【作者】 李冬；

【导师】 陈学思；

【作者基本信息】 中国科学技术大学 ， 高分子化学与物理， 2022， 博士

【摘要】 水凝胶是一类由聚合物交联形成的三维网络状材料,其在水中可以溶胀但不会溶解,水凝胶具有较高的含水量、良好的生物相容性、制造的便利性、可变的成分和理想的物理特性,因此在生物医学领域得到了广泛的应用。聚氨基酸水凝胶具有良好的生物相容性与生物降解性,其结构与原生细胞外基质相似,因而在生物医学领域受到越来越多的关注。聚氨基酸具有独特的二级结构,而二级结构对聚氨基酸水凝胶的凝胶性能具有显著的影响,通过调节聚氨基酸单元组分、链段长度、侧基或端基可以有效地调控聚氨基酸的二级结构和凝胶性能。然而,针对基于聚谷氨酸及其衍生物的残基手性调控对水凝胶性能的研究相对有限。因此,我们以对聚氨基酸链段中氨基酸残基手性的调控为基础,设计了三种基于聚乙二醇-聚谷氨酸的嵌段共聚物,研究从不同角度调控聚合物结构对聚氨基酸水凝胶的性能产生的影响:1.探究氨基酸残基手性含量对温度敏感聚氨基酸水凝胶性能的影响。我们合成了含有不同γ-乙基-L-谷氨酸酯(ELG)和/或γ-乙基-D-谷氨酸酯(EDG)残基含量的mPEG-聚氨基酸双嵌段共聚物,并制备了温度敏感水凝胶。我们证明可以通过调节氨基酸残基的手性和共聚物的二级结构来有效控制聚氨基酸温度敏感水凝胶的性质,而且手性谷氨酸残基的含量也会影响水凝胶的生物降解性以及在宿主内的炎症反应。2.探究聚氨基酸嵌段序列对温度敏感聚氨基酸水凝胶性能的影响。我们合成了两种含有不同聚氨基酸嵌段序列的mPEG-聚氨基酸三嵌段共聚物EG45ELG8.2(ELG0.5EDG0.5)8.2 和 EG45(ELG0.5EDG0.5)7.9ELG7.9。其中聚合物末端为ELG嵌段的共聚物EG45(ELG0.5EDG0.5)7.9ELG7.9比末端为ELG-co-EDG嵌段的共聚物EG45ELG8.2(ELG0.5EDG0.5)8.2显示出更好的凝胶化性能。我们证明可以通过调节手性聚氨基酸嵌段在共聚物中排布的序列来调节共聚物的二级结构,进而有效控制聚氨基酸温度敏感水凝胶的性质。3.探究共聚物拓扑结构和氨基酸残基手性对聚氨基酸酶交联水凝胶的降解性能的影响。我们基于前期研究中合成的具有不同聚合物拓扑结构和聚氨基酸链段残基手性的PEG/聚氨基酸嵌段共聚物进行研究。结果表明由D-谷氨酸单元组成的共聚物和水凝胶的降解速率明显低于由L-谷氨酸结构单元组成的样品,其中共聚物的拓扑结构也影响了聚(L-谷氨酸)基水凝胶的降解性。体内生物降解性和生物相容性研究表明,共聚物拓扑结构和聚氨基酸嵌段中的氨基酸残基手性会显著影响水凝胶在体内的降解行为和炎症反应。本研究为共聚物的拓扑结构和氨基酸残基手性对聚氨基酸基水凝胶的凝胶性质、生物降解性和生物相容性的影响提供了新的见解。更多还原

【Abstract】 Hydrogel is a kind of three-dimensional network material formed by polymer cross-linking,which can swell in water rather than dissolve.Hydrogels usually have high water content,good biocompatibility,convenience of manufacturing,variable composition and ideal physical properties,which make it a candidate with good potential in the field of biomedicine.Polypeptide hydrogels have good biocompatibility and biodegradability,as well as structures similar to the original extracellular matrix,and they have received more and more attention in the biomedical application.Polypeptides have unique secondary structures,which have a significant impact on the multiple properties of polypeptide hydrogels.By adjusting the residue components,length of polypeptide segments,side groups or end groups,the secondary structure and properties of polypeptide hydrogels can be effectively controlled.However,researches on the properties of hydrogels based on the chiral modulation of residues of polypeptides and their derivatives are limited yet.Therefore,based on the adjustment of the chirality of the amino acid residues in the polypeptide segments,we designed three types of poly(ethylene glycol)-polypeptide block copolymers,and studied the effects of the adjustment of the polymer structures from different perspectives on the performance of polypeptide hydrogels:1.The influence of the content of amino acid residues with different chirality on the performance of temperature-sensitive polypeptide hydrogels.We synthesized mPEG-polypeptide diblock copolymers with different residue contents of y-ethyl-Lglutamate(ELG)and/or y-ethyl-D-glutamate(EDG),and prepared a thermosensitive hydrogels.We proved that the properties of polypeptide thermosensitive hydrogels can be effectively controlled by adjusting the chirality of the residues and the secondary structure of copolymers,and the contents of chiral glutamic acid residues will also affect the biodegradability,as well as the inflammatory response of the hydrogels.2.The effect of polypeptide block sequence on the performance of thermosensitive polypeptide hydrogels.We synthesized two mPEG-polypeptide triblock copolymers EG45ELG8.2(ELG0.5EDG0.5)8.2 and EG45(ELG0.5EDG0.5)7.9ELG7.9 containing different polypeptide block sequences.The copolymer EG45(ELG0.5EDG0.5)7.9ELG7.9,whose ELG-co-EDG blocks are linked to the PEG blocks,showed better gelation performance than the copolymer EG45ELG8.2(ELG0.5EDG0.5)8.2.We proved that the secondary structures of the copolymers can be adjusted by tuning the block sequence of the chiral polypeptide block within the copolymers,thereby the properties of the polypeptide thermosensitive hydrogels can be effectively controlled.3.The influence of copolymer topologies and amino acid residue chirality on the degradation performance of polypeptide enzyme-crosslinked hydrogels.Our research is based on the PEG/polypeptide block copolymers with different topological structures of copolymers and residue chirality in polypeptide chains,which were synthesized in the previous research.The results showed that the degradation rates of copolymers and hydrogels composed of D-glutamic acid units are significantly lower than the samples composed of L-glutamic acid structural units,and the topological structure of the copolymers also affected the degradability of poly(L-glutamine acid)-based hydrogels.In vivo biodegradability and biocompatibility studies have shown that the topological structures of the copolymers and the chirality of amino acid residues in the polypeptide segments will significantly affect the degradation behaviors and inflammatory response of the hydrogels in vivo.This study provides new insights into the influence of the topological structures of the copolymers and the chirality of amino acid residues on the hydrogel properties,biodegradability and biocompatibility of polypeptide-based hydrogels.更多还原