Human Fibroblast‐Derived Matrix Hydrogel Accelerates Regenerative Wound Remodeling Through the Interactions with Macrophages

Abstract Herein, a novel extracellular matrix (ECM) hydrogel is proposed fabricated solely from decellularized, human fibroblast‐derived matrix (FDM) toward advanced wound healing. This FDM‐gel is physically very stable and viscoelastic, while preserving the natural ECM diversity and various bioactive factors. Subcutaneously transplanted FDM‐gel provided a permissive environment for innate immune cells infiltration. Compared to collagen hydrogel, excellent wound healing indications of FDM‐gel treated in the full‐thickness wounds are noticed, particularly hair follicle formation via highly upregulated β‐catenin. Sequential analysis of the regenerated wound tissues disclosed that FDM‐gel significantly alleviated pro‐inflammatory cytokine and promoted M2‐like macrophages, along with significantly elevated vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) level. A mechanistic study demonstrated that macrophages‐FDM interactions through cell surface integrins α5β1 and α1β1 resulted in significant production of VEGF and bFGF, increased Akt phosphorylation, and upregulated matrix metalloproteinase‐9 activity. Interestingly, blocking such interactions using specific inhibitors (ATN161 for α5β1 and obtustatin for α1β1) negatively affected those pro‐healing growth factors secretion. Macrophages depletion animal model significantly attenuated the healing effect of FDM‐gel. This study demonstrates that the FDM‐gel is an excellent immunomodulatory material that is permissive for host cells infiltration, resorbable with time, and interactive with macrophages, where it thus enables regenerative matrix remodeling toward a complete wound healing.