3D-printed multifunctional bilayer scaffold with sustained release of apoptotic extracellular vesicles and antibacterial coacervates for enhanced wound healing.

Full-thickness skin defects pose significant challenges to physical and psychological health while traditional skin grafting techniques are associated with limitations. Herein, we present a 3D-printed multifunctional bilayer scaffold that incorporates apoptotic extracellular vesicles (ApoEVs) and antibacterial coacervates to prevent wound infection and promote wound healing. The ApoEVs were continuously released from the lower layer of the scaffold with large pores to promote angiogenesis and collagen deposition. Meanwhile, the pH-responsive curcumin-containing coacervates were released from the upper layer of the scaffold with dense pores to exert antibacterial and reactive oxygen species scavenging ability. In vivo experiments showed that the scaffold accelerated wound healing and improved healing quality by promoting a more organized collagen arrangement and reducing hyperplastic scar tissue. Furthermore, it effectively reduced hyperplastic scar tissue, resulting in a decrease in the average scar area from 73.3 % to 19.9 %. RNA sequencing analysis revealed that the scaffold upregulated genes associated with cell proliferation and downregulated genes related to inflammation, indicating its potential therapeutic applications for wound healing. This multifunctional bilayer scaffold represents a promising candidate for the treatment of full-thickness skin defects, offering rationales for designing skin scaffolds for regenerative medicine applications.