A Hierarchically Micro- and Nanofibrous Hybrid Hydrogel Derived from Decellularized Skin Matrix with High Bioactivity and Tunable Mechanical Properties for Accelerated Wound Healing

Because of its exceptional biocompatibility and bioactivity, decellularized extracellular matrix (dECM) has attracted the interest of researchers in tissue regeneration and wound recovery. However, the processibility of such biomaterial remains a great challenge in tissue engineering. Herein, porcine decellularized skin matrix (pDSM) was enzymatically digested into a pDSM-sol, which was then mechanically mixed with micron-sized short pDSM fibers resulted from wet electrospinning, to eventually achieve a reinforced hybrid hydrogel with interpenetrating nano- and microstructures. The physical properties of this hybrid hydrogel were evaluated by varying the concentration of pDSM-sol, composition of the gel/fiber contents, and the length of short pDSM microfibers. Furthermore, bioscaffolds fabricated by such dual-scale nanofibrous hydrogels were tested in both in vitro laboratory conditions and in vivo living systems to evaluate their proficiency in wound repair. It’s noteworthy that the incorporation of short fibers led to the acceleration of the sol–gel transition, resulting in a significant enhancement of the hybrid hydrogel’s storage modulus, coupled with a reduction in its degradation rate. This hybrid hydrogel, co-cultured separately with human umbilical vein endothelial cells (HUVECs) and RAW264.7 cells, can promote the secretion of vascular endothelial growth factor (VEGF) from both cell types. Additionally, it facilitates the secretion of M2 phenotype characteristic proteins from RAW264.7 cells. Finally, the implantation of hybrid hydrogel scaffolds led to highly facilitated regeneration effects, including wound healing, collagen deposition, suppression of inflammation, and angiogenesis in a skin-defected rat model. These promising results indicate that such hybrid hydrogels with hierarchical micro- and nanofibrous structures have shown great application potential in future regenerative medicine.