Gellan gum/honey-based gels and hydrogels for cutaneous wound management

Wound healing is complex and still requires targeted therapies and advanced dressings despite current advances. Honey (HNY) is a multifunctional bioactive agent with demonstrated benefits across various phases of healing. Here, we present a wound stage-specific formulation strategy that combines a previously uncharacterized multiflora HNY from Monte Novo (Portalegre, Portugal) with gellan gum (GG) to develop gels for osmolarity-driven debridement and hydrogels for sustained release of bioactive components post-debridement, thereby enhancing therapeutic outcomes. The amount of sugars and phenolic compounds in the HNY were consistent with its hyperosmotic nature and anti-oxidant and anti-microbial activity. Gels were prepared using 0.1 and 0.2% GG with 50-90% HNY to reduce HNY's inherent flowability and enhance retention at the wound site, while maintaining extrudability. Hydrogels were formulated with higher GG (0.75 and 1.25%) to form mechanically stable crosslinked networks, and lower HNY (10-40%) to reduce osmolarity while preserving bioactivity. All gel formulations were extrudable and demonstrated effective water absorption. Those with higher GG and lower HNY exhibited increased viscosity, required greater force to flow, and displayed solid-like behavior, favoring wound retention. The 80% HNY-0.2% GG formulation balanced viscosity and osmotic strength, as confirmed by cytotoxicity results, while preserving anti-microbial activity indicating suitability for wound debridement. Hydrogels showed increased stiffness with higher GG and HNY while maintaining HNY's bioactive constituents. The 30% HNY-1.25% GG formulation demonstrated superior stability and sustained release of HNY components, including phenolic compounds at levels supporting anti-inflammatory and healing effects. Although initial HNY hydrogel exposure reduced cell metabolic activity, cells recovered over time, maintaining proliferation and migratory function. Collectively, these findings highlight the potential of GG/HNY gel/hydrogel formulations to support wound management across different healing stages, offering effective debridement through osmotic action and prolonged therapeutic support via controlled bioactive components release.