基于天然胶原自组装及多元羧酸NHS酯调控的胶原水凝胶制备及其结构与性能

Polymeric hydrogel, a hot issue of research in advanced materials, has been given a great attention in the fields of biomaterials including drug delivery since it has special three dimensional network structures and viscoelasticity. Collagen is a biological macromolecule and can self-assemble from solution into a hydrogel under special conditions in vitro. However, the self-assembled collagen hydrogel is structurally unstable and chemical crosslinking has been shown to be the best modification method. Aiming at the problems existed in the chemical crosslinking of self-assembled collagen hydrogel, the fund is to prepare the collagen hydrogel for drug delivery with a combination of collagen self-assembling and multiple carboxylic acidic N-hydroxysuccinimide esters based on the bionics concerning collagen bio- synthesis. The aggregation structure of collagen in solution was studied by the degree of cross-linking determination, fluorescence resonance energy transfer, and confocal reflectance microscopy. The phase change of collagen solution into gel was investigated by fluorescence polarization, two-dimensional fluorescence correlation spectroscopy and rheology. The structure, basic physicochemical properties and the loading-release property of collagen hydrogels were studied by atomic force microscopy, dynamic mechanical analysis, and the controlled release against typical anti-cancer drug. The relationship among these three aspects was accordingly disclosed. The means and principles for the preparation of the collagen hydrogel for drug delivery by collagen self-assembling and multiple carboxylic acidic N-hydroxysuccinimide esters were obtained to supply the preparation of collagen based hydrogels with academic basis.

高分子水凝胶因其特殊的三维网络结构和粘弹性能在药物载体等生物材料领域受到很大关注，是当今先进材料研究的热点之一。天然胶原是一种生物高分子，在体外一定溶液条件下能自组装形成水凝胶，但自组装胶原水凝胶的结构性能不稳定，已有研究表明化学交联是最有效的改性途径。针对目前自组装胶原水凝胶化学交联存在的问题，本项目拟依据胶原生物合成的仿生学原理，结合采用胶原自组装和多元羧酸NHS酯调控制备可用作药物载体的胶原水凝胶材料。采用交联度测定、荧光共振能量转移、共聚焦激光显微镜等手段研究溶液中胶原的聚集态结构；采用荧光偏振、二维荧光、流变等手段研究胶原溶液-凝胶相变行为；采用原子力显微镜、动态热机械分析以及对典型抗癌药物的控制释放等手段，研究胶原水凝胶的结构、基本理化性质和载药释药性能；揭示三个方面的关系并获得胶原自组装与多元羧酸NHS酯调控制备药物控释用胶原水凝胶的方法和原理，为胶原基水凝胶材料的制备提供理

高分子水凝胶因其自身所具有的独特性质，在组织工程、药物控释等生物医学材料领域的研究和应用受到了极大的关注，如以高分子水凝胶为载体的药物传输系统能够有效降低药物毒副作用，减少血药浓度的波动性，特别适用于一些毒副作用较大的抗癌药物或易失活的蛋白质和多肽药物的靶向释放。胶原作为一种天然高分子，分子的三股螺旋结构赋予其很多特性，如胶原具有低抗原性和良好的生物相容性，能促进血小板凝结和组织修复，还具有优良的保湿性能和明显促进细胞生长繁殖的优异性能，因而天然胶原作为一种生物材料已被广泛应用于生物医药、组织工程、整形和美容护肤等领域。天然胶原分子通过自组装能形成水凝胶，本项目将胶原自组装与化学共价交联巧妙结合，实现了在溶液-凝胶转化过程中胶原自组装及共价交联行为的有效调控，通过控制胶原水凝胶中纤维的聚集形态和共价交联程度，获得了结构和性能稳定的胶原水凝胶材料。项目按计划执行完成了申报书中的所有研究内容。采用生物相容性好、反应活性高、且链长可调的多元羧酸NHS酯调控自组装胶原水凝胶的交联程度，并将自组装胶原溶液中胶原的聚集态结构与胶原水凝胶的结构性能联系起来，获得了更好地控制胶原溶液-凝胶相变行为和胶原水凝胶的水凝胶纤维网络结构，从而实现了基于天然胶原自组装与多元羧酸NHS 酯的胶原水凝胶材料的可调控制备，获得的胶原凝胶具有优良的细胞生物学性能。该研究结果为天然胶原制备性能稳定优良的水凝胶以将其用于药物载体和生物医药等领域提供了科学依据。. 在本项目执行期间，共发表学术论文26篇，其中SCI收录论文18篇，EI收录论文1篇，北大中文核心期刊5篇，其它杂志2篇。参加国际学术会议发表论文2篇，授权中国发明专利2项，申请中国发明专利7项。此外，培养博士研究生毕业3人，硕士研究生毕业8人。