International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 214-223 http://medscipublisher.com/index.php/ijmms 215 2 Pathological and Molecular Basis of Chronic Wound Formation 2.1 Mechanisms of chronic inflammation and immune imbalance The main characteristic of chronic wounds is that the inflammatory response lasts for a long time and is abnormally regulated, which can disrupt the normal healing process. The inflammation of acute wounds can be controlled in time and is easy to repair, while chronic wounds remain in a state of severe inflammation all year round. Specifically, it is manifested as an increase in cytokines promoting inflammation (such as TNF-α and IL-1β), a higher activity of matrix metalloproteinases, and an excessive amount of reactive oxygen species (ROS) (Sousa et al., 2022). In addition, chronic wounds often have bacterial biofilms that constantly stimulate the immune system, prolonging the duration of inflammation and affecting healing (Raziyeva et al., 2021; Versey et al., 2021). Problems with the immune system caused by chronic wounds are often related to the inability of macrophages to function normally. Under normal circumstances, macrophages change from the pro-inflammatory M1 type to the restorative M2 type, helping to repair tissues. However, in wounds that have not healed for a long time, this transformation cannot be achieved. M1-type macrophages remain very active, thereby triggering persistent inflammation (Li et al., 2021). Meanwhile, immune cells such as neutrophils and mast cells either decrease in number or weaken in function, which further slows down wound healing (Raziyeva et al., 2021; Jabbari et al., 2025). This immune imbalance disrupts the microenvironment around the wound, causing immune cells to keep gathering and the tissue to be damaged, eventually slowing down the repair rate (Sousa et al., 2022). 2.2 Impaired cell function and delayed tissue repair Impaired cell function is an important pathological feature of chronic wounds, which affects various cells involved in repair. In chronic wounds, fibroblasts change from the type that helps with healing to the type with low activity, and their abilities to proliferate, move and secrete extracellular matrix (ECM) all weaken. The reduction in the number of keratinocytes, the slowdown in their movement speed and the increase in their death rate all slow down the process of re-epithelialization. Reduced numbers and impaired functions of endothelial cells and lymphocytes can also affect angiogenesis and nutrient delivery (Jabbari et al., 2025). Cellular aging, especially in the context of diabetes and aging, can amplify the above problems. Senescent cells gather on the wound surface, release pro-inflammatory molecules, resist apoptosis and inhibit regeneration, thereby maintaining inflammation. This kind of cellular imbalance caused by aging disrupts the wound environment, leading to reduced angiogenesis, limited ECM remodeling and delayed healing. Abnormal interactions among various cells form chronic cycles that are difficult to break, making traditional treatments ineffective (Yang et al., 2024). 2.3 The role of oxidative stress and microcirculation injury Oxidative stress is an important cause of chronic trauma. An appropriate amount of reactive oxygen species is beneficial for immune defense and signal transduction, but too much can harm cellular components, causing persistent inflammation and tissue damage (Hunt et al., 2024). Chronic wounds are generally accompanied by elevated levels of oxidative stress, weakened mitochondrial function and reduced protective heat shock proteins, which will cause more severe cell damage and slow down the healing process (Jabbari et al., 2025). Problems such as diabetes, obesity and aging can also make oxidative stress more severe, make it difficult for the body to control oxidative responses, prolong inflammation and affect tissue repair (Ukaegbu et al., 2025). Abnormal microcirculation function also plays an important role. Insufficient angiogenesis and microvascular damage can restrict the delivery of oxygen and nutrients, causing local hypoxia, which in turn triggers more severe oxidative stress and hinders wound healing. Oxidative stress, immune disorder and microvascular injury interact with each other and constitute the key mechanism of chronic wound occurrence, forming a vicious cycle of tissue damage and difficult repair (Hunt et al., 2024). Therefore, intervention methods targeting oxidative stress and microcirculation are of great value for the recovery and regeneration of chronic wounds (Wang, 2025).
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