基于亚胺硼酸盐和硼酸酯键的可注射自修复水凝胶及其多重响应性能研究

Iminoboronate Ester Cross-linked Hydrogels with Injectable, Self-healing and Multi-responsive Properties

报道了一种基于亚胺硼酸盐和硼酸酯键的动态共价交联水凝胶.该水凝胶是通过2-甲酰基苯基硼酸(2-FPBA)与超支化聚乙烯亚胺(PEI)末端的伯胺基团和海藻酸钠(SA)糖单元上的顺式二醇反应形成亚胺硼酸盐-硼酸酯交联结构制得.该水凝胶制备过程简单,所需高分子材料无需事先进行化学修饰;成胶条件温和,在室温下混合即可快速形成水凝胶.流变学实验表明,水凝胶力学强度随PEI、2-FPBA和SA中反应基团比例的变化而变化.同时,由于成胶所用化学键—亚胺硼酸盐和硼酸酯键—均为动态共价键,所得水凝胶还具有良好的自修复和可注射性能,可用作3D打印的水凝胶"墨水".体外降解实验结果表明,水凝胶对pH值、H_2O_2以及多种生物分子(如半胱氨酸、谷胱甘肽以及果糖等)都具有响应性,可用作蛋白药物响应性释放的载体.进一步体外细胞毒性实验表明,水凝胶对细胞没有明显的毒性,具有良好的生物相容性.

Injectable self-healing hydrogels are fancy candidates for biomedical applications,especially in such areas as minimally invasive surgical procedures,interventional therapy,and 3D bio-printing.Herein,a general and robust synthetic route to injectable self-healing hydrogels was developed based on a facile three-component reaction between the primary amine groups in hyperbranched poly(ethylenimine)(PEI),2-formylphenylboronic acid(2-FPBA),and the cis-diols in sodium alginate(SA).Briefly,2-FPBA reacted with PEI at first to generate a PEI/2-FPBA conjugate through forming iminoboronate bonds.The residual boronic acid groups in PEI/2-FPBA conjugate further reacted with cis-diols in the sugar unite of SA to generate iminoboronate ester linkages,thereby yielding the target product of hydrogels.The formation of iminoboronate and boronic acid ester bonds in iminoboronate ester linkages was confirmed by 1 H-and 11B-NMR spectra.Dynamic rheological measurements revealed that the storage modulus(G′)of hydrogels was dependent on the feeding molar ratios of primary amine groups in PEI,2-FPBA,and sugar units in SA.Moreover,the resulting hydrogels exhibited excellent self-healing and shear-thinning properties,given that both iminoboronate and boronic acid ester bonds are well known as dynamic covalent bonds.Based on these attributes,the hydrogels prepared were expected to have successful application in 3D printing by serving as a hydrogel'ink'.In addition,their responsiveness towards pH,H2O2,cysteine(Cys),glutathione(GSH),and fructose allowed an accelerated degradation process in acidic medium or in the presence of H2O2,Cys,GSH,or fructose;Scanning electron microscopy(SEM)observation further suggested a significant destruction of their porous structure after a period of degradation.As a result,these hydrogels proved quite applicable for the delivery of protein therapeutics with multi-responsive drug release properties.Their minimal cytotoxicity towards A549,HeLa,and L929 cells was also confirmed by the MTT assay.It is worth mentioning that with 2-FPBA functioning as the cross-linker,many other amine groups-rich polymers,even natural proteins,can be used to fabricate dynamic hydrogels with injectable,seal-healing,and multi-responsive properties.Therefore,hydrogels prepared from the strategy proposed in this study may hold tremendous potentials in tissue engineering,drug delivery,and 3D bio-printing.