Multi-crosslinking and Topological Entanglement Enable Silk Fibroin Hydrogels with Sustained Mechanical Softness for Neural Regeneration
Authors: TIAN Yuan, HOU Danni, JIANG Junzhong, LIU Xiaoyin, LIU Yu, WU Xiaoyang, XIAO Jiamei, WU Chengheng, WEI Dan, SUN Jing, CHERNOZEM Roman, DING Jie, ZHOU Liangxue, FAN Hongsong
Silk fibroin (SF) hydrogels are promising for neural regeneration but suffer from progressive stiffening due to excessive β-sheet assembly, limiting their use in traumatic brain injury (TBI) repair. This study introduces a dopamine (DA)-mediated synergistic topological entanglement strategy to construct an SF-DA/gelatin-DA composite hydrogel (SG). The system integrates covalent cross-linking, net cationic electrostatic repulsion, hydrogen bonding, and π-π stacking to regulate SF assembly dynamics at the molecular level. The resulting SG hydrogel maintains stable mechanical softness over extended periods, with a storage modulus of approximately 1.2 kPa after 28 days, compared to a 5-fold increase in pure SF hydrogels. The sustained softness promotes neural stem cell (NSC) proliferation and differentiation, with a 2.5-fold increase in βIII-tubulin expression and a 1.8-fold increase in GFAP expression after 14 days. In a rat TBI model, SG hydrogel implantation reduced glial scar formation by 40% and improved neurological function scores by 30% at 8 weeks. The hydrogel degrades at a rate of 12% per week, matching tissue regeneration. This multi-crosslinking approach offers a clinically translatable strategy for neural tissue engineering, addressing the critical bottleneck of mechanical instability in SF-based biomaterials.