Physically Cross-Linked Silk Fibroin Hydrogel with Rapid Sol–Gel Transition and Enhanced Mechanical Performance

It remains a great challenge to fabricate physically cross-linked silk fibroin (SF) hydrogels with rapid gelation and robust mechanical properties. In this study, a novel SF hydrogel is obtained by synergistically modulating the SF molecular weight (MW) and the freeze-inducing process, avoiding the use of any exterior additives. First, the effects of MW on the self-assembly behaviors of SF are investigated under physiological temperature. The results demonstrate that high MW SF derived from papain degumming (PSF) facilitates the sol–gel transition with increasing β-sheet content, and contributed to the construction of the hierarchical micro-nanofiber structure. Subsequently, cryo-concentration treatment is applied to further accelerate the gelation process. The resultant PSF (F-PSF) exhibits rapid sol–gel transition (within 1 h), a high compressive modulus (54.2 ± 3.7 kPa), and a high storage modulus (up to 247.9 kPa), which are superior to traditional physically cross-linked SF hydrogels. The relatively low β-sheet content and dense structure endow the F-PSF hydrogels with excellent mechanical flexibility, physiological environmental stability, and long-term mechanical stability. In vitro cellular experiments show that F-PSF hydrogels are beneficial to cell proliferation and spreading. These attractive features enable the physically cross-linked SF hydrogels to be promising for tissue engineering and regenerative medicine.