功能化石墨烯为模板仿生矿物材料的可控构筑及载药研究

发布时间：2018-11-03 09:44

【摘要】：自然界的生物矿物材料(骨骼、牙齿、珍珠及贝壳等)具有优异的机械强度及韧性,这是人工合成材料和天然地质矿物材料无法比拟的,因此,关于生物矿物材料的形成机理以及相关结构仿生材料的研究,一直是材料科学领域的研究热点之一。近年来,利用功能有机模板诱导生物矿物结晶生长己经取得很多令人鼓舞的成果。石墨烯及其功能化产物作为一种新兴材料已在很多领域得到广泛的应用,但其作为模板聚合物在生物矿化领域的研究还相对较少。不同官能团修饰的石墨烯作为模板,对生物矿物矿化生长诱导的过程中仍有一些问题等待我们研究。本利用功能化石墨烯作为模板,可控构筑了几种不同微观结构的石墨烯基生物矿化复合材料。随后,我们研究了其中两种石墨烯基生物矿化复合微球作为骨药物载体的生物相容性以及对抗癌药物DOX的负载及释放性能,以进一步拓宽生物矿化材料在医学领域的潜在应用。具体内容和结论如下:利用氧化石墨烯(GOs)作为模板,采用静态逐滴滴加CaCl2和Na2CO3溶液的方法,诱导CaCO3晶体在室温条件下缓慢结晶生长,成功得到了仅在生物体内存在的亚稳态CaCO3球霰石晶体;进一步研究矿化生长的动力学实验,结果表明结晶生长时间延长至24h,GOs/CaCO3亚稳态球霰石微球依旧稳定存在;通过进行反向滴加Ca2+和CO32-离子的实验,改变GOs/CaCl2混合溶液初始pH值的实验以及还原后的石墨烯作为模板的实验,进一步详细研究了 GOs对CaCO3结晶的作用过程,表明GOs对CaCO3结晶的影响与共表面-OH和Ca2+离子之间的相互作用密切相关。羧基化石墨烯(GO-COOH)与生物贝壳体内的聚天冬氨酸-几丁质有机模板非常接近,是一种理想的生物仿生材料模板。我们利川GO-COOH为模板,采用温和缓慢静态滴加CaCl2和Na2CO3溶液的方法在GO-COOH片层表面沉积CaCO3,成功得到了GO-COOH/CaCO3复合多层结构;矿化生长动力学实验表明,多层结构在结晶反应4 h时开始出现,并且随着时间的延长稳定存在;研究发现高浓度的CaCO3阻碍了GO-COOH/CaCO3复合材料多层结构的形成,选择适合的CaCO3浓度是形成多层结构的关键;通过GO-COOH/BaSO4 复合多层结构的形成,进一步证明了研究方法的普适性。本研究提供了一种有效构筑类似贝壳多层结构的新途径。利用四乙烯五胺修饰的石墨烯(rGO-TEPA)为模板诱导CaCO3矿化结晶,成功得到了具有粗糙表面和中空结构的rGO-TEPA/CaCO3微球;进一步利用rGO-TEPA/CaCO3复合中空微球作为抗癌药物DOX的药物载体,研究这种药物载体的生物相容性以及对药物的负载及释放性能;为了验证空心结构的重要性,我们通过改变反应物浓度、温度、时间等条件,制备了具有相同尺寸、不同形貌结构的rGO-TEPA/CaCO3复合实心晶体进行相同的负载药物以及体外模拟药物释放研究。结果表明rGO-TEPA/CaCO3复合空心载体微球具有优异DOX的负载,并可以在较低pH值条件下对药物响应性释放性能。利用rGO-TEPA/CaCO3复合实心微球作为中间体,在K2HPO4溶液中采取微波水热合成的方法,得到HA包覆rGO-TEPA/CaCO3微球的rGO-TEPA/CaCO3:HA复合微球;通过柠檬酸缓冲液除去中心未完全转变的CaCO3晶体,得到rGO-TEPA/HA中空复合微球;N2吸附-脱附测试结果表明这两种微球均具有典型多孔材料的Ⅳ-type等温线与H1滞后环。进一步利用这两种微球作为抗癌药物DOX的药物载体,研究药物载体的生物相容性以及对药物的负载及释放性能,结果表明所制备的两种药物载体均具有较好的生物相容性并且能够有效负载DOX和pH响应释放性能。综上所述,我们利用不同官能团类型的功能化石墨烯,即具有-OH的氧化石墨烯、具有-COOH的羧基化石墨烯、具有-NH2的四乙烯五胺修饰的石墨烯以及不含功能化基团的石墨烯作为模板,诱导CaCO3晶体结晶生长,得到具有不同晶型结构以及微观形貌的功能化石墨烯/碳酸钙复合生物矿物材料。随后,我们进一步研究了其中两种石墨烯基生物矿化复合微球作为骨药物载体,对抗癌药物DOX的负载及释放性能。希望本论文的研究可以为石墨烯基生物矿化材料在仿生材料、生物医用材料等领域应用提供参考。
[Abstract]:Natural mineral materials (bones, teeth, pearls, shells, etc.) have excellent mechanical strength and toughness, which is made of synthetic materials and natural geological mineral materials, and therefore, The formation mechanism of biological mineral material and the research of the related structure bionic materials have always been one of the hot topics in the field of material science. In recent years, many encouraging results have been achieved through the use of functional organic templates to induce the growth of biological mineral crystals. Graphene and its functional products have been widely used in many fields as a kind of emerging materials, but they are relatively few in the field of biomineralization as template polymers. As a template, different functional groups modified graphene still have some problems waiting for us to study in the process of mineralization and growth of biological minerals. The functionalized graphene is used as a template, and graphene-based biomineralized composite materials with different microstructures are controlled. Subsequently, we studied the biocompatibility of two graphene-based biomineralized composite microspheres as bone drug carrier and the loading and release properties of anti-cancer drug DOX, so as to further expand the potential application of biomineralized materials in medical field. The specific contents and conclusions are as follows: using graphene oxide (GOs) as a template, a static drop-by-drop addition of CaCl2 and Na2CO3 solution is used to induce the slow crystallization and growth of CaCO3 crystals at room temperature. The kinetics of mineralization growth was further studied. The results showed that the growth time of crystallization was extended to 24h, and that of GOs/ CaCO 3 was still stable, and by carrying out the experiment of reverse dropping of Ca ~ (2 +) and CO32-ions, The effect of GOs on the crystallization of CaCO3 was studied by changing the initial pH value of GOs/ CaCl2 solution and the reduction of graphene as template, indicating that the influence of GOD on the crystallization of CaCO3 was closely related to the interaction between the co-surface-OH and Ca2 + ions. The chlorosulfonated graphene (GO-COOH) is very close to the polyaspartic acid-chitin organic template in the biological shell body, and is an ideal biological bionic material template. The GO-COOH/ CaCO3 composite multi-layer structure was successfully obtained by depositing CaCO3 on the surface of GO-COOH layer by adding CaCl2 and Na2CO3 solution to the surface of GO-COOH. The kinetics of mineralization growth showed that the multi-layer structure began to appear when the crystallization reaction was 4h. The results show that high concentration of CaCO3 hinders the formation of multi-layer structures of GO-COOH/ CaCO3 composites, and the selection of suitable CaCO3 concentration is the key to the formation of multi-layer structures. Through the formation of GO-COOH/ BaSO4 composite multi-layer structures, the universality of the research methods is further proved. This study provides a new approach to construct a shell-like multi-layer structure. By using tetraethylene pentylamine modified graphene (rGO-TEPA) as a template to induce the mineralization and crystallization of CaCO3, the rGO-TEPA/ CaCO3 microspheres with rough surfaces and hollow structures are successfully obtained, and the rGO-TEPA/ CaCO3 composite hollow microspheres are further utilized as the drug carriers of the anti-cancer drug DOX, the biocompatibility of the drug carrier and the loading and release properties of the drug are studied; in order to verify the importance of the hollow structure, the same size is prepared by varying the concentration, temperature, time, etc. of the reactants, The rGO-TEPA/ CaCO3 composite solid crystals with different morphological structures were subjected to the same loading drugs as well as in vitro simulated drug release studies. The results show that rGO-TEPA/ CaCO3 composite hollow carrier microspheres have excellent DOX load and can release drug responsiveness at lower pH conditions. The rGO-TEPA/ CaCO3: HA composite microspheres were obtained by using rGO-TEPA/ CaCO3 composite solid microspheres as an intermediate, and the rGO-TEPA/ CaCO3: HA composite microspheres of the HA-coated rGO-TEPA/ CaCO3 microspheres were obtained. The N2 adsorption-desorption test results show that both microspheres have the type IV-type isotherm of typical porous material and H1 lag ring. further utilizes the two microspheres as the drug carrier of the anticancer drug DOX, studies the biocompatibility of the drug carrier and the loading and release performance of the drug, The results showed that both drug carriers had better biocompatibility and were able to effectively load DOX and pH response release properties. To sum up, we utilize functionalized graphene of different functional groups, namely graphene oxide having-OH, chlorosulfonated graphene having-COOH, graphene-modified graphene having-NH2, and graphene without a functional group as a template, and inducing crystal growth of CaCO3 crystal to obtain functionalized graphene/ calcium carbonate composite biological mineral material with different crystal structure and micro-morphology. Subsequently, we studied two kinds of graphene-based biomineralized composite microspheres as the carrier of bone drugs, and the loading and release properties of anti-cancer drug DOX. It is hoped that the research of this paper can provide references for the application of graphene-based biomineralization materials in bionic materials, biomedical materials and other fields.
【学位授予单位】：哈尔滨工程大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R318.08;O613.71

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