Photopolymerizable placenta-derived ECM hydrogel enhances hUC-MSC-mediated wound healing via coordinated immunomodulation and angiogenesis.

Mesenchymal stromal/stem cells (MSCs) hold great promise for regenerative medicine due to their potent immunomodulatory properties and favorable safety profile. However, their low survival, poor retention, and limited engraftment in injured tissues remain major barriers to clinical efficacy. Here, we engineered a photopolymerizable composite hydrogel derived from human placental extracellular matrix (PEM) and methacrylated hyaluronic acid (HAMA) to provide a biomimetic three-dimensional microenvironment for human umbilical cord MSCs (hUC-MSCs). The resulting PEM/HAMA (PH) hydrogel formed an interconnected porous, cytocompatible, and mechanically stable scaffold that enabled uniform cell encapsulation and maintained hUC-MSC viability above 80% after 72 h of culture. In vitro, PH significantly enhanced hUC-MSC mediated endothelial proliferation, migration, and tube formation. In vivo, the hUC-MSC loaded PH hydrogel (PHM) preserved MSC activity under inflammatory stress, promoted macrophage polarization from the pro-inflammatory (M1) to anti-inflammatory (M2) phenotype, stimulated angiogenesis, and markedly accelerated wound closure in a murine full-thickness skin defect model. Together, these findings identify a placenta derived photopolymerizable extracellular matrix (ECM) hydrogel as an effective stem cell delivery platform and provide a translatable strategy to overcome current limitations in MSC survival and therapeutic efficacy.