Construction of heparin-based hydrogel incorporated with Cu5.4O ultrasmall nanozymes for wound healing and inflammation inhibition

Yuan Peng; Danfeng He; Xin Ge; Yifei Lu; Yuanhao Chai; Yixin Zhang; Zhengwei Mao; Gaoxing Luo; Jun Deng; Yan Zhang

doi:10.1016/j.bioactmat.2021.02.006

Construction of heparin-based hydrogel incorporated with Cu5.4O ultrasmall nanozymes for wound healing and inflammation inhibition

Bioact Mater. 2021 Mar 9;6(10):3109-3124. doi: 10.1016/j.bioactmat.2021.02.006. eCollection 2021 Oct.

Authors

Yuan Peng¹, Danfeng He², Xin Ge³, Yifei Lu², Yuanhao Chai⁴, Yixin Zhang¹, Zhengwei Mao⁵, Gaoxing Luo², Jun Deng², Yan Zhang¹

Affiliations

¹ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai, 200011, China.
² Institute of Burn Research, Southwest Hospital, State Key Lab of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
³ Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
⁴ McKelvey School of Engineering, Washington University in Saint Louis, One Brookings Drive Saint Louis, MO, 63130, USA.
⁵ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.

Abstract

Excessive production of inflammatory chemokines and reactive oxygen species (ROS) can cause a feedback cycle of inflammation response that has a negative effect on cutaneous wound healing. The use of wound-dressing materials that simultaneously absorb chemokines and scavenge ROS constitutes a novel 'weeding and uprooting' treatment strategy for inflammatory conditions. In the present study, a composite hydrogel comprising an amine-functionalized star-shaped polyethylene glycol (starPEG) and heparin for chemokine sequestration as well as Cu_5.4O ultrasmall nanozymes for ROS scavenging (Cu_5.4O@Hep-PEG) was developed. The material effectively adsorbs the inflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, decreasing the migratory activity of macrophages and neutrophils. Furthermore, it scavenges the ROS in wound fluids to mitigate oxidative stress, and the sustained release of Cu_5.4O promotes angiogenesis. In acute wounds and impaired-healing wounds (diabetic wounds), Cu_5.4O@Hep-PEG hydrogels outperform the standard-of-care product Promogram® in terms of inflammation reduction, increased epidermis regeneration, vascularization, and wound closure.

Keywords: Hydrogels; Inflammatory chemokines; Nanozymes; Reactive oxygen species; Wound healing.