NO_3)_2-(NH_4)_2HPO_4-PEG system.SEM and TEM results showed that the particle size of ZnTCP decreased with increasing zinc content in the particle,about 200～500 nm.
(4) Preparation and characterization of ZnTCP/FHA coating.The nano ZnTCP particles were added to prepare ZnTCP/FHA biphasic coating on titanium substrate.We used two ways to regulate the zinc content in the coating:add different amount of ZnTCP particles in the colloidal solution(Series 1);add the same amount of ZnTCP particles in the colloidal solution(Series 2).The obtained coating from the colloidal solution is composed of two phases:HA and TCP.All the coatings exhibited a heterogeneous surface with micro-scaled roughness.The EDX results showed that there existed an obvious amount of zinc in the agglomerated ZnTCP particles.The zinc release behavior of ZnTCP/FHA coating was slow and sustained for up to tens of days.Moreover,the zinc release process could be regulated by changing zinc content in the coating.
(5) In vitro and in vivo test of ZnTCP/FHA coating.The ZnTCP/FHA coating (Series 2) could support osteoblasts growth and showed statistically increase in cell viability in comparison with the TCP/FHA coating and FHA coating.In vivo results showed new bone formed in the gap created at the implantation site,and was in direct contact with the ZnTCP/FHA coating after 12 weeks implantation. These evaluations demonstrated that the ZnTCP/FHA coating had good cytocompatibility,the capability of accelerating bone formation and osteointegration with the implant.
(6) Electrochemical deposition of calcium phosphate/collagen extracellular matrix(ECM) mimicked layer composed of calcium phosphate/collagen was assembled on titanium substrates using electrolytic deposition method.The oxidized titanium substrates were used to simulate those with FHA bottom layers in this research.We systematically investigated the micro-structure of the layer under different parameters and the ECM mimicked layer formation mechanisms were discussed.The crystal phase of Calcium phosphate changed with the deposition parameters:at 3.0 V,pH:3.6,Ca~(2+):4.5 mM,pO_4~(3-):9 mM,the crystal was OCP;at 3.0 V,pH:3.6,Ca~(2+):4.5 mM,PO_4~(3-):9 mM,forming amorphous phase. The formation of the calcium phosphate/collagen layer involved two different electro-chemical behaviors:electrolytic deposition of Ca-P and electrophoretic deposition of collagen molecules.It is believed that the simultaneously occurrence of these two kinds of deposition was crucial to form a homogenous layer.The calcium phosphate/collagen coating showed good osetoblast cells biocompatibility.
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