Treating chronic wounds, such as diabetic foot ulcers, venous leg ulcers, and pressure ulcers, has always been a challenge in modern medicine. In the United States alone, the annual cost of treating chronic wounds is estimated to be 25 billion dollars [1]. Prolonged or excessive inflammation is one of the feature of chronic wound [2]. For physiological wound healing, there were four temporally and spatially overlapping phases: hemostasis, inflammation, proliferation, and remodeling phases [3,4]. Appropriate inflammation is an integral part of the physiological phase of wound healing, serving to remove cell debris and potential pathogens, including bacteria, from the wound [5]. Once the wound is cleared of pathogens and cell debris, inflammatory cells undergo by pyroptosis without causing further tissue damage and aggravating inflammation. If the leukocytes are hindered from infiltrating or clearing the wound, or if they cannot be disposed of by apoptosis, entering the proliferation phase of wound healing is delayed or inhibited, and through pro-inflammatory stimulation, the wound will be in an inflammatory cycle that is difficult to break and difficult to heal [6,7], thus becoming a chronic wound.

Chronic wounds stall in the inflammation phase of healing leading to excessive levels of proinflammatory cytokines, proteases, ROS, and senescent cells, as well as the presence of persistent infection and dysfunctional fibroblasts and endothelial cells at the wound, making it difficult for them to proliferate normally and express relevant beneficial factors to promote wound healing. Therefore, any approach that can reduce long-term inflammation or restore the biological function of cells which damaged by inflammation will be beneficial for chronic wound healing. It has been reported that succinate has a great effect on the pyroptosis of inflammatory cells, modulating the phenotype and function of immune cells [8,9]. And succinate can induce the inactivation of GSDMD and prevent cells pyroptosis [10,11]. Therefore the introduction of succinate can be considered for the treatment of chronic wounds. However, succinate is a small molecule substance, which is inconvenient to use as a wound dressing, so it can be considered to be combined with biological materials such as chitosan, alginic acid and hyaluronic acid, etc. to prepare wound dressing materials.

As wound dressing, chitosan (CS), a deacetylated derivative of chitin, is a naturally occurring amino polysaccharide with favorable biological properties such as antibacterial activity and hemostatic [12,13]. In addition, anti-inflammatory effects of chitosan have also been reported. For example, chitosan reduces LPS-induced inflammation in the intestinal epithelial cell line [14] and also attenuates the progression of inflammatory bowel disease by inhibiting the NF-κB pathway [15]. However, chitosan is insoluble in water under physiological pH conditions, which greatly limits its application.

Succinylated chitosan (NSC) is synthesized by partial succinylation of chitosan amine groups which not only introduces succinic acid in the chitosan molecular chain, but also improve CS solubility at physiological pH greatly [16,17]. NSC, characterized by its hydrophilic property is deemed safe and biocompatible due to its lack of pro-inflammatory activities [18]. In addition, NSC has shown a protective effect on intestinal inflammation by down-regulating LPS-induced inflammatory responses of macrophages [19]. NSC can also attenuate acute skin inflammation by inhibiting inflammatory neutrophils [20]. NSC possesses a unique ability to suppress pro-inflammatory responses of activated macrophages [18]. Nevertheless, previous studies on immunological functions of NSC are limited to immune cells such as macrophages and inflammatory neutrophils [18,20]. Thus, it will be of interest to explore the effects of NSC on dysfunctional HUVEC cells affected by chronic wounds.

In this study, we aimed to explore the ability of succinylated chitosan in the regulating the function of dysfunctional HUVEC cells which induced by high glucose and TNF-α, and promoting wound healing. Through the in vitro cell experiments, we found that NSC can effectively prevent the continued development of inflammation in injured cells and restore the physiological function of injured cells. In vivo animal experiments shows that NSC can effectively promote skin wound healing. These results indicate that NSC is a promising biomaterial for the treatment of chronic wounds.