An engineered and scalable human cell-derived extracellular matrix demonstrates advantages over recombinant collagen in biomimicry and wound healing.

Skin wound healing remains a major clinical challenge due to impaired regeneration and incomplete restoration of dermal architecture, creating the need for biomaterials that reconstruct the human extracellular matrix (ECM) microenvironment, especially the collagen-rich structural network. Current strategies to obtain human-relevant collagen primarily include genetically engineered recombinant collagen and ECM directly produced by human cells. Although recombinant collagen has been extensively developed, it represents a simplified surrogate of native human collagen, and the biosynthesis of fully mature human collagen remains technically challenging. Therefore, we developed an engineered and scalable strategy to fabricate human cell-derived engineered ECM (HE-ECM) from human fibroblasts and systematically compared it with commercial recombinant collagen. Physicochemical analyses demonstrated that HE-ECM preserved native-like porous matrix architecture, collagen triple-helical integrity, enhanced thermal stability, and a more complex protein composition. HE-ECM significantly enhanced fibroblast viability, proliferation, and migration in vitro and accelerated wound closure with improved tissue organization in a rat full-thickness skin defect model. Overall, this controllable and donor-independent fabrication strategy enables scalable production of human collagen-rich HE-ECM that more faithfully recapitulates the native skin microenvironment than recombinant collagen, thereby suggesting its potential as a biomimetic platform for tissue regeneration.