基于氨基酸两性离子的水凝胶生物材料：制备与眼科应用

The aim of this project is to prepare amino acids based zwitterionic hydrogel biomaterials by epoxy chemistry and explore their applications in the ophthalmic area. Epoxy hydrogels will be prepared by photo- or thermal copolymerization of 2-hydroxyethyl methacrylate (HEMA), glycidyl methacrylate (GMA) and other monomers, or graft polymerization of GMA onto silicone hydrogels. Then, amino acids including neutral, basic and acidic ones will be grafted into the epoxy hydrogels by ring opening reaction of epoxy groups with α-amino groups. Therefore, libraries of amino acids based zwitterionic HEMA hydrogels and silicone hydrogels will be obtained. The relationship among their compositions and hydrophilicity, anti-dehydration, anti-fouling and equilibrium water content will be investigated in detail in order to have insights into the interaction of hydrogel backbones with water molecules. The loading and release behavior of hyaluronic acid（HA）in the cationic hydrogels derived from basic amino acids will be studied to test the potential of the hydrogels as biomacromolecular carriers. The contact lens of the amino acids based zwitterionic HEMA and silicone hydrogels will be fabricated using plastic molds, and will be evaluated following GB Standards. This project focuses on the studies of novel amino acids based zwitterionic hydrogels at the molecular level to overcome the shortages of poor hydrophilicity, fast dehydration and ease of fouling of conventional hydrogel contact lenses. Because of the strong binding ability of zwitterions to water molecules, the amino acids based zwitterionic hydrogels should be promise for the development of novel contact lenses with comfort and safety.

本项目目的是利用氨基酸两性离子库，通过环氧化学途径，研究制备一系列基于氨基酸两性离子的水凝胶生物材料，探索在眼科领域的应用。由甲基丙烯酸缩水甘油酯(GMA)与甲基丙烯酸羟乙酯(HEMA)等单体通过热或光引发共聚合制备环氧HEMA水凝胶，或在硅水凝胶表面接枝GMA制备环氧硅水凝胶，通过各种（中性、碱性、酸性）氨基酸的伯胺基与环氧开环反应，制备结合氨基酸两性离子的HEMA水凝胶和硅水凝胶库，研究材料组成、结构与亲水性、脱水性、生物粘附等之间关系。研究结合碱性氨基酸的阳离子水凝胶对透明质酸的负载和控制释放行为。采用接触镜模具，制备基于氨基酸两性离子的HEMA水凝胶和硅水凝胶接触镜，根据标准进行物理化学和生物学评价。本项目针对水凝胶接触镜亲水性差、易脱水、生物粘附等问题，系统利用氨基酸两性离子强烈结合水分子的特性，在分子水平上开展基于氨基酸两性离子的新型水凝胶材料研究，有望开发全新安全舒适的接触镜

水凝胶角膜接触镜是涉及数以亿计患者眼睛健康的Ⅲ类医疗器械。增强表面亲水性、抗粘附性能，有利于提高佩戴者舒适性和眼睛健康。本项目利用氨基酸的两性离子特征，研究制备一系列具有亲水、抗粘附性能的水凝胶和硅水凝胶，确定材料组成、结构与性能之间关系，制备基于氨基酸两性离子的水凝胶接触镜，为开发性能优异的角膜接触镜奠定基础。此外，开展超短肽两性离子水凝胶，氨基酸两性离子改性超滤膜等探索。主要结果如下：基于氨基酸库，通过点击化学建立了基于氨基酸两性离子的水凝胶和硅水凝胶制备方法，成功制备出氨基酸两性离子水凝胶库，水凝胶的水接触角低至20°左右，亲水性显著提高，蛋白沉积量最低达到6μg/cm2。这是因为膜表面形成-NH2+-和-COO--两性离子致密水化层，阻止了蛋白分子的靠近。碱性氨基酸两性离子水凝胶具有抑菌性，可以有效负载高分子量透明质酸，并在模拟体液中持续释放达到10小时以上，用作眼科医疗器械有明显优势。类似地，成功制备出基于氨基酸两性离子的硅水凝胶库，接触角最低达到50°左右，具有亲水性和抗蛋白沉积作用。采用聚丙烯模具制备成功基于氨基酸的水凝胶和硅水凝胶接触镜，亲水性好，抗蛋白沉积，无细胞毒性。兔眼24天连续佩戴未引起角膜、虹膜、晶状体等结构形态明显变化，具有良好的组织相容性。硅水凝胶接触镜的接触角最低达到45°，抗蛋白沉积效果显著优于市场硅水凝胶接触镜产品，有产业化前景，将满足国内市场对高端硅水凝胶接触镜的迫切需求。通过点击化学将超短肽甘氨酰甘氨酸（GG）和二甘氨酰甘氨酸（GGG）两性离子接枝到硅水凝胶表面，制备成功表面接枝超短肽的硅水凝胶角膜接触镜，具有亲水性、抗粘附性和眼组织相容性，有临床应用前景。进一步将氨基酸两性离子接枝技术拓展用于超滤膜抗粘附改性，成功制备具有亲水性和抗蛋白沉积的聚醚砜等超滤膜，成功纺制抗粘附改性中空纤维，为产业化奠定基础。并进行纳米药物前期探索。发表论文24篇，授权发明专利3项，申请发明专利1项。