Sprayable Hybrid Gel with Cannabidiol, Hyaluronic Acid, and Colloidal Silver: A Multifunctional Approach for Skin Lesion Therapy

<b>Background/Objectives</b>: This study presents the development and characterization of a novel thermoresponsive hydrogel composed of hyaluronic acid (HA), poloxamer 407, cannabidiol (CBD), and colloidal silver (Ag), designed for topical antimicrobial therapy. <b>Methods</b>: The Ag-CBD complex was first synthesized and subsequently incorporated into a HA-poloxamer gel matrix to produce a stable, sprayable formulation with suitable physicochemical properties for dermal applications. <b>Results</b>: The HA-Ag-CBD hybrid gel exhibited a physiological pH, a gelation temperature compatible with skin surface conditions, and favorable rheological behavior, including thixotropy and shear thinning-critical for uniform application and retention under dynamic conditions. Release studies confirmed a sustained delivery profile, supporting prolonged local activity of CBD and colloidal Ag. Antimicrobial assays demonstrated that the HA-Ag-CBD hybrid gel retained potent activity against <i>Staphylococcus aureus</i> and <i>Candida albicans</i>, with minimum inhibitory and bactericidal concentrations (MIC/MBC) statistically comparable to those of the unencapsulated Ag-CBD complex. Against <i>E. coli</i>, the HA-Ag-CBD hydrogel exhibited primarily bacteriostatic activity, with a low MIC (9.24 μg/mL) but a substantially higher MBC (387.35 μg/mL), consistent with the intrinsic structural resistance of Gram-negative bacteria. In contrast, bactericidal activity was more pronounced against Gram-positive strains, reflecting differential susceptibility related to bacterial envelope properties. CBD consistently demonstrated superior antimicrobial efficacy to colloidal Ag, while the Ag-CBD combination produced slightly enhanced, mainly additive effects, likely due to complementary membrane disruption and intracellular Ag⁺ ion activity. Cytotoxicity assays on normal human dermal fibroblasts confirmed that the HA-Ag-CBD hybrid gel maintained >70% cell viability at therapeutically relevant concentrations, in accordance with ISO 10993-5:2009 guidelines, and effectively mitigated the inherent cytotoxicity of the Ag-CBD complex. <b>Conclusions</b>: The HA-Ag-CBD hybrid gel demonstrates strong potential as a biocompatible, multifunctional topical formulation for the treatment of infected wounds and skin lesions. Future work will focus on in vivo evaluation, assessment of skin permeation, and further development to support translational applications.