Immune-Active Ionic Liquid (HistaGE) for Transdermal Delivery of Histamine in Diabetic Wound Healing
Biomedical Engineering
Rachita Kiran
Abstract
Diabetic foot ulcers are difficult to heal due to impaired blood circulation, chronic inflammation, and the strong barrier function of the stratum corneum, which limits the effectiveness of topical therapies. Histamine is a vasodilatory and immune-active molecule with potential to enhance local perfusion and support tissue repair, but its therapeutic use requires a formulation capable of stable, controlled, and sustained delivery. In this study, we developed an ionic-liquid formulation termed HistaGE by directly combining histamine with geranic acid at molar ratios of 1:2, 1:3, and 1:4. Geranic acid, a biocompatible ionic-liquid component known to disrupt lipid packing in the stratum corneum, serves as the permeability-enhancing agent. The resulting cream-like formulations were characterized using ¹H NMR spectroscopy and evaluated ex vivo on porcine skin using Franz diffusion cells. Histamine permeation across skin layers and into the receptor chamber was quantified using Pauly’s colorimetric assay. All HistaGE formulations enhanced histamine delivery relative to PBS and CAGE controls, with the 1:2 ratio exhibiting the most favorable viscosity, physical stability, and permeation behavior. A 48-hour time-course experiment further demonstrated sustained histamine release from HistaGE (1:2), confirming its ability to modulate diffusion through ionic pairing. Overall, these findings highlight HistaGE as a promising immune-active ionic cream capable of enabling prolonged and controlled transdermal histamine delivery for potential application in diabetic wound healing.