多重响应性的智能水凝胶的制备及其应用

发布时间：2018-05-16 13:51

本文选题：刺激响应 + 超分子水凝胶　；参考：《华东师范大学》2017年硕士论文

【摘要】：水凝胶是具有可延展性的三维网状交联的软质材料,能够吸收大量水分,并能保持自身整体性质不变而被塑造成各种形状,具有很强的可变形性。水凝胶因为和人体组织具有相似的三维结构和弹性等,而作为生物材料被广泛应用于多个领域,比如在药物运输方面,组织工程方面,以及组织修复方面。在现实的生物体微环境中,如细胞外基质(Extra Cellular Matrix,ECM)的动态变化往往伴随着多种发育和疾病过程的发生。ECM的结构和组成的具体变化最终会导致基体生物物性的改变,进一步对细胞行为产生巨大的影响,包括细胞迁移、排列、增殖、形貌变化、祖细胞的分化等。同时在组织发育、肌纤维化、肿瘤生长,和心肌梗塞的过程中,基质的软硬也会发生相应的改变。不仅如此,生物体不同部位的软硬程度也是不一样的。例如,健康乳腺组织的弹性模量大概是100-200 Pa,而乳腺肿瘤组织则硬的多,大约是1-4 kPa。这是由于病变过程中,乳腺周围ECM的重塑和基质蛋白增生,胶原蛋白的不断沉积导致的,而且肿瘤的硬度随着时间以及疾病发展的严重程度会逐渐增加。再比如,在大鼠的肌纤维化过程当中,小鼠体内组织的硬度在其他任何组织学证据都检测不出已出现纤维化过程的时候,已经开始变硬了。因此为了适应生物系统本身复杂性的需求,我们对精确调节水凝胶机械性能和物理化学性质的能力也有了更高的要求,制备出硬度以及形态可调节的材料对模仿生物进程和检测疾病等方面具有很重要的意义。但静态的水凝胶不能根据环境的变化来对自身进行调节,为了适应生物体的动态变化,刺激响应性水凝胶开始受到大家的广泛关注。这些响应的刺激源包括pH,氧化还原反应,酶,温度,磁场,电场,超声和光等。而在这些刺激响应水凝胶中,光响应和酸响应水凝胶相对来说得到了更多的青睐和关注。其中光刺激作为远程调控的代表,能够定时、定点地在不接触水凝胶本身的情况下,仅仅通过光源的强度、波长等参数的变化来具体调节水凝胶的形状、强度等各项性能。此外,pH值的变化也会造成水凝胶的结构以及各项性能的改变,而生物体内也正存在不同的酸碱度环境,例如在细胞内环境中,内涵体和溶酶体都是酸性的环境;在器官水平上,胃肠道的特殊环境也存在明显的pH梯度值;除此之外,癌症和炎症化反应也会导致局部酸化。酸刺激响应作为药物控制释放的信号而广泛应用于生物医疗体系当中。因此我们主要从光响应和酸响应入手,研究多重光响应和细菌酸响应的水凝胶体系。论文的主要研究结果如下:一、设计了能够同时对两种不同的光源均有响应性的水凝胶。光响应性水凝胶可通过光刺激响应来调控自身的尺寸和力学性能,这种在时间空间上可控调节的水凝胶材料在很多领域里面具有很重要的应用。目前,已经有多个研究报道了对紫外光作出响应的水凝胶体系。然而,能同时对紫外光和近红外光两种光源做出响应的智能水凝胶之前并没有人尝试过。因此,我们设计了一种双光响应的超分子水凝胶。这个水凝胶具有光调控的主客体识别性质,温度响应性,和近红外光热能力。并且,这个水凝胶可以快速自愈合,在紫外和近红外光的调控下,能够变软或者变硬。除了可以调节水凝胶的硬度之外,还可以通过紫外光或者近红外光来调节水凝胶的弯曲方向。这种智能水凝胶有希望作为一种生物材料,通过紫外光照和近红外光照来调节细胞微环境。二、设计了酸刺激响应性水凝胶,可在细菌感染时按需释放出抗生素药物。在生物体系中,特别是细菌的生长环境中,由于细菌在生长过程中会分泌质子,细胞生长环境都是酸性的。而氨基糖苷类药物作为一类治疗细菌感染的广谱抑菌药物,在临床上却有很多不足,低于细菌最小抑制浓度持续给药会形成细菌生物膜,高剂量给药则会给患者带来不良副作用(例如,高剂量下的肾毒性和耳毒性)。因此,为了解决临床使用剂量上的矛盾,我们设计了一种酸响应调控按需给药的氨基糖苷水凝胶。用氨基糖苷药物自身做交联剂,交联氧化的多糖聚合物——右旋糖酐(葡聚糖)。并且这个水凝胶的模量、降解速率和释放速率可以在成胶过程中通过调节氨基糖苷剂量来精确调控。此外,由于氨基糖苷药物是通过进入细胞内部作用于核糖体影响蛋白质合成从而发挥药效,该过程需要消耗能量,因而该类药物仅对需氧菌有效,对于厌氧菌是没有任何作用的。为了完善抑菌材料的抗菌谱,我们引入了治疗厌氧菌的硝唑类药物-奥硝唑。我们在氨基末端的树形高分子上部分修饰了奥硝唑药物,和氨基糖苷药物一起与氧化的右旋糖酐反应成胶。所制备出的水凝胶不仅对需氧菌具有良好的治疗效果,也能高效抑制厌氧菌,并且药物的释放速率是按需可调节的。综上所述,本论文提供了一种制备刺激响应性的多功能水凝胶的新方法。相对于传统的高分子水凝胶而言,我们制备的多功能水凝胶能够在光的刺激下精确调节自身的形貌以及软硬度,并且可以按需进行药物的释放和自降解。并且我们制备水凝胶的方法简单易行。特别是我们制备的酸响应性水凝胶,能够自动识别细菌,按需给药,之后能够自行降解,没有任何副作用,具有很高的临床应用价值。
[Abstract]:Hydrogels are soft materials with extendible three-dimensional network crosslinking. They are able to absorb a large amount of water and maintain their own overall properties and are molded into various shapes and have strong deformability. Hydrogels have been widely used as biomaterials because they have similar three-dimensional structure and elasticity with human tissues. Areas, such as drug transport, tissue engineering, and tissue repair. Dynamic changes in the actual microenvironment, such as the extracellular matrix (Extra Cellular Matrix, ECM), are often accompanied by specific changes in the structure and composition of a variety of developmental and disease processes that eventually lead to the biological properties of the matrix. Changes have a great effect on cell behavior, including cell migration, arrangement, proliferation, morphologies, and differentiation of progenitor cells. In the process of tissue development, muscle fibrosis, tumor growth, and myocardial infarction, the soft and hard matrix of the matrix changes accordingly. Not only that, the soft and hard degree of different parts of the organism is also not. The same. For example, the elastic modulus of the healthy breast tissue is about 100-200 Pa, while the breast tumor tissue is much harder, about 1-4 kPa., which is due to the remodeling of ECM around the breast and the proliferation of matrix protein, the continuous deposition of collagen, and the severity of the swelling of the tumor with time and the severity of the disease. For example, in the process of muscle fibrosis in rats, the hardness of the tissues in the mice has begun to harden when any other histologic evidence does not detect the process of fibrosis. Therefore, in order to adapt to the needs of the complexity of the biological system, we can accurately regulate the mechanical properties and physics of the hydrogel. The ability of chemical properties also has higher requirements. The preparation of hardness and morphologically adjustable materials is of great importance to mimic biological processes and detect diseases. However, static hydrogels can not adjust themselves according to the changes of the environment to stimulate responsive hydrogels in order to adapt to the dynamic changes of raw materials. The stimuli of these responses include pH, redox reaction, enzyme, temperature, magnetic field, electric field, ultrasound and light, and in these irritation hydrogels, the light response and acid response hydrogels have gained more attention and attention. In the absence of contact with the hydrogel itself, the shape and strength of the hydrogel are regulated only by the changes of the intensity and wavelength of the light source. In addition, the changes in the pH value also result in the changes in the structure and various properties of the hydrogel, and there are also different acidity and alkalinity environment in the organism, such as cells. In the internal environment, both endosomes and lysosomes are acidic environments; there is an obvious pH gradient in the special environment of the gastrointestinal tract at the organ level; in addition, cancer and inflammatory reactions also lead to local acidification. Acid stimulation response as a signal for drug control release should be widely used in biological medical systems. The main research results of the paper are as follows: first, the hydrogels which can respond to two different light sources are designed. The optical responsive hydrogels can regulate their size and mechanical properties by the light stimulus response. Hydrogel materials controlled in time and space are very important in many fields. At present, there have been many studies on the hydrogel system that responds to ultraviolet light. However, before the intelligent hydrogels that respond to two sources of ultraviolet light and near infrared light, we have not tried. A double light response supramolecular hydrogel has been designed. This hydrogel has a light regulated host and guest recognition, temperature response, and near infrared photothermal capacity. And the hydrogel can be quickly self healing and can be softened or hardened under the regulation of ultraviolet and near infrared light. Besides the hardness of the hydrogel, the hydrogels can be adjusted. The flexural direction of hydrogels can be regulated by ultraviolet or near infrared light. This intelligent hydrogel is expected to be used as a biological material to regulate cell microenvironment through ultraviolet light and near infrared light. Two, an acid irritation responsive hydrogel is designed to release antibiotic drugs on demand in a bacterial infection. In the growing environment, especially in the growth environment of bacteria, the cell growth environment is acidic because of the secretion of protons in the growth process, and the aminoglycoside drugs as a kind of broad-spectrum bacteriostat to treat bacterial infection, there are many shortcomings in clinical. Therefore, in order to solve the contradiction in clinical dosage, we designed an aminoglycoside hydrogel which is regulated by the acid response, the crosslinking agent of aminoglycoside drug itself, the crosslinked polysaccharide polymer, dextran. Anhydride (dextran). And the modulus, degradation rate and release rate of this hydrogel can be regulated accurately by the dosage of aminoglycoside during the gelation process. In addition, as aminoglycoside drugs play the effect by entering the cell inside the ribosome to influence the protein synthesis, the process needs to consume energy, thus the process needs to be consumed. In order to improve the antimicrobial spectrum of the bacteriostat, we have introduced the nitrazole in the treatment of anaerobic bacteria, ornidazole. We modify the ornidazole drug on the amino terminal tree, and react with the oxidized dextran together with the amino glucoside. Glue. The prepared hydrogels not only have good therapeutic effect on aerobic bacteria, but also effectively inhibit anaerobes, and the release rate of the drug is regulated according to demand. In summary, this paper provides a new method for preparing the multifunctional hydrogels for stimulating response. The multi-functional hydrogels can adjust their morphologies and softness under the light of light, and can release and self degrade drugs on demand. And the method of preparing hydrogels is simple and easy. In particular, the acid responsive hydrogel prepared by us can automatically recognize bacteria, give medicine according to the need, and then biodegradable, It has no side effects and has high clinical value.

【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R318.08

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