Development of an Adhesive Hydrogel-based Platform Using Disulfide Bonds for Endogenously Improving Nitric Oxide Concentration for Diabetic Wounds

The prevalence of diabetes is rapidly increasing. However, comprehensive management, including diagnosis and treatment for diabetes, is not being properly conducted. Diabetes is becoming more prevalent due to insulin resistance, which worsens with age-related decreases in muscle mass and physical activity, as well as the use of multiple medications for chronic diseases. Diabetic patients can suffer from various complications in the cardiovascular system, kidneys, peripheral nerves, etc., due to chronic vascular damage. The risk of complications is very high due to disruptions in the immune system. Patients with diabetes and cardiovascular diseases experience increased blood viscosity and narrowed blood vessels, leading to impaired blood circulation in peripheral vessels and various related diseases. Therefore, it is crucial to repair vascular damage and effectively form new blood vessels.<br/>Nitric oxide, an endogenous gaseous signaling molecule, is involved in various physiological processes such as cardiovascular homeostasis regulation, cell proliferation, and cancer cell apoptosis. Specifically, nitric oxide can induce vascular dilation by increasing the expression of cGMP in smooth muscle cells. Current clinical treatments using nitric oxide involve inhaling high-pressure nitric oxide gas, which delivers nitric oxide to the lungs. However, due to the short half-life of nitric oxide, it is challenging to use this method for effective delivery. Although hydrogels for transdermal and local delivery of nitric oxide are being developed in the research field, they have not been applied in clinical treatments. The biggest issue is that to deliver nitric oxide externally to the reduced levels within the blood vessels, it is necessary to continuously inject a carrier that releases nitric oxide into the affected area or apply hydrogels transdermally. Additionally, as these methods do not effectively increase the nitric oxide concentration within the blood vessels, they are limited in treating diseases caused by permanently reduced nitric oxide levels due to vascular damage or aging.<br/>Herein, we developed a platform that can normalize abnormal nitric oxide concentrations in the vascular system by utilizing the breakdown and bonding characteristics of disulfide bonds to intrinsically regulate the release of nitric oxide within the human body, thereby upregulating nitric oxide levels. We controlled the nitric oxide release by adjusting the properties of surrounding functional groups of the disulfide bonds. Based on this, we verified the changes in the chain mobility of the disulfide bonds and consequently controlled the breakdown of GSNO, an intrinsic nitric oxide-releasing substance in the human body. For validation of promoting wound healing efficiency for chronic wounds caused by diabetes, this system helps normalize vascular dilation functions and promotes vascular formation in peripheral vessels, thereby inducing wound healing. The platform being developed in this study for endogenously improving nitric oxide concentration is unique in that it intrinsically increases nitric oxide levels, unlike existing nitric oxide-based treatments. Additionally, it is expected to contribute to treating chronic diseases such as open wounds and chronic vascular diseases, thereby improving the overall health level of the population and enhancing the quality of life for ordinary citizens suffering from diabetes complications and vascular diseases.