A Catechol-Modified Quaternized Chitosan/PEG Hydrogel for Diabetic Wound Healing: Synergistic Effects of TGF-β3 Delivery, Angiogenesis, and Antibacterial Activity

Xiu Yang^1*Zheng-Chao Zhang¹BO LIU¹Yunan Lu¹Xue-Yi He¹Hui-Dong Chen¹Jia-Xun Yang²Jia-Yu He¹Yiren Zhu¹Chang-Li Huang²Wubing He¹

• ¹Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
• ²Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China

Background: Diabetic foot ulcers (DFUs) represent a challenging chronic wound model, often plagued by biofilm formation that sustains inflammation and impedes healing. Transforming growth factor-beta 3 (TGF-β3) is a promising cytokine for tissue regeneration, yet its delivery within the hostile, infected wound milieu remains problematic. This study addresses the intertwined challenges of microbial resistance and healing impairment by developing a multifunctional injectable hydrogel that couples inherent antibacterial activity with sustained TGF-β3 release. Methods: A catechol-modified quaternized chitosan (QCS-Catechol) was synthesized and crosslinked with benzaldehyde-terminated 4-arm polyethylene glycol (4-arm PEG-CHO) to form the BP-QS/TGF-β3 hydrogel. Its physicochemical properties, injectability, adhesion, and mechanical strength were characterized. Antibacterial efficacy was evaluated against Staphylococcus aureus and Escherichia coli. The biocompatibility and therapeutic potential of the BP-QS/TGF-β3 hydrogel were evaluated through in vitro assays (CCK-8, apoptosis, hemolysis) and in a streptozotocin-induced diabetic mouse model, respectively, against controls including PBS, BP-QS (blank hydrogel), and free TGF-β3 solution. Wound closure kinetics, histology (H&E, Masson's trichrome), and immunohistochemistry (CD31, Ki-67) were analyzed. Results: The BP-QS/TGF-β3 hydrogel demonstrated rapid gelation (~3 min), excellent injectability, robust tissue adhesion (28.5 ± 2.1 J/m²), and suitable mechanical properties. It exhibited outstanding biocompatibility and potent, broad-spectrum antibacterial efficiency (>94%). The sustained release of TGF-β3 significantly enhanced fibroblast migration and proliferation in vitro. In diabetic mice, the BP-QS/TGF-β3 treatment achieved the most rapid wound closure, with the lowest relative wound deficit (7.30% ± 2.76% on day 12), significantly outperforming the PBS control, BP-QS hydrogel, and free TGF-β3 solution groups (p < 0.01). Histological analyses revealed enhanced granulation tissue formation, collagen deposition (724.61 ± 60.12 μm), angiogenesis, and cell proliferation. No systemic toxicity was observed. Conclusions: The BP-QS/TGF-β3 hydrogel synergizes potent antibacterial action with sustained TGF-β3 delivery to disrupt the vicious cycle of biofilm infection and healing failure. This integrated, multidisciplinary strategy effectively targets the core pathology of diabetic wounds, offering a promising therapeutic platform for managing biofilm-infected chronic wounds.