本文選題：仿生材料　切入點(diǎn)：類GAG聚合物　出處：《蘇州大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：仿生材料學(xué),是指從分子水平上研究天然物質(zhì)的結(jié)構(gòu)特點(diǎn)和構(gòu)效關(guān)系,進(jìn)而開(kāi)發(fā)出類似或優(yōu)于原天然物質(zhì)功能的新型材料。仿生的策略廣泛應(yīng)用于生物材料領(lǐng)域,通過(guò)模擬生命體中各種生物物質(zhì)(如蛋白質(zhì)和細(xì)胞等)的分子結(jié)構(gòu),促進(jìn)相關(guān)的生物反應(yīng),將有利于材料與生命體的融合及材料生物功能的實(shí)現(xiàn)。生物物質(zhì)之間的相互作用大致可分為活性結(jié)合與惰性排斥兩種,前者是實(shí)現(xiàn)生命體內(nèi)各種生理活動(dòng)的途徑,后者是保證各種生物活性激活的特異性和準(zhǔn)確性的前提。因此,生物材料的仿生策略也應(yīng)包含惰性和活性兩個(gè)方面,即,在惰性背景之上特異性激活目標(biāo)生物學(xué)過(guò)程,這樣才能保證其功能的有效性。而仿生的核心環(huán)節(jié)則是模擬生物物質(zhì)的功能性分子結(jié)構(gòu),進(jìn)而實(shí)現(xiàn)類似的生物相互作用。細(xì)胞是生物體基本的結(jié)構(gòu)和功能單元,其功能的實(shí)現(xiàn)依賴于細(xì)胞膜特殊的分子構(gòu)成。細(xì)胞膜的磷脂結(jié)構(gòu)提供了細(xì)胞內(nèi)外環(huán)境之間的惰性屏障,而磷脂雙分子層中結(jié)合的膜蛋白和膜糖等分子則介導(dǎo)了細(xì)胞與周圍環(huán)境之間的信息、物質(zhì)和能量的交換。本論文從仿生的角度出發(fā),通過(guò)分子設(shè)計(jì),分別模擬細(xì)胞膜中對(duì)細(xì)胞分化起關(guān)鍵作用的糖胺聚糖(glycosaminoglycan, GAG)成分以及作為惰性屏障的磷脂分子結(jié)構(gòu),探索了這些仿生分子在誘導(dǎo)干細(xì)胞向神經(jīng)方向分化以及抗蛋白吸附方面的功能性。具體包含以下兩部分內(nèi)容：1.仿細(xì)胞膜糖結(jié)構(gòu)的GAG類似物的合成及其對(duì)干細(xì)胞向神經(jīng)方向分化行為的影響。GAG是細(xì)胞膜表面主要的糖結(jié)構(gòu),能夠結(jié)合細(xì)胞質(zhì)基質(zhì)中多種蛋白質(zhì),是細(xì)胞信息傳遞過(guò)程中的主要媒介,特別在調(diào)控干細(xì)胞行為方面有顯著影響。然而,GAG分子結(jié)構(gòu)的多樣性與不可控制性限制了其在生物工程方面的廣泛應(yīng)用。通過(guò)分子設(shè)計(jì),模擬關(guān)鍵的GAG功能性分子結(jié)構(gòu),制備結(jié)構(gòu)精確可控的GAG類似物,則可以取代天然GAG,實(shí)現(xiàn)相應(yīng)的生物學(xué)功能。GAG的功能性分子結(jié)構(gòu)主要包含硫酸酯基團(tuán)和糖環(huán)結(jié)構(gòu),因此本論文分別采用小分子合成及共聚的方式實(shí)現(xiàn)了這兩種結(jié)構(gòu)的有機(jī)結(jié)合,獲得了GAG類似物。首先,對(duì)糖類分子p-環(huán)糊精(β-cyclodextrin, β-CD)進(jìn)行磺化改性,制備GAG類似物。分別通過(guò)硫-溴點(diǎn)擊反應(yīng)與銅催化疊氮-端炔環(huán)加成反應(yīng)在β-CD上修飾了磺酸基團(tuán),得到分子結(jié)構(gòu)有所差異的磺化β-CD:β-CD-(S-SO3Na)7與β-CD-(N3-SO3Na)7。細(xì)胞實(shí)驗(yàn)結(jié)果表明,這兩種GAG類似物加入細(xì)胞培養(yǎng)液中均可促進(jìn)L929細(xì)胞及胚胎干細(xì)胞生長(zhǎng),與天然GAG肝素相比,細(xì)胞數(shù)量沒(méi)有明顯差別,說(shuō)明具有良好的細(xì)胞相容性。在誘導(dǎo)干細(xì)胞向神經(jīng)方向分化的過(guò)程中,β-CD-(S-SO3Na)7與β-CD-(N3-SO3Na)7表現(xiàn)出較肝素更高的促分化效率。培養(yǎng)14天時(shí),β-CD-(S-SO3Na)7與β-CD-(N3-SO3Na)7促進(jìn)干細(xì)胞向神經(jīng)分化的效率分別為肝素的1.2倍與1.9倍,而未磺化的β-CD其效率僅為肝素的0.6倍,與空白對(duì)照組相比無(wú)顯著差異。因此,通過(guò)對(duì)糖類分子p-CD的磺化改性,可模擬天然GAG分子在促干細(xì)胞分化方面的生物學(xué)功能。在此基礎(chǔ)上,為了進(jìn)一步模擬GAG的長(zhǎng)鏈結(jié)構(gòu),并調(diào)節(jié)功能性組分的相對(duì)含量,提出了制備GAG類似物的新概念,即,將GAG分子中“磺酸基團(tuán)”與“糖基團(tuán)”單元進(jìn)行拆分和重組。首先,分別合成含有“磺酸基團(tuán)”與“糖基團(tuán)”的單體,利用可逆加成-斷裂鏈轉(zhuǎn)移聚合(Reversible Addition-Fragmentation Chain Transfer Polymerization, RAFT)共聚合和方式將兩種功能性單元進(jìn)行組合。通過(guò)改變投料比,可以精確調(diào)控共聚物中“磺酸基團(tuán)”與“糖基團(tuán)”的相對(duì)含量。細(xì)胞實(shí)驗(yàn)結(jié)果表明,該GAG類似物具有良好的細(xì)胞相容性,加入干細(xì)胞培養(yǎng)液中能夠促進(jìn)干細(xì)胞增殖。在誘導(dǎo)干細(xì)胞向神經(jīng)方向分化的過(guò)程中,GAG類似物的存在能夠提高分化效率,提高的程度與共聚物的組分相關(guān)。當(dāng)磺酸基團(tuán)與糖基團(tuán)比例接近1：1時(shí),共聚物促干細(xì)胞向神經(jīng)分化的效率最高,是肝素的3.1倍。因此,這種類GAG共聚物可以通過(guò)精確調(diào)控功能單元的組成,實(shí)現(xiàn)更優(yōu)于天然GAG的生物學(xué)功能。2.仿細(xì)胞膜磷脂結(jié)構(gòu)的兩性離子聚合物表面的制備及其抗蛋白吸附性能研究。磷脂雙分子層外壁的兩性離子結(jié)構(gòu)是賦予細(xì)胞膜惰性屏障功能的關(guān)鍵,因此利用兩性離子分子修飾的材料表面具有良好的抗污性能,而發(fā)展簡(jiǎn)單普適的修飾方法則是使兩性離子表面得以廣泛應(yīng)用的關(guān)鍵環(huán)節(jié)。本文將末端帶有黏性分子3,4-二羥基苯基-L-丙氨酸(3,4-dihydroxyphenyl-L-alanine, DOPA)的兩性離子聚合物修飾在材料表面,研究了其抗蛋白質(zhì)吸附的功能。利用修飾了DOPA的原子轉(zhuǎn)移自由基聚合物(AtomTransfer Radical Polymerization, ATRP)引發(fā)劑分別引發(fā)單體磺酸基甜菜堿(sulfobetaine, SB)和羧酸基甜菜堿(carboxybetaine, CB)的聚合,制備了具有不同分子量的聚磺酸甜菜堿聚合物(poly (sulfobetaine), pSB)與聚羧酸甜菜堿聚合物(poly (carboxybetaine), pCB),并將其修飾在聚二甲基硅氧烷彈性體(polydimethylsiloxane, PDMS)表面。蛋白質(zhì)吸附結(jié)果表明,聚合物分子量在一定范圍內(nèi)的增加有利于提高相應(yīng)聚合物改性表面的抗蛋白質(zhì)吸附能力；增加聚合物末端的DOPA數(shù)量有利于獲得更為致密的聚合物修飾層,從而進(jìn)一步提高了改性表面的抗蛋白質(zhì)吸附能力。此外,在聚合物接枝過(guò)程中加入多巴胺小分子,也有利于提高聚合物層的致密性,從而進(jìn)一步降低蛋白質(zhì)吸附量。本論文從仿生細(xì)胞膜的角度出發(fā)分別獲得了具有生物活性的GAG類似物及具有生物惰性的兩性離子分子修飾的材料表面。未來(lái)的努力方向應(yīng)是在材料界面將兩者有機(jī)結(jié)合,抑制非特異性反應(yīng)的同時(shí)促進(jìn)目標(biāo)生物活性,實(shí)現(xiàn)更全面的仿生功能。
[Abstract]:Biomimetic materials science, refers to the structure characteristics of the natural substances at the molecular level and structure-activity relationship, and develop new materials similar to or better than the original natural material function. Biomimetic strategy is widely used in the field of biological materials, through the simulation of various biological substances in life (such as protein and cell molecular structure, etc.) promote the biological reaction related, will be conducive to the realization of material and material life of the fusion and biological function. The interaction between biological materials can be divided into two kinds of binding activity and inert exclusion, the former is the way to realize the life in a variety of physiological activities, which is a prerequisite to ensure the specificity and accuracy of activation of various biological activity the strategy of bionics. Therefore, biological materials should also include two aspects, namely inert and active, activation of target biological processes in an inert background on specific, so as to protect Validity of their function. And it is the core link of bionic simulation of functional molecular structure of biological materials, so as to realize the interaction of similar biological cells. The organism is the structure and function of the basic unit, to achieve its function depend on the specific cell membrane phospholipids. The molecular structure of cell membrane provides inert barrier between the cells of the internal and external environment, and the combination of the phospholipid bilayer membrane proteins and membrane sugar molecules mediate between the cell and the surrounding environment information, the exchange of material and energy. From the point of view of biomimetic, through molecular design, simulate glycosaminoglycan plays a key role in cell differentiation in cell membranes (glycosaminoglycan, GAG) as well as the composition of phospholipid molecular structure of inert barrier, explored these bionic molecules in inducing stem cells to neural differentiation and anti protein adsorption. Can. Includes the following two parts: the synthesis and its effect on neural stem cell differentiation to the direction of the behaviors of the.GAG analogues of GAG 1. cell membrane mimetic structure of sugar is sugar structure of cell membrane surface mainly, can be combined with a variety of proteins in the cytoplasmic matrix, the cell information transmission medium in the process, especially significant effects in the regulation of stem cell behavior. However, the diversity of the molecular structure of GAG and could not be controlled to limit its application in biological engineering. Through molecular design, simulation GAG functional molecular structure key, GAG analogs are prepared accurately controllable structure, can replace natural functional GAG. The molecular structure of biological functions of the corresponding.GAG mainly contains sulfate group and sugar ring structure, so this paper respectively using small molecule synthesis and copolymerization of the structure of these two kinds of organic With access to the GAG analogues. First of all, the carbohydrate molecules p- cyclodextrin (P -cyclodextrin, P -CD) were sulfonated, preparation of GAG analogues. By sulfur bromine click reaction with copper - catalyzed azide alkyne cycloaddition reaction of sulfonic acid groups in modified beta -CD, obtained by the sulfonation beta -CD: beta -CD- molecular structure difference (S-SO3Na) 7 and -CD- (N3-SO3Na) 7. beta cells. The experimental results show that these two kinds of GAG analogues were added into the culture medium can promote the growth of L929 cells and embryonic stem cells, compared with natural GAG heparin, there was no difference in the number of cells, that has good cell compatibility. The differentiation of neural stem cells in the direction of induction, beta 7 and beta -CD- (S-SO3Na) -CD- (N3-SO3Na) 7 showed heparin can promote the differentiation of higher efficiency. When cultured for 14 days, beta -CD- (S-SO3Na) 7 and -CD- (N3-SO3Na) beta 7 promotes stem cells to neural differentiation efficiency respectively. 1.2 times and 1.9 times of heparin, and non sulfonated beta -CD and its efficiency is only 0.6 times of heparin, and the blank control group had no significant difference. Therefore, through sulfonation of carbohydrate molecules modified p-CD, mimics the natural biological function of GAG molecule in promoting stem cell differentiation on the basis of this aspect. In order to further simulate the structure, long chain GAG, and adjust the relative content of functional components, puts forward a new concept, the preparation of GAG analogues, GAG molecule "sulfonic acid groups" and "sugar group" unit of split and reorganization. Firstly, monomers were synthesized containing sulfonic acid groups. With "sugar group", addition fragmentation chain transfer polymerization (Reversible Addition-Fragmentation Chain Transfer using a reversible Polymerization, RAFT) and the copolymerization of two functional units are combined. By changing the feed ratio, can accurately control the copolymer" The relative content of sulfonic acid groups "and" sugar group ". The cell experiment results show that the GAG analogs has a good biocompatibility, add dry cell culture medium can promote the proliferation of stem cells. The differentiation of neural stem cells in the direction of induction, GAG analogs can improve the differentiation efficiency, and the degree of the compositions of the copolymers increased. When sulfonic acid and sugar group ratio close to 1:1, copolymer of promotion of stem cell differentiation into neurons of the highest efficiency is 3.1 times of heparin. Therefore, this kind of GAG copolymer can be composed by precise control function unit, realize the biological function of.2. cell membrane mimetic structure of phospholipid is better than natural GAG is an amphoteric ion polymer surface preparation and anti protein adsorption properties of zwitterionic structure. The phospholipid bilayer wall is given the key to the cell membrane inert barrier function, because of this Has good anti fouling properties by surface materials of zwitterionic molecular modification, and the modified method is simple and universal development is the key factor of the zwitterionic surface has been widely used. This paper will end with sticky molecules 3,4- two hydroxy phenyl alanine -L- (3,4-dihydroxyphenyl-L-alanine, DOPA) of the zwitterionic polymer modified on the surface of the material, study the anti protein adsorption function. Using modified DOPA atom transfer radical polymer (AtomTransfer Radical, Polymerization, ATRP) initiator respectively Inimer sulfo betaine (sulfobetaine, SB) and carboxyl betaine (carboxybetaine, CB) polymerization, were prepared with different molecular weight poly (sulfobetaine polymer poly (sulfobetaine), pSB) and poly carboxylic acid betaine polymer (poly (carboxybetaine), pCB), and the modified poly two methyl silicone An elastomer (polydimethylsiloxane, PDMS). The surface protein adsorption results showed that the molecular weight of the polymer increases in a certain range can improve the surface modification of the corresponding polymer anti protein adsorption capacity; increase the number of the end of the polymer DOPA is beneficial to obtain a more compact polymer modified layer, so as to further improve the modified surface resistance protein adsorption ability. In addition, adding dopamine small molecules in the polymer grafting process, but also help to improve the density of the polymer layer, thus further reducing the amount of adsorbed protein. This paper from the perspective of bionic membrane were obtained GAG analogues with biological activity and surface material of zwitterionic molecular modification of biologically inert.. the directions for future work should be in the material interface combining the nonspecific reaction and the goal of promoting students The activity of the material to achieve a more comprehensive bionic function.

【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：TB391

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