Bioinspired\nCollagen Scaffold Loaded with bFGF-Overexpressing\nHuman Mesenchymal Stromal Cells Accelerating Diabetic Skin Wound Healing\nvia HIF‑1 Signal Pathway Regulated Neovascularization

The healing of severe\nchronic skin wounds in chronic diabetic patients\nis still a huge clinical challenge due to complex regeneration processes\nand control signals. Therefore, a single approach is difficult in\nobtaining satisfactory therapeutic efficacy for severe diabetic skin\nwounds. In this study, we adopted a composite strategy for diabetic\nskin wound healing. First, we fabricated a collagen-based biomimetic\nskin scaffold. The human basic fibroblast growth factor (bFGF) gene\nwas electrically transduced into human umbilical cord mesenchymal\nstromal cells (UC-MSCs), and the stable bFGF-overexpressing UC-MSCs\n(bFGF-MSCs) clones were screened out. Then, an inspired collagen scaffold\nloaded with bFGF-MSCs was applied to treat full-thickness skin incision\nwounds in a streptozotocin-induced diabetic rat model. The mechanism\nof skin damage repair in diabetes mellitus was investigated using\nRNA-Seq and Western blot assays. The bioinspired collagen scaffold\ndemonstrated good biocompatibility for skin-regeneration-associated\ncells such as human fibroblast (HFs) and endothelial cells (ECs).\nThe bioinspired collagen scaffold loaded with bFGF-MSCs accelerated\nthe diabetic full-thickness incision wound healing including cell\nproliferation enhancement, collagen deposition, and re-epithelialization,\ncompared with other treatments. We also showed that the inspired skin\nscaffold could enhance the <i>in vitro</i> tube formation\nof ECs and the early angiogenesis process of the wound tissue <i>in vivo</i>. Further findings revealed enhanced angiogenic potential\nin ECs stimulated by bFGF-MSCs, evidenced by increased AKT phosphorylation\nand elevated HIF-1α and HIF-1β levels, indicating the\nactivation of HIF-1 pathways in diabetic wound healing. Based on the\nsuperior biocompatibility and bioactivity, the novel bioinspired skin\nhealing materials composed of the collagen scaffold and bFGF-MSCs\nwill be promising for healing diabetic skin wounds and even other\nrefractory tissue regenerations. The bioinspired collagen scaffold\nloaded with bFGF-MSCs could accelerate diabetic wound healing via\nneovascularization by activating HIF-1 pathways.