Abstract
Wound healing involves a complex cascade of regenerative processes, particularly angiogenesis and immunomodulation, the orchestration of which is highly important for efficient repair of tissue defects. However, there is currently a lack of feasible strategies to coordinate angiogenesis and immunomodulation during cutaneous wound management, leading to non-healed skin defects a persistent clinical challenge. In this study, by harnessing the natural immunomodulatory property of splenic matrix and the intrinsic angiogenic effects of apoptotic vesicles (ApoVs), we developed a composite system loading ApoVs derived from stem cells of human exfoliated deciduous teeth (SHED-ApoVs) onto a porcine decellularized splenic matrix-based hydrogel (pDSMG). This pDSMG/SHED-ApoVs system maintains sustainable release of functionalized ApoVs to boost angiogenesis in the early phase of wound healing. Furthermore, the system also preserves the pDSMG capacity of immunomodulation, such as promoting M2 macrophage polarization, Treg differentiation and anti-inflammatory cytokines. With these synergistic effects, pDSMG/SHED-ApoVs creates an optimal regenerative microenvironment and significantly accelerates cutaneous wound healing, which is mechanistically mediated through inhibiting the glycolytic metabolism. Collectively, an innovative bioactive material system of pDSMG/SHED-ApoVs has been established, which safeguards efficient wound healing through concerted actions on angiogenesis and immunomodulation. With translational advantages of pDSMG/SHED-ApoVs, this approach holds potential for clinical wound management.