石墨烯/聚合物复合材料在组织工程支架及药物载体中的应用研究
摘要
石墨烯(graphene, GNS)是碳原子紧密堆积成单层二维蜂窝状晶格结构的一种碳质新材料。自2004年英国Manchester大学的Geim等发现GNS以来,因其独特的结构和优异的力学、电学、热学及化学性能,对其研究和应用已备受关注。利用GNS作为填充材料增强聚合物的力学强度以及利用聚合物作为GNS的修饰材料对GNS进行功能化可能是复合材料领域最有前景的研究。目前,GNS及其衍生物在生物医药方面的研究和应用还处在探索阶段,如何根据实际需求对GNS/聚合物复合材料进行组织工程支架、药物载体等研究是极富挑战的工作。本课题以GNS及其衍生物GO为主要研究对象,探讨研究了GO与聚乙烯醇(PVA)复合、GO与壳聚糖(CS)复合、GNS与聚丙烯酸(PAA)复合,进行性能表征,并研究了GNS/聚合物复合材料在组织工程支架以及药物载体中的应用。主要研究内容和结果如下：
1、利用静电纺丝法制备氧化石墨烯(GO)/聚乙烯醇(PVA)纳米纤维支架。研究了PVA静电纺丝的条件以及GO加入对PVA纳米纤维的形貌、结构、机械性能及生物相容性的影响。随着GO加入量的增加,GO/PVA纳米纤维支架的直径逐渐变细并出现串珠样结构。拉伸测试发现,随着GO的加入,纳米支架的拉伸强度和弹性模量呈现先增加后降低的趋势,当GO含量为1wt%时,拉伸强度和弹性模量最大,比纯PVA纤维支架分别增加了22%和57%,当GO含量大于3wt%时,力学性能逐渐降低。成骨细胞体外培养的研究中,与纯PVA纤维支架相比,成骨细胞在GO/PVA复合纤维支架表面表现出较高的粘附,增殖和细胞活性。表明了GO/PVA复合纤维支架在组织工程领域具有良好的应用潜能。
2、利用冷冻干燥法制备了氧化石墨烯(GO)／壳聚糖(CS)多孔干凝胶。研究了GO加入对CS干凝胶形貌、结构、机械性能的影响,并探讨了其对盐酸阿霉素(DOX)的吸附及释放性能。随着GO浓度的增加,凝胶的孔径减小,压缩强度增大。复合凝胶的多孔状结构及较大的比表面积使药物吸附能力增强,当加入5wt%的GO时,GO/CS对DOX的载药量可达96mg/g,比纯CS增加了240%,同时DOX35d的释放量仅为17.4%。表明了复合凝胶具有良好的药物吸附和缓慢释放性能,可用于药物载体。
3.采用电弧放电技术制备得到较大量的GNS片,尺寸大小为50-200nm,具有良好热稳定性。利用原位聚合丙烯酸单体法制得功能化的GNS (PAA-GNS),实现了GNS在水中较好的溶解性和在体液中的稳定性,实现了阿霉素的高效担载和pH控制释放,当DOX浓度为0.35mg/ml时载药量可达2.183mg/mg,DOX在不同pH的累积释放量为：pH2>pH7>pH10。PAA-GNS是一种较为理想的纳米载体。
Graphene (GNS) is a new carbon material which is closely stacking of carbon atoms to form monolayer two-dimensional honeycomb structure. Since it was found by Geim et al. from Manchester University in2004, GNS and its derivative graphene oxide (GO) has sparked a boom in science and industry circles by virtue of its unique structure and excellent mechanical, electrical, thermal and chemical properties. GNS as a filler material to reinforce mechanical strength of polymer and polymer as the modified materials to functionalize GNS may be the most promising research in composite material field. But the application of GNS in biological medicine is still at the stage of exploration, it will be a challenge to conduct research of GNS/polymer composites for tissue engineering scaffolds and drug carrier to give full play to its excellent properties. In the reseach, we prepared and characterized GO/polyvinyl alcohol (PVA), GO/chitosan (CS) and GNS/polyacrylic acid (PAA) composites around the excellent properties of GNS and its derivative, and studied their applications in tissue engineering scaffolds and drug carrier. The main contents and results are summarized as follows:
1. GO/PVA nanofibrous scaffold was fabricated by electrospinning technology. The conditions of the PVA electrospinning and the influence of GO on the morphology, microstructure, mechanical properties and biocompatibility of PVA nanofiber were investigated. As the content of GO increased, the diameter of GO/P VA nanofibers turned to be thinner and appearing beaded structure. Increasing the content of GO up to1wt%increased the mechanical strength, but further increasing GO up to3-5%caused the decrease of mechanical strength. When GO content was1wt%, the tensile strength and elastic modulus of GO/PVA were22%and57%higher than pure PVA scaffold. On GO/PVA composite scaffold, the attachment and growth of osteoblasts were good, and the viability and morphology of cells were better than pure PVA scaffold which indicated the composite scaffolds have potential application in tissue engineering field.
2. GO/chitosan(CS) composite porous xerogels were prepared by a freeze-drying method. The influence of GO content on the morphology, microstructures, mechanical property of CS xerogel and its ability for adsorption and release of doxorubicin hydrochloride (DOX) were investigated. The adding of GO dereased the pore size of the xerogels, but increased the compressive strength. The porous structure of the composites as well as large surface of GO enhanced the drug adsorption ability. When the content of GO was5wt%, the DOX loading ability of GO/CS composites could reach96mg/g, which was240%higher than that of pure CS. The in vitro drug release showed there was only17.4%of DOX release after35d. It indicated good drug adsorption and slow release performance of GO/CS composite porous xerogels, which can be used for drug carrier.
3. Large quantities of small size GNS sheets with diameters of50-200nm were prepared by arc discharge technology. PAA functionalized GNS (PAA-GNS) was prepared by in-situ polymerization of acrylic monomers. By functionalization, the surfaces of GNS sheets were grafted with-COOH groups which improved the solubility and stability of GNS. This also facilitated chemical binding of DOX to the GNS and realized efficient loading and pH controlled release. With the increase of the initial DOX concentration, the loading capacity of DOX increased and reached2.183mg/mg when the DOX concentration was0.35mg/ml, and the release ratio of DOX in pH2was about twice that of pH7and about seven times of pH10, which indicated that PAA-GNS was the ideal nano carrier.
1、利用静电纺丝法制备氧化石墨烯(GO)/聚乙烯醇(PVA)纳米纤维支架。研究了PVA静电纺丝的条件以及GO加入对PVA纳米纤维的形貌、结构、机械性能及生物相容性的影响。随着GO加入量的增加,GO/PVA纳米纤维支架的直径逐渐变细并出现串珠样结构。拉伸测试发现,随着GO的加入,纳米支架的拉伸强度和弹性模量呈现先增加后降低的趋势,当GO含量为1wt%时,拉伸强度和弹性模量最大,比纯PVA纤维支架分别增加了22%和57%,当GO含量大于3wt%时,力学性能逐渐降低。成骨细胞体外培养的研究中,与纯PVA纤维支架相比,成骨细胞在GO/PVA复合纤维支架表面表现出较高的粘附,增殖和细胞活性。表明了GO/PVA复合纤维支架在组织工程领域具有良好的应用潜能。
2、利用冷冻干燥法制备了氧化石墨烯(GO)／壳聚糖(CS)多孔干凝胶。研究了GO加入对CS干凝胶形貌、结构、机械性能的影响,并探讨了其对盐酸阿霉素(DOX)的吸附及释放性能。随着GO浓度的增加,凝胶的孔径减小,压缩强度增大。复合凝胶的多孔状结构及较大的比表面积使药物吸附能力增强,当加入5wt%的GO时,GO/CS对DOX的载药量可达96mg/g,比纯CS增加了240%,同时DOX35d的释放量仅为17.4%。表明了复合凝胶具有良好的药物吸附和缓慢释放性能,可用于药物载体。
3.采用电弧放电技术制备得到较大量的GNS片,尺寸大小为50-200nm,具有良好热稳定性。利用原位聚合丙烯酸单体法制得功能化的GNS (PAA-GNS),实现了GNS在水中较好的溶解性和在体液中的稳定性,实现了阿霉素的高效担载和pH控制释放,当DOX浓度为0.35mg/ml时载药量可达2.183mg/mg,DOX在不同pH的累积释放量为：pH2>pH7>pH10。PAA-GNS是一种较为理想的纳米载体。
Graphene (GNS) is a new carbon material which is closely stacking of carbon atoms to form monolayer two-dimensional honeycomb structure. Since it was found by Geim et al. from Manchester University in2004, GNS and its derivative graphene oxide (GO) has sparked a boom in science and industry circles by virtue of its unique structure and excellent mechanical, electrical, thermal and chemical properties. GNS as a filler material to reinforce mechanical strength of polymer and polymer as the modified materials to functionalize GNS may be the most promising research in composite material field. But the application of GNS in biological medicine is still at the stage of exploration, it will be a challenge to conduct research of GNS/polymer composites for tissue engineering scaffolds and drug carrier to give full play to its excellent properties. In the reseach, we prepared and characterized GO/polyvinyl alcohol (PVA), GO/chitosan (CS) and GNS/polyacrylic acid (PAA) composites around the excellent properties of GNS and its derivative, and studied their applications in tissue engineering scaffolds and drug carrier. The main contents and results are summarized as follows:
1. GO/PVA nanofibrous scaffold was fabricated by electrospinning technology. The conditions of the PVA electrospinning and the influence of GO on the morphology, microstructure, mechanical properties and biocompatibility of PVA nanofiber were investigated. As the content of GO increased, the diameter of GO/P VA nanofibers turned to be thinner and appearing beaded structure. Increasing the content of GO up to1wt%increased the mechanical strength, but further increasing GO up to3-5%caused the decrease of mechanical strength. When GO content was1wt%, the tensile strength and elastic modulus of GO/PVA were22%and57%higher than pure PVA scaffold. On GO/PVA composite scaffold, the attachment and growth of osteoblasts were good, and the viability and morphology of cells were better than pure PVA scaffold which indicated the composite scaffolds have potential application in tissue engineering field.
2. GO/chitosan(CS) composite porous xerogels were prepared by a freeze-drying method. The influence of GO content on the morphology, microstructures, mechanical property of CS xerogel and its ability for adsorption and release of doxorubicin hydrochloride (DOX) were investigated. The adding of GO dereased the pore size of the xerogels, but increased the compressive strength. The porous structure of the composites as well as large surface of GO enhanced the drug adsorption ability. When the content of GO was5wt%, the DOX loading ability of GO/CS composites could reach96mg/g, which was240%higher than that of pure CS. The in vitro drug release showed there was only17.4%of DOX release after35d. It indicated good drug adsorption and slow release performance of GO/CS composite porous xerogels, which can be used for drug carrier.
3. Large quantities of small size GNS sheets with diameters of50-200nm were prepared by arc discharge technology. PAA functionalized GNS (PAA-GNS) was prepared by in-situ polymerization of acrylic monomers. By functionalization, the surfaces of GNS sheets were grafted with-COOH groups which improved the solubility and stability of GNS. This also facilitated chemical binding of DOX to the GNS and realized efficient loading and pH controlled release. With the increase of the initial DOX concentration, the loading capacity of DOX increased and reached2.183mg/mg when the DOX concentration was0.35mg/ml, and the release ratio of DOX in pH2was about twice that of pH7and about seven times of pH10, which indicated that PAA-GNS was the ideal nano carrier.
引文
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