本文選題：刺激響應 + 超分子水凝膠　； 參考：《華東師范大學》2017年碩士論文

【摘要】：水凝膠是具有可延展性的三維網(wǎng)狀交聯(lián)的軟質材料,能夠吸收大量水分,并能保持自身整體性質不變而被塑造成各種形狀,具有很強的可變形性。水凝膠因為和人體組織具有相似的三維結構和彈性等,而作為生物材料被廣泛應用于多個領域,比如在藥物運輸方面,組織工程方面,以及組織修復方面。在現(xiàn)實的生物體微環(huán)境中,如細胞外基質(Extra Cellular Matrix,ECM)的動態(tài)變化往往伴隨著多種發(fā)育和疾病過程的發(fā)生。ECM的結構和組成的具體變化最終會導致基體生物物性的改變,進一步對細胞行為產(chǎn)生巨大的影響,包括細胞遷移、排列、增殖、形貌變化、祖細胞的分化等。同時在組織發(fā)育、肌纖維化、腫瘤生長,和心肌梗塞的過程中,基質的軟硬也會發(fā)生相應的改變。不僅如此,生物體不同部位的軟硬程度也是不一樣的。例如,健康乳腺組織的彈性模量大概是100-200 Pa,而乳腺腫瘤組織則硬的多,大約是1-4 kPa。這是由于病變過程中,乳腺周圍ECM的重塑和基質蛋白增生,膠原蛋白的不斷沉積導致的,而且腫瘤的硬度隨著時間以及疾病發(fā)展的嚴重程度會逐漸增加。再比如,在大鼠的肌纖維化過程當中,小鼠體內組織的硬度在其他任何組織學證據(jù)都檢測不出已出現(xiàn)纖維化過程的時候,已經(jīng)開始變硬了。因此為了適應生物系統(tǒng)本身復雜性的需求,我們對精確調節(jié)水凝膠機械性能和物理化學性質的能力也有了更高的要求,制備出硬度以及形態(tài)可調節(jié)的材料對模仿生物進程和檢測疾病等方面具有很重要的意義。但靜態(tài)的水凝膠不能根據(jù)環(huán)境的變化來對自身進行調節(jié),為了適應生物體的動態(tài)變化,刺激響應性水凝膠開始受到大家的廣泛關注。這些響應的刺激源包括pH,氧化還原反應,酶,溫度,磁場,電場,超聲和光等。而在這些刺激響應水凝膠中,光響應和酸響應水凝膠相對來說得到了更多的青睞和關注。其中光刺激作為遠程調控的代表,能夠定時、定點地在不接觸水凝膠本身的情況下,僅僅通過光源的強度、波長等參數(shù)的變化來具體調節(jié)水凝膠的形狀、強度等各項性能。此外,pH值的變化也會造成水凝膠的結構以及各項性能的改變,而生物體內也正存在不同的酸堿度環(huán)境,例如在細胞內環(huán)境中,內涵體和溶酶體都是酸性的環(huán)境;在器官水平上,胃腸道的特殊環(huán)境也存在明顯的pH梯度值;除此之外,癌癥和炎癥化反應也會導致局部酸化。酸刺激響應作為藥物控制釋放的信號而廣泛應用于生物醫(yī)療體系當中。因此我們主要從光響應和酸響應入手,研究多重光響應和細菌酸響應的水凝膠體系。論文的主要研究結果如下:一、設計了能夠同時對兩種不同的光源均有響應性的水凝膠。光響應性水凝膠可通過光刺激響應來調控自身的尺寸和力學性能,這種在時間空間上可控調節(jié)的水凝膠材料在很多領域里面具有很重要的應用。目前,已經(jīng)有多個研究報道了對紫外光作出響應的水凝膠體系。然而,能同時對紫外光和近紅外光兩種光源做出響應的智能水凝膠之前并沒有人嘗試過。因此,我們設計了一種雙光響應的超分子水凝膠。這個水凝膠具有光調控的主客體識別性質,溫度響應性,和近紅外光熱能力。并且,這個水凝膠可以快速自愈合,在紫外和近紅外光的調控下,能夠變軟或者變硬。除了可以調節(jié)水凝膠的硬度之外,還可以通過紫外光或者近紅外光來調節(jié)水凝膠的彎曲方向。這種智能水凝膠有希望作為一種生物材料,通過紫外光照和近紅外光照來調節(jié)細胞微環(huán)境。二、設計了酸刺激響應性水凝膠,可在細菌感染時按需釋放出抗生素藥物。在生物體系中,特別是細菌的生長環(huán)境中,由于細菌在生長過程中會分泌質子,細胞生長環(huán)境都是酸性的。而氨基糖苷類藥物作為一類治療細菌感染的廣譜抑菌藥物,在臨床上卻有很多不足,低于細菌最小抑制濃度持續(xù)給藥會形成細菌生物膜,高劑量給藥則會給患者帶來不良副作用(例如,高劑量下的腎毒性和耳毒性)。因此,為了解決臨床使用劑量上的矛盾,我們設計了一種酸響應調控按需給藥的氨基糖苷水凝膠。用氨基糖苷藥物自身做交聯(lián)劑,交聯(lián)氧化的多糖聚合物——右旋糖酐(葡聚糖)。并且這個水凝膠的模量、降解速率和釋放速率可以在成膠過程中通過調節(jié)氨基糖苷劑量來精確調控。此外,由于氨基糖苷藥物是通過進入細胞內部作用于核糖體影響蛋白質合成從而發(fā)揮藥效,該過程需要消耗能量,因而該類藥物僅對需氧菌有效,對于厭氧菌是沒有任何作用的。為了完善抑菌材料的抗菌譜,我們引入了治療厭氧菌的硝唑類藥物-奧硝唑。我們在氨基末端的樹形高分子上部分修飾了奧硝唑藥物,和氨基糖苷藥物一起與氧化的右旋糖酐反應成膠。所制備出的水凝膠不僅對需氧菌具有良好的治療效果,也能高效抑制厭氧菌,并且藥物的釋放速率是按需可調節(jié)的。綜上所述,本論文提供了一種制備刺激響應性的多功能水凝膠的新方法。相對于傳統(tǒng)的高分子水凝膠而言,我們制備的多功能水凝膠能夠在光的刺激下精確調節(jié)自身的形貌以及軟硬度,并且可以按需進行藥物的釋放和自降解。并且我們制備水凝膠的方法簡單易行。特別是我們制備的酸響應性水凝膠,能夠自動識別細菌,按需給藥,之后能夠自行降解,沒有任何副作用,具有很高的臨床應用價值。
[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.

【學位授予單位】：華東師范大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R318.08

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