改性HAP基多孔生物陶瓷的制备与性能研究
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摘要
多孔羟基磷灰石(HAP)基生物陶瓷因为与人体骨骼的无机化合成分相似,具有很好的生物相容性和成骨与诱导骨形成的导向作用,已被广泛用作生物体硬组织修复。目前,有关多孔HAP陶瓷在医学领域的研究已经延伸到将其作为药物载体以及抗肿瘤活性上,且发现将多孔陶瓷作为药物载体有广泛的应用前景和重要的研究价值。本论文以多孔陶瓷作为药物控释缓释载体为研究背景,为制备出满足实际需要的多孔体,对材料的组成进行了设计,研制了以纳米生物玻璃作为增强相、纳米炭粉为成孔剂的工艺,并对多孔材料的结构和性能进行了表征。采用不同溶液对多孔陶瓷进行了渗透与反渗透评估,通过体外RSC96细胞与材料的作用,对其进行生物学评价等。主要内容如下：
合成了形貌不同的羟基磷灰石纳米粒子,并分析讨论了影响HAP形貌的主要参数。通过异质凝结机制,利用TEOS水解对经十二烷醇酯化后的HAP纳米粒子进行表面SiO2包覆改性(HAPSi050),研究了不同SiO2含量对产物包覆率及其在水和酸溶液中溶解性能的影响。改性后获得的粒子通过FT-IR、XRD、 SEM-EDS、HR-TEM、TG-DSC和Zeta电位等分析方法表征合成的SiO2改性HAP的结构与性能,并观察了其在水溶液中的悬浮稳定性能。结果表明：SiO2包覆层厚度大约为3nm,表面改性后,Zeta电势均为负值,粒子在水溶液中的悬浮稳定性提高了5倍,抗酸溶解能力增强。
通过W/O型微乳液技术合成了SiO2-CaO-P2O5系统生物活性玻璃纳米粒子,探讨了水与表面活性剂的摩尔比ω的变化对合成的纳米粒子结构和性能的影响。并对合成的粒子进行了体外降解和与RSC96细胞联合培养的研究。采用FTIR、 XRD、SEM-EDS、XRF、TEM、BET比表面积分析仪和激光粒度分析仪等手段对合成的和经过降解的纳米玻璃粒子进行表征,结果表明：合成的球形纳米玻璃粒子尺寸在100nnm左右,分布均匀,分散性较好；颗粒之间彼此连接而具有微孔结构,测得的比表面积和孔体积分别为137.9cm3/g和0.37cm3/g。测定降解过程中降解介质pH值、离子溶出行为表明：材料在生理环境中,经过较短的时间即可在玻璃颗粒表面形成类骨HCA,同时有离子溶出现象发生,说明材料具有较高的体外生物活性和良好的降解性能。材料在降解过程中溶液的pH值略呈上升的趋势,基本处于中性。MTT实验测试细胞增殖表明材料能促进细胞的增殖,说明合成的纳米玻璃粒子有良好的细胞亲和性,可作为生物材料使用。
以HAPSi050纳米粉体为原料,SiO2-CaO-P2O5系统生物玻璃为增强相,纳米活性炭粉作造孔剂,制备出了孔径彼此贯通、分布均匀、且孔隙率可调的多孔生物陶瓷。利用XRD、SEM等手段测试多孔体的相组成及微观形貌,采用万能试验机、硬度计以及渗透率测试仪测定多孔孔体的力学性能及流体渗透率。并应用ANSYS软件和图像处理技术进一步分析孔形貌对力学性能的影响。结果发现：抗折强度随烧结温度和生物玻璃含量的增加而升高,气孔率和渗透率则随相应因素的升高而降低。气孔率和渗透率随炭粉含量增加呈上升趋势,但是抗弯强度却逐渐降低。图像处理和ANSYS分析表明：试样中孔越圆、近圆形孔的数量越多、孔分布越均匀,多孔体力学性能越高。
多孔陶瓷经模拟体液浸泡,测定矿化过程中材料失重率、抗折强度的变化和采用扫描电子显微镜(SEM)观察材料微观结构变化表明：浸泡初期试样表面即有类骨磷灰石形成,预示着材料有较好的生物矿化能力。但同时,试样的质量和抗折强度降低。之后,随着试样表面类骨磷灰石数量的增多,试样的质量和强度又开始回升并逐渐增加。将RSC96细胞与多孔陶瓷体外联合培养,通过细胞增殖、细胞毒性、SEM观察进行生物学评价。噻唑蓝(MTT)比色法表明多孔体材料能促进细胞的增殖；吉姆萨和荧光探针技术测试细胞毒性表明多孔材料与对照组单相HAP一致；SEM观察表明RSC96细胞在多孔材料上铺展良好,证明多孔体具有良好的细胞亲和性和生物活性。
As a new kind of functional material, porous hydroxyapatite(HAP) bioceramics have been developed and some of them are now applied to repair and reconstruct diseased or damaged bones or tissues. At present, the porous HAP-based ceramic has extended to use as drug carrier and antitumor activity, due to it not only possess good biocompatiblity but also can modulate cellular activities, including cell adhesion, migration, DNA synthesis, and protein secretion, implying a promising application in biomedical field. In this dissertation, A novel porous bioceramics with the good bioactivity, biocompatibility and degradablility were designed and synthesized for bone regeneration and drug delivery. The structure and properties of the synthesized porous body were characterized by different methods. Biological evaluation of materials was carried out, via soaked simulated body fluid(SBF), by cultivating RSC96Schwann cells on the surface of the materials. The major work is summarized as the following:
The ball,rod and fibrous HAP nanoparticles were synthesized successfully in this part.The influences of reaction temperature, dropping speed of solution,the change of pH value and stirring speed on the particle morphology were investigated.Nanophase HAP particles were coated with silica via the hydrolysis of tetraethyl orthosilicate after a dodecyl alcohol based esterification reaction. The silicate-coated HAP(HAPSi050) particles were characterized by TEM, SEM, XRD, FTIR, thermogravimetry and differential scanning calorimetry (DSC), sedimentation time and zeta potential (ξ) studies. A sequential change in infrared spectral features characteristic of HAP was accompanied by an increase in features characteristic of silica as revealed by FTIR. The results indicate that the SiO2Coating thickness is about3nm. The silica coating enhanced the colloidal stability of HAP in aqueous suspensions and antiacid dissolving capacity. This behavior can be explained based on a heterocoagulation coating mechanism in which silica clusters adsorb onto the HAP particle surface.
The system of SiO2-CaO-O5bioactive glasses (BG) with a particle size less than100nm were successfully synthesized by W/O microemulsion approach.XRD, SEM and EDX analyses,X-ray fluorescence (XRF), laser particle size analyzer,TEM,FTIR, BET N2gas adsorption analysis techniques were utilized in order to evaluate the phase composition, dimension,morphology,interconnectivity of pores and particle size of the synthesized BG respectiveely. The measured BET specific surface area and pore volume was137.9cm2/g and0.37cm3/g respectively.The results of the degradation in vitro show that the pH value of degradation medium tended to rise but still in the range of neutral during the whole degradation time. That improved the BG is biodegradable.MTT assay showed that BG has been shown to have good biocompatibility and is also beneficial to the survival of Schwann cells,which can promote cell proliferation.
During the preparation of porous HAPSi050-based ceramics with carbon powder, which was used as pore producer, and the SiO2-CaO-P2O5system bioglass as the reinforced phase.the calcinations temperatures,bioglass content,carbon powder content and the holding time were analyzed. The phase composition and microstructure of porous body were investigated by XRD and SEM. The universal testing machine, hardness tester, and permeability tester were used to determine the mechanical properties and fluid permeability of porous body. Result indicates that The bending strength would improve along with the increase of sintering temperature and bioglass content, the porosity and thepermeability were lower as a result. With the increase of carbon powder content, the porosity and permeability increases, but the bending strength gradually reduce as a result.The number of shapeless inter-agglomerate pores decreased and amount of spherical intra-agglomerate pores increased on increasing the sintering temperature from1100℃to1250℃. The shape of pores also changed with thermal treatment of specimens; the small pores remained spherical while the larger pores became more spherical in shape, as was proved by image analysis. A three-dimensional, finite element unit cell model was applied to evaluate the influence of pore shape on the mechanical strength of HAPSi050-based ceramics. By analyzing the effect of the shape of pores to the fracture toughness of sintered porous bioceramics, it was observed that the more spherical the pores were, the tougher became the bioceramics. After sintering at1250℃for2h, measured toughness was1.29MPa m1/2, which is a relatively high value for this type of bioceramics.
The sample,which was soaked in SBF solution,lost the mass quickly in the beginning because of the dissolution.The dissolution reduced the decrease of the bending strength.After5days,the bone-like hydroxyapatite layer emerged,and it existed in the form of tiny crystallite,which size was30～50nm,and the mass of sample was growing.The bending strength should increase with the longer time,and the bone-like hydroxyapatite layer over-covered the sample surface completely after25days. After cultivating RSC96Schwann cells on the surface of porous materials, Biological evaluation were carried out through cell proliferation, cytotoxicity and SEM observation. The viability using MTT assay of RSC96cells seeded on porous ceramics disc showed that porous ceramics could promote cells adhesion and proliferation. Giemsa test and Fluorescent probe technology indicated that cytotoxicity of porous ceramics is similar to HAP, which suggested it is non-toxic. The SEM results showed that porous samples has better cell affinity than HAP. All of the above results suggested that the porous ceramic was non-toxic and could support the cell attachment and proliferation.
合成了形貌不同的羟基磷灰石纳米粒子,并分析讨论了影响HAP形貌的主要参数。通过异质凝结机制,利用TEOS水解对经十二烷醇酯化后的HAP纳米粒子进行表面SiO2包覆改性(HAPSi050),研究了不同SiO2含量对产物包覆率及其在水和酸溶液中溶解性能的影响。改性后获得的粒子通过FT-IR、XRD、 SEM-EDS、HR-TEM、TG-DSC和Zeta电位等分析方法表征合成的SiO2改性HAP的结构与性能,并观察了其在水溶液中的悬浮稳定性能。结果表明：SiO2包覆层厚度大约为3nm,表面改性后,Zeta电势均为负值,粒子在水溶液中的悬浮稳定性提高了5倍,抗酸溶解能力增强。
通过W/O型微乳液技术合成了SiO2-CaO-P2O5系统生物活性玻璃纳米粒子,探讨了水与表面活性剂的摩尔比ω的变化对合成的纳米粒子结构和性能的影响。并对合成的粒子进行了体外降解和与RSC96细胞联合培养的研究。采用FTIR、 XRD、SEM-EDS、XRF、TEM、BET比表面积分析仪和激光粒度分析仪等手段对合成的和经过降解的纳米玻璃粒子进行表征,结果表明：合成的球形纳米玻璃粒子尺寸在100nnm左右,分布均匀,分散性较好；颗粒之间彼此连接而具有微孔结构,测得的比表面积和孔体积分别为137.9cm3/g和0.37cm3/g。测定降解过程中降解介质pH值、离子溶出行为表明：材料在生理环境中,经过较短的时间即可在玻璃颗粒表面形成类骨HCA,同时有离子溶出现象发生,说明材料具有较高的体外生物活性和良好的降解性能。材料在降解过程中溶液的pH值略呈上升的趋势,基本处于中性。MTT实验测试细胞增殖表明材料能促进细胞的增殖,说明合成的纳米玻璃粒子有良好的细胞亲和性,可作为生物材料使用。
以HAPSi050纳米粉体为原料,SiO2-CaO-P2O5系统生物玻璃为增强相,纳米活性炭粉作造孔剂,制备出了孔径彼此贯通、分布均匀、且孔隙率可调的多孔生物陶瓷。利用XRD、SEM等手段测试多孔体的相组成及微观形貌,采用万能试验机、硬度计以及渗透率测试仪测定多孔孔体的力学性能及流体渗透率。并应用ANSYS软件和图像处理技术进一步分析孔形貌对力学性能的影响。结果发现：抗折强度随烧结温度和生物玻璃含量的增加而升高,气孔率和渗透率则随相应因素的升高而降低。气孔率和渗透率随炭粉含量增加呈上升趋势,但是抗弯强度却逐渐降低。图像处理和ANSYS分析表明：试样中孔越圆、近圆形孔的数量越多、孔分布越均匀,多孔体力学性能越高。
多孔陶瓷经模拟体液浸泡,测定矿化过程中材料失重率、抗折强度的变化和采用扫描电子显微镜(SEM)观察材料微观结构变化表明：浸泡初期试样表面即有类骨磷灰石形成,预示着材料有较好的生物矿化能力。但同时,试样的质量和抗折强度降低。之后,随着试样表面类骨磷灰石数量的增多,试样的质量和强度又开始回升并逐渐增加。将RSC96细胞与多孔陶瓷体外联合培养,通过细胞增殖、细胞毒性、SEM观察进行生物学评价。噻唑蓝(MTT)比色法表明多孔体材料能促进细胞的增殖；吉姆萨和荧光探针技术测试细胞毒性表明多孔材料与对照组单相HAP一致；SEM观察表明RSC96细胞在多孔材料上铺展良好,证明多孔体具有良好的细胞亲和性和生物活性。
As a new kind of functional material, porous hydroxyapatite(HAP) bioceramics have been developed and some of them are now applied to repair and reconstruct diseased or damaged bones or tissues. At present, the porous HAP-based ceramic has extended to use as drug carrier and antitumor activity, due to it not only possess good biocompatiblity but also can modulate cellular activities, including cell adhesion, migration, DNA synthesis, and protein secretion, implying a promising application in biomedical field. In this dissertation, A novel porous bioceramics with the good bioactivity, biocompatibility and degradablility were designed and synthesized for bone regeneration and drug delivery. The structure and properties of the synthesized porous body were characterized by different methods. Biological evaluation of materials was carried out, via soaked simulated body fluid(SBF), by cultivating RSC96Schwann cells on the surface of the materials. The major work is summarized as the following:
The ball,rod and fibrous HAP nanoparticles were synthesized successfully in this part.The influences of reaction temperature, dropping speed of solution,the change of pH value and stirring speed on the particle morphology were investigated.Nanophase HAP particles were coated with silica via the hydrolysis of tetraethyl orthosilicate after a dodecyl alcohol based esterification reaction. The silicate-coated HAP(HAPSi050) particles were characterized by TEM, SEM, XRD, FTIR, thermogravimetry and differential scanning calorimetry (DSC), sedimentation time and zeta potential (ξ) studies. A sequential change in infrared spectral features characteristic of HAP was accompanied by an increase in features characteristic of silica as revealed by FTIR. The results indicate that the SiO2Coating thickness is about3nm. The silica coating enhanced the colloidal stability of HAP in aqueous suspensions and antiacid dissolving capacity. This behavior can be explained based on a heterocoagulation coating mechanism in which silica clusters adsorb onto the HAP particle surface.
The system of SiO2-CaO-O5bioactive glasses (BG) with a particle size less than100nm were successfully synthesized by W/O microemulsion approach.XRD, SEM and EDX analyses,X-ray fluorescence (XRF), laser particle size analyzer,TEM,FTIR, BET N2gas adsorption analysis techniques were utilized in order to evaluate the phase composition, dimension,morphology,interconnectivity of pores and particle size of the synthesized BG respectiveely. The measured BET specific surface area and pore volume was137.9cm2/g and0.37cm3/g respectively.The results of the degradation in vitro show that the pH value of degradation medium tended to rise but still in the range of neutral during the whole degradation time. That improved the BG is biodegradable.MTT assay showed that BG has been shown to have good biocompatibility and is also beneficial to the survival of Schwann cells,which can promote cell proliferation.
During the preparation of porous HAPSi050-based ceramics with carbon powder, which was used as pore producer, and the SiO2-CaO-P2O5system bioglass as the reinforced phase.the calcinations temperatures,bioglass content,carbon powder content and the holding time were analyzed. The phase composition and microstructure of porous body were investigated by XRD and SEM. The universal testing machine, hardness tester, and permeability tester were used to determine the mechanical properties and fluid permeability of porous body. Result indicates that The bending strength would improve along with the increase of sintering temperature and bioglass content, the porosity and thepermeability were lower as a result. With the increase of carbon powder content, the porosity and permeability increases, but the bending strength gradually reduce as a result.The number of shapeless inter-agglomerate pores decreased and amount of spherical intra-agglomerate pores increased on increasing the sintering temperature from1100℃to1250℃. The shape of pores also changed with thermal treatment of specimens; the small pores remained spherical while the larger pores became more spherical in shape, as was proved by image analysis. A three-dimensional, finite element unit cell model was applied to evaluate the influence of pore shape on the mechanical strength of HAPSi050-based ceramics. By analyzing the effect of the shape of pores to the fracture toughness of sintered porous bioceramics, it was observed that the more spherical the pores were, the tougher became the bioceramics. After sintering at1250℃for2h, measured toughness was1.29MPa m1/2, which is a relatively high value for this type of bioceramics.
The sample,which was soaked in SBF solution,lost the mass quickly in the beginning because of the dissolution.The dissolution reduced the decrease of the bending strength.After5days,the bone-like hydroxyapatite layer emerged,and it existed in the form of tiny crystallite,which size was30～50nm,and the mass of sample was growing.The bending strength should increase with the longer time,and the bone-like hydroxyapatite layer over-covered the sample surface completely after25days. After cultivating RSC96Schwann cells on the surface of porous materials, Biological evaluation were carried out through cell proliferation, cytotoxicity and SEM observation. The viability using MTT assay of RSC96cells seeded on porous ceramics disc showed that porous ceramics could promote cells adhesion and proliferation. Giemsa test and Fluorescent probe technology indicated that cytotoxicity of porous ceramics is similar to HAP, which suggested it is non-toxic. The SEM results showed that porous samples has better cell affinity than HAP. All of the above results suggested that the porous ceramic was non-toxic and could support the cell attachment and proliferation.
引文
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