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.