Yuhui Chen,1,* Ying Li,1,* Haoning Song,1,* Xiaochun Liu,1 Hongan Zhang,1 Jiaxin Jiang,2 Hongsheng Liu,2 Ribo Zhuo,1 Guoyun Cheng,1 Jia Fang,1 Lei Xu,1 Yong Qi,1 Dawei Sun1 

1Department of Orthopedics and Traumatology, The Affiliated Guangdong second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, 510315, People’s Republic of China; 2Guangdong Huayi Biomedical Science and Technology Center, Guangzhou, Guangdong, 511450, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Lei Xu, Department of Orthopedics and Traumatology, Guangdong second Provincial General Hospital of Jinan University, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, Guangdong, People’s Republic of China, Email orthoxl@163.com Dawei Sun, Department of Orthopedics and Traumatology, Guangdong second Provincial General Hospital of Jinan University, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, Guangdong, People’s Republic of China, Email sundw@gd2h.org.cn

Background: A paramount issue in the realm of chronic wound healing among diabetic patients is the pervasive inflammatory response that persistently thwarts angiogenesis, thereby precipitating protracted delays in the healing process of such wounds. Employing zeolitic imidazolate framework-8 (ZIF-8) as a drug delivery platform, integrated within a temperature-sensitive injectable hydrogel, presents an intriguing strategy for the closure of various irregular wounds, modulation of inflammatory responses, and promotion of angiogenesis.
Methods: Herein, ZIF-8 loaded with curcumin (Cur) combined with methylcellulose/carboxymethyl chitosan (MCC) thermosensitive hydrogel was described. The assessment encompassed the temperature-sensitive properties, pH-responsive release, antimicrobial activity, and ROS scavenging capabilities of the MCC@ZIF-8@Cur hydrogel. A series of studies were conducted to explore its biocompatibility, pro-angiogenic effects, and macrophage M2 polarization induction. Additionally, a full-thickness skin defect model of diabetic rat was established to investigate the hydrogel’s multifaceted efficacy in facilitating wound repair, mitigating inflammatory responses, and fostering angiogenesis.
Results: The thermosensitive MCC@ZIF-8@Cur hydrogel possess the attribute of being injectable and capable of in situ formation (gelation temperature of ≥ 28 °C), thereby establishing an effective physical barrier for a multitude of irregular wound profiles. The incorporation of ZIF-8@Cur confers the hydrogel with exceptional antibacterial properties and the capability to eliminate reactive oxygen species (ROS). Moreover, the pH-responsive MCC@ZIF-8@Cur hydrogel continuously releases Cur and Zn2+, mitigating inflammation, inducing M2 polarization of macrophages, and promoting angiogenesis. This creates a favorable immune microenvironment conducive to skin regeneration, thereby accelerating the healing of diabetic wounds. In vivo studies have demonstrated a markedly accelerated wound healing ratio in rats within the hydrogel group compared to the Control group (p< 0.001). By the 14th day of wound healing, the MCC@ZIF-8@Cur hydrogel group achieved a remarkable healing ratio of 97.22%, considerably surpassing the Control group (72.98%), showcasing remarkable potential for treating diabetic wounds.
Conclusion: The findings demonstrate the successful creation of a temperature-sensitive hydrogel that exhibits remarkable antibacterial properties and ROS scavenging capabilities. This hydrogel effectively suppresses inflammatory responses, modulates the polarization of macrophages towards the M2 phenotype, and promotes angiogenesis, thus fostering a favorable immune microenvironment for skin regeneration. These attributes collectively augur promising prospects and applications in the healing of diabetic wounds.

Keywords: diabetic wound, thermosensitive hydrogel, inflammatory microenvironment, macrophage polarization, angiogenesis