Engineering the Lymphatic Network: A Solution to Lymphedema

Abstract

Secondary lymphedema is a life‐long disorder characterized by chronic tissue swelling and inflammation that obstruct interstitial fluid circulation and immune cell trafficking. Regenerating lymphatic vasculatures using various strategies represents a promising treatment for lymphedema. Growth factor injection and gene delivery have been developed to stimulate lymphangiogenesis and augment interstitial fluid resorption. Using bioengineered materials as growth factor delivery vehicles allows for a more precisely targeted lymphangiogenic activation within the injured site. The implantation of prevascularized lymphatic tissue also promotes in situ lymphatic capillary network formation. The engineering of larger scale lymphatic tissues, including lymphatic collecting vessels and lymph nodes constructed by bioengineered scaffolds or decellularized animal tissues, offers alternatives to reconnecting damaged lymphatic vessels and restoring lymph circulation. These approaches provide lymphatic vascular grafting materials to reimpose lymphatic continuity across the site of injury, without creating secondary injuries at donor sites. The present work reviews molecular mechanisms mediating lymphatic system development, approaches to promoting lymphatic network regeneration, and strategies for engineering lymphatic tissues, including lymphatic capillaries, collecting vessels, and nodes. Challenges of advanced translational applications are also discussed.

Post-traumatic lymphedema: review of the literature and surgical treatment options

“…The selection of donor site is dictated primarily by minimizing morbidity [42] . Donor site complications specific to VLNT include lymphocele, lymphatic fistula, and lymphedema of donor limb [43] . Donor site iatrogenic lymphedema can be reduced using reverse lymphatic mapping [44] , which uses technetium-99 sulfur colloid and ICG to distinguish between lymph nodes draining the trunk and those draining the extremities.…”

The Lymphatic Endothelium in the Context of Radioimmuno-Oncology

“…Mutations in numerous genes involved in the initial formation of lymphatic vessels (including valves) as well as in the growth and expansion of the lymphatic system are identified in about one-third of affected individuals [155]. Alterations of the VEGFR3 signaling pathway are a common feature of primary lymphedema, and supplementation with VEGFCreleasing patches or administration of HGF or ANG-2 improves the lymphedema condition, at least in animal models [156]. Secondary lymphedema, however, can be triggered in response to surgery or irradiation of lymphatic vessels.…”

Engineering transplantable human lymphatic and blood capillary networks in a porous scaffold

“…14 However, other growth factors including FGF-2 and FGFR can also promote LEC proliferation and migration. 14 The Angiopoietin 2/Tie2 pathway is an important signalling pathway in lymphatic differentiation and maturation, but not lymphatic sprouting 10 and PDGFR and PDGF-BB also have roles in LEC migration and lymphatic vessel formation. 14 The lymphatic system comprises specialized blind ending capillaries (termed initial lymphatics, terminal lymphatics or lymphatic capillaries) 12 which drain into larger pre-collectors and then collecting lymphatics that take the interstitial fluid and immune cells back to lymph nodes and the central venous system.…”

“…14 The Angiopoietin 2/Tie2 pathway is an important signalling pathway in lymphatic differentiation and maturation, but not lymphatic sprouting 10 and PDGFR and PDGF-BB also have roles in LEC migration and lymphatic vessel formation. 14 The lymphatic system comprises specialized blind ending capillaries (termed initial lymphatics, terminal lymphatics or lymphatic capillaries) 12 which drain into larger pre-collectors and then collecting lymphatics that take the interstitial fluid and immune cells back to lymph nodes and the central venous system. The lymphatic capillaries and the collecting ducts are lined internally by lymphatic endothelium which share some cell markers with blood vascular endothelium (CD31, vWF, VE-cadherin).…”

“…15 LECs also express cell markers not expressed by blood microvascular endothelial cells including PROX1, LYVE-1, podoplanin and VEGFR3. [14][15][16] Structurally the lymphatic capillary differs from the blood capillary in that they are wide blind ending sacs and have a discontinuous basal lamina, and overlapping endothelial cells. 13,17 Approaches for lymphatic network regeneration have focused on models of skin wound healing or more commonly lymphoedema (chronic swelling of the limbs because of interstitial fluid accumulation due to lymphatic capillary loss or disfunction).…”