Venous
leg ulcers (VLUs) are one of the most common
ulcers of the lower extremity. VLU affects many individuals worldwide, could pose a significant socioeconomic burden to the healthcare system, and has major psychological and physical impacts on the affected individual. VLU often occurs in association with post-thrombotic syndrome, advanced chronic venous disease,
varicose veins, and venous
hypertension. Several demographic, genetic, and environmental factors could trigger chronic venous disease with venous dilation, incompetent valves, venous reflux, and venous
hypertension. Endothelial cell injury and changes in the glycocalyx, venous shear-stress, and adhesion molecules could be initiating events in VLU. Increased endothelial cell permeability and leukocyte infiltration, and increases in inflammatory
cytokines,
matrix metalloproteinases (
MMPs), reactive
oxygen and
nitrogen species,
iron deposition, and tissue metabolites also contribute to the pathogenesis of VLU. Treatment of VLU includes compression
therapy and endovenous ablation to occlude the axial reflux. Other interventional approaches such as subfascial endoscopic perforator surgery and iliac venous
stent have shown mixed results. With good
wound care and compression
therapy, VLU usually heals within 6 months. VLU healing involves orchestrated processes including hemostasis,
inflammation, proliferation, and remodeling and the contribution of different cells including leukocytes, platelets, fibroblasts, vascular smooth muscle cells, endothelial cells, and keratinocytes as well as the release of various biomolecules including
transforming growth factor-β,
cytokines,
chemokines,
MMPs, tissue inhibitors of
MMPs (TIMPs),
elastase,
urokinase plasminogen activator,
fibrin,
collagen, and
albumin. Alterations in any of these physiological
wound closure processes could delay VLU healing. Also, these histological and soluble
biomarkers can be used for VLU diagnosis and assessment of its progression, responsiveness to healing, and prognosis. If not treated adequately, VLU could progress to non-healed or granulating VLU, causing physical immobility, reduced quality of life,
cellulitis, severe
infections,
osteomyelitis, and neoplastic transformation. Recalcitrant VLU shows prolonged healing time with advanced age,
obesity,
nutritional deficiencies, colder temperature, preexisting venous disease,
deep venous thrombosis, and larger
wound area. VLU also has a high, 50-70% recurrence rate, likely due to noncompliance with compression
therapy, failure of
surgical procedures, incorrect
ulcer diagnosis, progression of venous disease, and poorly understood pathophysiology. Understanding the molecular pathways underlying VLU has led to new lines of
therapy with significant promise including biologics such as bilayer living skin construct, fibroblast derivatives, and extracellular matrices and non-biologic products such as
poly-N-acetyl glucosamine, human placental membranes amnion/chorion allografts,
ACT1 peptide inhibitor of
connexin 43,
sulodexide,
growth factors,
silver dressings,
MMP inhibitors, and modulators of reactive
oxygen and
nitrogen species, the immune response and tissue metabolites. Preventive measures including compression
therapy and venotonics could also reduce the risk of progression to chronic
venous insufficiency and VLU in susceptible individuals.