Biofunctional evaluation of madecassoside-loaded ADAG hydrogels: enhancing cell migration and macrophage polarization

Abstract

The regeneration of chronic wounds is critically challenged by a dysregulated inflammatory microenvironment and impaired cellular motility. To address this, developed a multifunctional ADAGMAD hydrogel by incorporating the anti-inflammatory triterpenoid Madecassoside (MAD) into a Schiff base network of alginate dialdehyde and gelatin. This study demonstrates that the ADAGMAD system exhibits a controlled, sustained degradation profile with a neutral pH, maintaining structural integrity while dynamically increasing porosity to facilitate tissue ingrowth. In vitro, the ADAGMAD extract significantly enhanced key regenerative processes in fibroblasts, boosting collagen synthesis (168.2 ± 19.3 µg/mL at 48 h) and accelerating wound closure, achieving ~ 90% closure within 15 h. Crucially, under an inflammatory challenge, the hydrogel demonstrated profound immunomodulatory capacity by drastically downregulating pro-inflammatory M1 markers (iNOS, COX 2) and inducing a potent, ~ 25-fold upregulation of the anti-inflammatory cytokine TGF β to polarize macrophages toward a pro-healing M2 phenotype. These findings confirm that the ADAGMAD hydrogel successfully functions as an active, immunomodulatory platform that synergistically provides structural support, controlled drug release, and direct management of the wound microenvironment, presenting a highly promising strategy for advanced chronic wound care and soft tissue regeneration.

Graphical abstract