Study on Berberine/Glycyrrhizic Acid Monoammonium Salt Self-Assembled Hydrogel for Diabetic Wound Healing

Abstract

Diabetic chronic wounds face multiple intractable healing obstacles including sustained inflammation, severe infection, insufficient angiogenesis and defective collagen deposition. Current dressings fail to simultaneously relieve all these pathological defects. Herein, we constructed a carrier-free binary self-assembled Glycyrrhizic acid monoammonium salt–Berberine (GB) hydrogel composed of berberine and glycyrrhizic acid monoammonium salt, which forms interconnected nanofiber networks via one-pot thermally assisted small-molecule co-assembly without chemical crosslinking or exogenous polymer carriers. Relying on intermolecular non-covalent interactions, this single supramolecular material integrates anti-inflammatory, broad-spectrum antibacterial, pro-angiogenic, and collagen-regenerative multifunctions, which simultaneously ameliorates multiple core pathological obstacles of diabetic wounds within one formulation. We systematically characterized its physicochemical features, biocompatibility, and antibacterial and anti-inflammatory activities, as well as in vivo wound repair performance. This hydrogel formed uniform nanofibrous architectures with favorable viscoelastic properties and pH-dependent sustained release. In vitro assays verified its outstanding biosafety, broad-spectrum bacteriostasis against Escherichia coli and Staphylococcus aureus, and potent inhibitory effects on pro-inflammatory cytokines TNF-α and IL-6, with bacterial inhibition rates reaching ~88% against E. coli and ~70% against S. aureus. In diabetic mouse full-thickness infected wound models, the GB hydrogel simultaneously alleviated local inflammation, accelerated wound closure and facilitated ordered collagen deposition and mature microvessel formation, achieving a 73.10% wound closure rate at day 7 and 58.01% collagen deposition fraction at day 14, thus exhibiting equivalent or superior repair capacity compared with commercial hydrogel dressings. This carrier-free supramolecular system based on natural herbal small molecules provides a safe, convenient, and integrated therapeutic strategy for diabetic infected chronic wounds, with promising clinical translation potential.