可注射高强度双网络水凝胶的制备及软骨修复应用研究

Injectable hydrogel is promising for application in drug delivery and tissue engineering because of their carrier property together with easy-operation perspective, while double-network (DN) hydrogel has exhibited attractive mechanical property. However, the report of injectable DN hydrogel is rare, mainly because of the two-step synthesis procedure of double networks. Herein, we intend to construct DN hydrogel with injectability under physiological condition through the inclusion of dynamic covalent crosslinks, together with the incorporation of secondary forces like ionic interaction. Benzoic-imine, phenylborate and disulfide bonds will be introduced for the formation of double-network by adjusting the crosslinking kinetics of the individual crosslinking. A series of characterization on the rheology behavior, phase separation, polymer conformation will be performed to discover the regulation for gaining subsequent sol-gel transitions of the two polymer networks in one particular solution regime. The structure-property relationship of injectable DN hydrogel will be also studied by examining the regimes formed by various polymers, type of crosslink and injection condition in order to select the candidates with desirable mechanical property for using as a scaffold for cartilage reparation. In vitro and in vivo tests will be finally carried out to assess the capacity of the hydrogel as an extracellular matrix for 3D cell encapsulation and proliferation, chondrocyte differentiation and furthermore the potential application for osteochondral repair.

可注射水凝胶和双网络水凝胶在组织工程领域均有良好的应用前景，但双网络水凝胶复杂的交联过程限制了它的可注射性，反之注射过程也会影响凝胶的力学性能。本项目针对软骨缺损等治疗对承力水凝胶支架材料的需求，提出在高分子混合体系中引入两种动态相互作用，实现两个高分子网络的次序交联，以制备在生理环境条件下可注射的双网络水凝胶的思路。本工作将以聚糖、PVA等生物相容性高分子为主链构建多重交联，研究两种动态相互作用的匹配性对交联反应动力学、相转变和互穿网络结构的影响，重点解决双网络凝胶的加工过程控制和力学性能控制等问题，掌握注射制备高强度双网络水凝胶的方法。同时，研究凝胶体系对细胞的三维装载与输运能力，通过膝关节软骨缺损动物模型，明确以注射方法植入凝胶支架对于软骨修复的作用。

针对水凝胶可加工性与力学性能间矛盾以及骨科治疗对承力水凝胶植入材料的迫切需求，本项目研究利用动态共价键和多种动态相互作用协同调控凝胶相转变动力学，实现两个高分子网络的快速、逐次交联，以制备生理环境条件下可注射的双网络水凝胶；提出可加工高性能杂化高分子水凝胶的渝渗网络模型，通过调控高分子链间相互作用控制无机颗粒点阵与高分子形成渝渗网络的应变响应，实现高分子水凝胶从塑性到刚性的转变，一定程度解决了水凝胶加工性和力学性能矛盾；利用生物活性物质的矿化过程实现水凝胶力学性能的“活性”增长，制备出压缩模量100MPa级、力学性能比拟松质骨的超高模量杂化双网路高分子水凝胶。以此为基础，获得了满足围关节骨折复位和骨软骨修复要求的填充型承力水凝胶材料，首次使用高分子水凝胶联合金属内固定实现了对围关节骨折骨缺损部位的结构稳定，促进了软骨和骨损伤修复，避免了关节面二次塌陷，为克服围关节骨折如胫骨平台骨折的临床治疗难题提供了新的材料基础和可行的治疗途径。