Calcium ions released from alginate hydrogel promote wound healing by enhancing fibroblast activity

Hydrogels are widely used as wound dressings owing to their biocompatibility, high water content, and ability to mimic extracellular matrix functions. Alginate (ALG) is a natural polysaccharide that forms ionically crosslinked hydrogels in the presence of calcium, where Ca²⁺ not only stabilizes the crosslinked network but also regulates cell behavior, which is essential for wound repair. In this study, ALG hydrogels were prepared with CaCl₂ at 20, 50, 100, and 200 mM, and their gelation, rheological properties, calcium ion release, and cellular responses were systematically evaluated. The 100 mM CaCl₂ formulation exhibited the optimal mechanical stability and bioactivity, markedly promoting fibroblast proliferation, migration, and extracellular matrix organization in vitro. Application of this hydrogel to a rat model with full-thickness skin defects significantly accelerated wound closure and tissue regeneration. Transcriptomic analysis further confirmed activation of the calcium signaling pathway in fibroblasts. These findings highlight the pivotal role of Ca²⁺ in orchestrating fibroblast activity, providing an optimized alginate-based dressing for effective wound healing.