Comprehensive management of diabetic ulceration: strategies and perspectives.

Diabetic Ulceration (DU) is a main category of nonhealing chronic wounds and tends to be vulnerable and ulcerated repeatedly. Prolonged hyperglycemia microenvironment, together with immunochemotactic response dysfunction, eventually contributes to the refractory wound that is hard to heal. In the chronic DU, there exist obstacles such as diabetic wound bacterial infection, persistent inflammation, suppressed angiogenesis, and reduced growth factor proliferation with decreased hypoxia inducible factor 1 alpha (HIF-1α) expression, and these issues have persisted in hindering the rational and effective wound tissue regeneration. In this review, we provide a comprehensive summary of therapeutic approaches that target the four phases of DU healing at glycemic control, anti-bacteria, anti-inflammatory, angiogenesis, and matrix remodeling. In the anti-bacteria and anti-inflammatory therapies, we discuss novel bioactive materials and a variety of antibacterial agents and anti-inflammatory therapies including herbal medicines, to handle the problems posed by wound-resistant bacteria, biofilms and the constant inflammatory microenvironment of DU. In later healing stages, following the healing process of DU, we summarized the usage of active metal ions, special gas molecules, growth factor production and HIF-1α stabilization to treat angiogenesis and matrix remodeling afterwards. In this review, we evaluate recent advances in each of these potential therapies and highlight their ability to improve DU healings in different stages.