Chronic diabetic ulcers affect more than 131 million people worldwide and are linked to roughly $755 billion in healthcare costs each year. A comprehensive review by Yi Ru and colleagues examines why these wounds resist healing, focusing on how immune cell populations change over time during the healing process.
In normal healing, macrophages shift from pro-inflammatory M1 states toward pro-reparative M2 states, allowing inflammation to subside. In diabetic wounds, that transition breaks down, leaving macrophages locked in inflammatory states. Neutrophil extracellular traps become poorly regulated, and mast cell degranulation differs substantially from normal wounds, both contributing to sustained inflammation. Dendritic cells also become less effective at clearing dead cellular material, a process tied to reduced activity of the SLC7A11 transporter.
T cells play a role as well: regulatory T cells decline in number and function, while specialized dendritic epidermal T cells show lower activation and reduced production of growth factors. B cells and natural killer cells are less studied, but emerging evidence suggests B cells can encourage macrophages to adopt M2 states and help reduce excessive inflammation.
The review highlights new treatments that directly modify immune activity, including topical anti-cytokine biologics and drugs that promote M2 macrophage polarization. Mesenchymal stem cell therapies and extracellular vesicles are also promising, along with advanced biomaterials and smart dressings that deliver immune-modifying substances to the wound.