Exposed chronic wounds are often covered with hypoxic tissue and are accompanied by necrosis, ongoing inflammation, and anaerobic infection. Since the oxygen in the atmosphere can only penetrate about 0.3 mm of tissue, and it is difficult for the oxygen circulating in the blood to reach the chronic wound through the damaged blood vessels, a solution for local oxygen delivery is urgently needed.

Recently, Prof. Zhang Zhongtao and Prof. Yao Hongwei from Beijing Friendship Hospital affiliated to Capital Medical University and Cheng Yuhao's team from Nanjing University School of Medicine and School of Life Sciences have studied a nanoparticle that can locally deliver dissolved oxygen to the wound site by adding lyophilized oxygen, thereby changing the traditional gel-type wound dressing (Fig. 1). A related research paper, Nano-oxygenated hydrogels for locally and permeably hypoxia relieving to heal chronic wounds, was published in the journal Biomaterials.

Fig.1 Schematic diagram of the structure of NOX-gel and the treatment of chronic wounds

Hydrogel Material:

Perfluoronaphthalene-coated human serum albumin (FDC@HSA), hyaluronic acid

1. NOX-gel improves cell migration and vascularization

The results of dynamic light scattering (DLS) showed that the hydrodynamic diameter of NOX-gel was 496.3 nm, and in addition, there was no large difference in the oxygen content of NOX-gel before and after lyophilization. The researchers chose CoCl2 to treat the cultured cells, which resulted in high expression of HIF-1α. Tests have shown that NOX gel has a protective effect against hypoxia and down-regulation of HIF-1α. Next, the researchers evaluated the relative viability of the cells, and the results showed that NOX-gel could significantly promote granulation tissue production by releasing oxygen, further reversing the effect of cellular hypoxia on HSF proliferation. Angiogenesis is the key to recovering chronic trauma and providing continuous oxygen. Catheterization experiments using human umbilical vein endothelial cells (HUVECs) were performed to determine the angiogenesis capacity of NOX-gel gel, and the results showed that the NOX-gel group significantly improved the formation of vascular branch points (Fig. 2).

Fig.2 In vitro cytotoxicity of NOX-gel gel and therapeutic effect of wound healing

2. NOX-gel gel promotes wound healing in acute and chronic diabetes

Next, the researchers verified whether NOX-gel can promote cell proliferation and angiogenesis in vivo, and the results showed that in the acute wound model of non-diabetic mice and the chronic wound model of diabetic mice, NOX-gel can deliver oxygen to the wound tissue, further alleviate the hypoxia effect, and accelerate wound closure. In addition, histopathology of HE and Masson staining showed that the granulation tissue thickness of wounds treated with NOX-gel was significantly higher than that of the control group, and that significantly more collagen was produced than wounds treated with other dressings (Figure 3).

Fig.3 NOX-gel gel promotes wound healing in diabetic mice

3. NOX-gel can alleviate the hypoxia phenomenon of diabetic wounds and promote angiogenesis

To investigate whether the rapid healing of wounds by NOX-gel may be due to its delivery of oxygen to the wound tissue, further alleviating hypoxia, immunohistochemistry (IHC) analysis of HIF-1α antibody was performed, which further demonstrated that NOX-gel treatment can successfully prevent hypoxia. In addition, the density of HIF-1α-positive cells in the DM+NOX-gel group was significantly reduced at day 6 and 12 after the gel intervention, confirming that the gel can sustainably improve the hypoxia status of diabetic wounds. In the process of wound healing, the investigators explored the pro-angiogenic ability and anti-inflammatory effect of NOX-gel through CD31 and CD68 staining, respectively, and confirmed that NOX-gel can effectively improve hypoxia, reduce inflammatory response, and promote diabetic wound neoangiogenesis (Fig. 4).