Abstract

Electrical Stimulation in the Treatment of Lymphedema and Associated Skin Ulcers

Mirko Baglivo, MS,1 Francesco Martelli, MS,2 Stefano Paolacci, PhD,3 Elena Manara, PhD,1,4 Sandro Michelini, MD, PhD5 and Matteo Bertelli, MD, PhD4. Lymphatic Research Biology, 2019.

Background: Lymphedema is a disorder in which lymph accumulates in the interstitial spaces due to poor lymphatic flow resulting from hypoplasia or aplasia of the lymphatic vessels, or to morpho-functional alterations that impair lymphatic flow. Lymphedema is a debilitating condition associated initially with inflammation that then degenerates into hardening of affected tissues and the formation of ulcers on the skin of affected limbs. No definitive treatment is available. The only therapy for lymphedema consists of physiotherapy, surgery, and compression to reduce impairment, which only treats the symptoms, not the causes. A possible new therapy that could reinforce the treatment of lymphedema progression and complications is electrical stimulation (ES). Many studies underline the effects of electric currents on the different cell mechanisms associated with disease.

Methods and Results: In this review, we summarize the effects of ES on the molecular and cellular processes involved in the pathophysiology of lymphedema, highlighting their therapeutic potential for edema reduction, ulcer repair, and restoration of lymphatic flow in vitro and in vivo.

Conclusions: ES exerts its effect on the main stages that characterize lymphedema, from its onset to ulcer formation. There are few evidences on lymphatic models and more molecular studies are needed to understand the mechanism of action of this application in the treatment of lymphedema.

Main findings

• Effects of ES on protein drainage. ES in vivo has been associated with increased protein drainage in vivo.
• Electro-stimulated rats showed increased lymphatic uptake of interstitial proteins due to improved lymphatic flow, although ES did not cause any significant decrease in induced traumatic edema.
• Studies of the effects of ES on wound healing are more numerous. Physiologically, there exists a potential difference between the various dermal layers caused by the movement of ions across cell membranes. The phenomenon is known as skin battery. positive surface charge, such as macrophages, neutrophils, epithelial stem cells, fibroblasts, and keratinocytes, which are necessary for wound repair.19 EScanpromotetissuerepairbystimulatingcellmigrationon the site of the ulcer.
• Unfortunately, few studies regardES in relation to the lymphaticsystem. This is why the present review also considered ES with other experimental models. ES has effects on the proliferation of cells involved in inflammation, angiogenesis, and wound healing.
• ES is known to induce expression of certain inflammatory factors.
• ES can also be used to modulate the consequences of lymphedema by stimulating wound healing. The role of fibrosis in wound healing is problematical because fibrosis of lymphatic tissue compromises its functioning. It would therefore be useful to repair wounds by controlling fibrosis. In this direction, ES also promotes trans-differentiation of fibroblasts into myofibroblasts, the latter associated with a laxer and more reversible form of fibrosis. This could improve wound healing and reduce edema volume and hardness, even in advanced stages of the disease, without compromising the function and contractility of lymphatic tissue. More studies are needed.
• In conclusion, ES has been applied as a therapeutic option in lymphology. Since the data available in the literature are highly varied, more molecular studies are needed regarding role of ES in lymphatic models.