基于动态化学交联作用的自修复型胶原水凝胶构建及调控

Collagen hydrogels have been widely applied as biomedical materials and skin-care products due to their superior bio-imitability, biocompatibility and the capacity to promote cellular growth, etc. However, collagen hydrogels prepared via existing technology are vulnerable to stress-induced formation of cracks and they cannot be able to self-repair the cracks. The idea proposed in the present project that self-repairing collagen hydrogels with dynamic networks can be constructed by the introduction of reversible chemical cross-links (Schiff’s Base) between cross-linking agent and collagen molecules, is based on the concept of dynamic chemistry. In addition, this project is aimed to achieve coordination control between self-healing capacity, mechanical properties and stabilities of the self-repairing collagen hydrogels. Firstly, the influence of the reversible cross-linking on both of the molecular structure and aggregation structure of collagen will be ascertained. Secondly, by evaluating the macro-observation results as well as by examining the rheological properties, we will focus on the self-repairing behaviors of damaged collagen hydrogels, and then the self-repairing mechanism of collagen hydrogels will be elucidated. Additionally, the relationship of coordinated control between mechanical properties, stabilities and self-repairing property will be ascertained. By combing all the investigations as above, finally the structure-activity relationship will be established completely between the molecular structure of reversible cross-linking agent and the properties of collagen hydrogels. In the present project, we tried to break through the pre-existing research ideas on collagen hydrogels, that is, to research and develop a kind of self-repairing collagen hydrogels, which is of great significance for brodening the application fields of collagen and for promoting the high-value ultization of animal biomass.

胶原水凝胶具有仿生性高、生物相容性好及促进细胞生长等优良性能，在生物医学与美容护肤材料等领域得到广泛应用。然而，现有技术制备的胶原水凝胶存在易破裂且无法自主修复的问题。本项目基于动态化学理论，利用交联剂与胶原分子生成动态亚胺键，引入可逆化学交联位点，构建可自修复的胶原水凝胶网络，并实现水凝胶材料自修复性能、力学性能及稳定性的协调控制。首先探明交联对胶原分子结构、聚集态结构的影响规律；再通过宏观观测评价和流变学性质测定，重点研究胶原水凝胶受损后的自修复行为，进而阐明自修复机理；此外，明确胶原水凝胶的其它重要性能如力学性能、热稳定性与自修复性能之间的协调控制关系。综上研究，最终完整构建交联剂分子结构与胶原水凝胶自修复性能等多种重要性能间的构效关系。本项目力图突破胶原水凝胶材料现有研究思路，研发一种具有自修复性能的新型胶原水凝胶，这对于拓宽胶原应用领域、促进动物生物质的高值转化利用具有重要意义。

传统方法制备的胶原基水凝胶受到外力作用时易破损且无法自主修复。本课题从动态交联的角度出发，选用双端苯甲醛基聚乙二醇（DF-PEG）与胶原侧链氨基反应，同时为了提高交联密度并获得抗菌性，在上述体系中引入壳聚糖，DF-PEG与胶原和壳聚糖之间生成大量动态亚胺键，从而获得具有自修复效果的胶原基水凝胶。首先对合成的DF-PEG进行表征，测定其基本结构；再将其用于交联胶原/壳聚糖制备水凝胶，采用多种方法和技术研究DF-PEG与胶原/壳聚糖分子之间的作用力；在此基础上，研究了交联作用对胶原热稳定性的影响；揭示了DF-PEG交联作用对胶原/壳聚糖体系流变性质的影响；考察了胶原/壳聚糖水凝胶的可注射能力；综合分析DF-PEG对胶原/壳聚糖的上述影响机制，明确了胶原/壳聚糖体系内存在的DF-PEG与胶原/壳聚糖之间的交联作用、胶原与壳聚糖之间的氢键作用、静电作用及链段缠结作用等复杂作用；考察了胶原基水凝胶的自修复效果，结合上述分析，明确了自修复机制；研究了胶原/壳聚糖水凝胶的抗菌性能和粘附效果。此外，动物实验表明胶原/壳聚糖具有良好的止血性能和促伤口愈合能力。为进一步提高胶原基水凝胶网络结构稳定性，在胶原体系中引入改性天然大分子-双醛瓜尔胶，并加入硼砂，构建由动态亚胺键、可逆硼酸酯键、氢键及大分子间缠结作用稳定的网络体系。结果表明该水凝胶模量明显增大，且具有优良的热稳定性、可注射性、自修复能力及伤口愈合能力。总之，本项目通过引入动态交联键，制备出具有良好热稳定性、可注射性及促伤口愈合的快速自修复型胶原基水凝胶，对于拓宽胶原应用范围，推动动物生物质在美容护肤、生物医学材料等领域的高值化利用具有重要意义。