Joseph D. Raffetto

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.

Venous leg ulcer (VLU) is one of the most common lower extremity ulcerated wound, and is a significant healthcare problem with implications that affect social, economic, and the well-being of a patient. VLU can have debilitating related problems which require weekly medical care and may take months to years to heal. The pathophysiology of VLU is complex, and healing is delayed in many patients due to a persistent inflammatory condition. Patient genetic and environmental factors predispose individuals to chronic venous diseases including VLU. Changes in shear stress affecting the glycocalyx are likely initiating events, leading to activation of adhesion molecules on endothelial cells, and leukocyte activation with attachment and migration into vein wall, microcirculation, and in the interstitial space. Multiple chemokines, cytokines, growth factors, proteases and matrix metalloproteinases are produced. The pathology of VLU involves an imbalance of inflammation, inflammatory modulators, oxidative stress, and proteinase activity. Understanding the cellular and biochemical events that lead to the progression of VLU is critical. With further understanding of inflammatory pathways and potential mechanisms, certain biomarkers could be revealed and studied as both involvement in the pathophysiology of VLU but also as therapeutic targets for VLU healing.

Chronic venous leg ulcers (VLU) affect around 1% of the adult population in the Western world. The impact of VLU is both social and economic, with significant expenditures on active venous ulcers to provide medical treatment and eventual healing. At the core of VLU is venous hypertension which affects the venous macrocirculation. The changes incurred in venous hemodynamics leads to microcirculatory changes affecting the postcapillary venule and surrounding tissues. Inflammation by leukocytes affecting the venous endothelium, promotes a complex cascade and activation of adhesion molecules expression, chemokines and cytokines released, altered growth factor responses, and activation of protease (e.g. tPA) and proteinase (e.g. MMPs) activity that causes dysregulation and compromise of tissue integrity with eventual dermal damage and ulcer development. A critical component to treating VLU is correcting the abnormal venous hemodynamics and compression therapy. Unfortunately, VLU recurrence ranges between 30–70%, and other modalities in therapy along with compression are required. The goal for adjuvant products is to restore the balance from an inflammatory chronic wound to that of a reparative wound that will promote provisional matrix and epithelialization. There are many products on the market that can be used as adjuvant to compression therapy, but it must be recognized that there is a paucity of clinical trials that have evaluated the clinical effectiveness of specific products with clearly defined end points, and most importantly a healed VLU with a low recurrence rate. This review will discuss the fundamentals of VLU inflammation, and evaluate the available literature that may have benefit in reducing inflammation and lead to effective VLU healing.

Chronic venous disease (CVD) is a debilitating condition with a prevalence between 60-70%. The disease pathophysiology is complex and involves genetic susceptibility and environmental factors, with individuals developing visible telengiectasias, reticular veins, and varicose veins. Patient with significant lower extremity symptoms have pain, dermal irritation, swelling, skin changes, and are at risk of developing debilitating venous ulceration. The signature of CVD is an increase in venous pressure referred to as venous hypertension. The various symptoms presenting in CVD and the clinical signs that are observed indicate that there is inflammation, secondary to venous hypertension, and it leads to a number of inflammatory pathways that become activated. The endothelium and glycocalyx via specialized receptors are critical at sensing changes in shear stress, and expression of adhesion molecules allows the activation of leukocytes leading to endothelial attachment, diapedisis, and transmigration into the venous wall/valves resulting in venous wall injury and inflammatory cells in the interstitial tissues. There is a complex of cytokines, chemokines, growth factors, proteases and proteinases, produced by activated leukocytes, that are expressed and unbalanced resulting in an environment of persistent inflammation with the clinical changes that are commonly seen, consisting of varicose veins to more advanced presentations of skin changes and venous ulceration. The structural integrity of protein and the extracellular matrix is altered, enhancing the progressive events of CVD. Work focusing on metabolic changes, miRNA regulation, inflammatory modulation and the glycocalyx will further our knowledge in the pathophysiology of CVD, and provide answers critical to treatment and prevention.