Injectable Thermosensitive Placental ECM –Copper Hydrogel With Endothelial Progenitor Cells for Pressure Ulcer Repair

ABSTRACT

Pressure ulcers remain challenging to treat because ischemia, extracellular matrix disruption, and impaired angiogenesis create a wound microenvironment that limits effective regeneration. Here, an injectable thermosensitive hydrogel has been developed based on human placenta‐derived soluble extracellular matrix (sECM) and low‐dose copper sulfate (CuSO ₄ ), combined with endothelial progenitor cells (EPCs), to address multiple aspects of this pathology. Hydrogels were formulated using methylcellulose and characterized for rheological properties, swelling, degradation, and microstructure. EPC phenotype, viability, and proliferative activity were assessed by flow cytometry, live/dead staining, and MTT assay. Therapeutic performance was evaluated in a magnet‐induced ischemic pressure ulcer model using macroscopic and histological analyses. Incorporation of sECM and CuSO ₄ modified gelation behavior, improved mechanical properties, and increased pore size. Low‐dose CuSO ₄ (0.1% w/v) supported EPC viability and proliferation, whereas higher concentrations were cytotoxic. In vivo, hydrogels containing EPCs markedly accelerated wound closure, reducing wound area to 32.72% ± 1.04% at day 7, 11.33% ± 1.46% at day 14, and 1.24% ± 0.66% at day 21, compared with 17.35% ± 0.68% residual wound area in controls at day 21. Histological analysis further demonstrated enhanced tissue regeneration, with increased hair follicle density (up to 10 ± 0.63 vs. 1 ± 0.6 in controls) and greater collagen deposition (up to 85.26% ± 0.75% vs. 74.32% ± 0.75% in controls). These findings indicate that a placental ECM–copper hydrogel incorporating EPCs provides a promising biomaterial approach for pressure ulcer repair by combining structural support with pro‐angiogenic and cellular contributions.