Copper ion-chelated supramolecular polymer/hyaluronic acid hydrogel promotes wound healing in diabetes

Daoqiang Lu; Wenchong Yu; Danni Zhao; Fei Qi; Xiu Wang; Qiang Fu; Jie Li; Fang Yang; Riwang Li; Xiaoxiao Wang; Haotian Lan; Jieyan Wang; Honglin Zhang; Dahai Liu; Jun Wang; Xiaodong Zhao

doi:10.1016/j.ijbiomac.2025.145615

Copper ion-chelated supramolecular polymer/hyaluronic acid hydrogel promotes wound healing in diabetes

Int J Biol Macromol. 2025 Jun 27:145615. doi: 10.1016/j.ijbiomac.2025.145615. Online ahead of print.

Authors

Daoqiang Lu¹, Wenchong Yu², Danni Zhao³, Fei Qi⁴, Xiu Wang⁵, Qiang Fu⁶, Jie Li⁵, Fang Yang⁷, Riwang Li⁵, Xiaoxiao Wang⁵, Haotian Lan⁶, Jieyan Wang⁶, Honglin Zhang⁶, Dahai Liu⁸, Jun Wang⁹, Xiaodong Zhao¹⁰

Affiliations

¹ Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528231, Guangdong Province, China; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510280, Guangdong Province, China.
² Foshan Clinical Medical School of Guangzhou University of Chinese Medicine, Foshan 528031, Guangdong Province, China.
³ The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510280, Guangdong Province, China.
⁴ School of Clinical Medicine, Anhui Medical College, Hefei 232221, Anhui Province, China.
⁵ Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528231, Guangdong Province, China.
⁶ School of Medicine, Foshan University, Foshan 528000, Guangdong Province, China.
⁷ School of Food Science and Engineering, Foshan University, Foshan 528000, Guangdong Province, China.
⁸ Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528231, Guangdong Province, China. Electronic address: dliu@fosu.edu.cn.
⁹ Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Animal Science and Technology, Foshan University, Foshan 528231, Guangdong Province, China. Electronic address: wangjun@fosu.edu.cn.
¹⁰ Foshan Clinical Medical School of Guangzhou University of Chinese Medicine, Foshan 528031, Guangdong Province, China; Foshan Fosun Chancheng Hospital, Foshan 528031, Guangdong Province, China.. Electronic address: zxd@fsccyy.com.

PMID: 40582679
DOI: 10.1016/j.ijbiomac.2025.145615

Abstract

Hydrogel wound dressings have shown promising potential for treating diabetic wounds, but their efficacy is limited by the complex wound microenvironment and the lack of integrated treatment strategies. In this study, a series of multifunctional hydrogel adhesives with anti-inflammatory, antibacterial, and angiogenesis-promoting properties was synthesized using free radical polymerization. The raw materials included methacrylated hyaluronic acid (HAMA), 3-(bis(pyridin-2-ylmethyl)amino)propyl methacrylate (DPAMA), and N-[tris(hydroxymethyl)methyl]acrylamide (THMA). Cu²⁺ ions were incorporated into the hydrogels through their strong affinity for dipicolylamine and carboxylic acid groups. Adhesion strength of the hydrogel ranged from 8 to 14 kPa, and tensile strength was 14.9 kPa. The inhibition zones against Escherichia coli and Staphylococcus aureus were 16.16 mm and 14.5 mm, respectively. ELISA results showed that the HTDC2 hydrogel (containing 3 mg/mL Cu²⁺) significantly reduced TNF-α and IL-1β expression. The HTDC2 hydrogel significantly promoted full-thickness skin wound healing in diabetic mice, achieving over 85 % closure by day 14. Western blot data showed that TNF-α and IL-1β protein levels in HTDC2 group decreased 3.5-fold on day 10 compared with control. Angiogenesis, immunofluorescence, and immunohistochemistry results confirmed that HTDC2 promoted angiogenesis and reduced pro-inflammatory factor expression. In summary, the proposed supramolecular polymer/hyaluronic acid hydrogel is promising as a diabetic wound dressing.

Keywords: Adhesive; Antibacterial and anti-inflammatory; Diabetic wound healing.