In Situ Photo-Cross-Linking Hydrogel Accelerates Diabetic Wound Healing through Restored Hypoxia-Inducible Factor 1-Alpha Pathway and Regulated Inflammation

The hypoxia-inducible factor 1-alpha (HIF-1a) pathway plays a key role in regulating angiogenesis during wound healing. However, the diabetic condition hampers the stabilization of HIF-1a and thus inhibits the subsequent angiogenesis, and meanwhile, the function and phenotype transition of macrophage are impaired in the diabetic condition, which leads to prolonged and chronic inflammation. Both angiogenesis inhibition and inflammatory dysfunction make diabetic wound healing a major clinical challenge. Here, borosilicate (BS), a new group of bioceramics with a coupled network of interconnected [BO3] and [SiO4] which can incorporate therapeutic ions such as Cu2+, is synthesized and combined with silk fibroin (SF), a biocompatible natural amino acid polymer whose composition and structure are similar to a natural extracellular matrix (ECM), to obtain a compound system which can transform into a SF-MA-BS hydrogel under UV radiation via methacryloyloxy (MA) groups modified on both BS and SF. When in use, the compound system can thoroughly spread to the whole wound surface and be in situ photo-cross-linked to form an integral SF-MA-BS hydrogel that firmly adheres to the wound, protects the wound from external contamination, and further spontaneously promotes wound regeneration by releasing therapeutic ions. The wound repair of Streptozotocin-induced diabetic rats shows that diabetic wound healing is obviously accelerated by SF-MA-BS, interestingly the HIF-1a pathway is restored via interaction between HIF-1a and Cu2+, and angiogenesis is therefore enhanced. Meanwhile, inflammation is well regulated by SF-MA-BS, and long-term detrimental inflammation is avoided. These findings indicate that the SF-MA-BS hydrogel regenerates diabetic wounds, and further clinical trials are anticipated.