Translation Prospects of a Novel <scp>ECM</scp>‐Silk Fibroin/Alginate <scp>3D</scp>‐Printed Scaffold for Treatment of Full‐Thickness Skin Wounds: An In Vitro and In Vivo Study

ABSTRACT The development of bioinks incorporating extracellular matrix (ECM) has attracted significant interest for creating three‐dimensional (3D)‐printed structures that simulate natural skin, aiming to facilitate profound wound healing. In our study, we utilized the potential of human placenta, renowned for its abundant structural proteins and growth factors essential for wound recovery, as a basis for an ECM‐based bioink. Different concentrations (1.5%, 3% and 5% w/v) of decellularized/solubilized placental ECM were integrated into silk fibroin/alginate to generate a printable bioink. The biocompatibility of the printed hydrogels was studied in vitro. Our refined ECM‐based bioink at a 5% w/v concentration was administered to full‐thickness wounds in a mouse model. The ECM‐based frameworks, due to their distinct structure, created a non‐cytotoxic environment conducive to in vitro cell adhesion, infiltration, and proliferation. Crucially, they did not provoke an adverse immune reaction in the host. Implanting the 3D‐printed ECM scaffold into deep wounds resulted in increased formation of granulation tissue, angiogenesis, and re‐epithelialization compared to scaffolds lacking ECM and untreated wounds. Our findings decisively demonstrate that the 5% ECM 3D scaffold promotes regeneration of deep wounds in vivo, creating a skin substitute with cellular organization closely resembling normal skin. This advancement sets the stage for future clinical exploration and holds tremendous promise for advancing wound healing therapies.