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Table 2 Summary of Approaches for Lymphatic Tissue Engineering

From: Lymphatic Tissue Engineering and Regeneration

Technique Method Model system Results Ref.
Hydrogels hLECS overlaid with Fibrin, Collagen I, and Fibrin-Collagen I composite hydrogels In vitro -In absence of fibroblasts, no capillary formation
-When hLECs with 40% dermal fibroblasts, branching capillaries developed within 21 days in vitro
Fibrin and collagen ratios varied in hydrogels In vitro -LECs organized the most extensively in fibrin-only hydrogels, with slender networks and narrow lumens
-Fibrin hydrogels stable for only 6 days
hLECs co-cultured with ASCs in fibrin hydrogels and supplemented with VEGF-C In vitro -In the presence of ASCs, LECs formed tubules and networks
-25ng/mL VEGF-C supplementation improved network formation
HA-hydrogel Lewis rat -Mice that received HA-hydrogel demonstrated decreased scarring and decreased collagen deposition
-HA treated group's ejection fraction was rescued to almost pre-MI baseline
Biochemical Stimuli LECs supplemented with VEGF-A and VEGF-C In vitro -In vitro formation of lymphatic capillaries
-Increased density of lymphatic capillary branching, compared to factor-free medium
VEGF-C administered with skin graft Mouse -Lymphatic regeneration temporally and spatially associated with pattern of VEGF-C they were exposed to [43]
VEGF-C administered with autologous lymph node transfer Domestic pig (female) -Induced lymphangiogenesis [213]
VEGF-C gene therapy Mouse, Rabbit -Regenerated damaged lymphatic networks
-Reduced edema
[211, 214218]
ANGPT1/2/TIE2 Proposed -Guide postnatal maturation of LVs [222]
TGF-β Proposed -Primary ligand in ALK1 pathway which regulates differentiation of premature LECs into mature LECs [223]
PDGF-B, HGF, and/or Adrenomedullin Proposed -Enhance proliferation, migration, and tubule formation of LECs [222, 224, 225]
Co-culture LECs seeded on sheets of fibroblasts In vitro -Stable 3D lymphatic capillary networks spontaneously organized without exogenous materials [228]
LECs and dermal fibroblasts co-cultured for six weeks In vitro -LECs spontaneously organized and formed vasculature that resembled native in vivo tissue
-Microvasculature stable for multiple weeks
Interstitial Flow (IF) IF through collagen gels containing phorbol 12-myristate 13-acetate In vitro -Induced blood and lymphatic endothelial cell organization [232]
Low level IF added to 3D fibrin matrix containing VEGF In vitro -Complex capillary morphogenesis
-Computational model showed that IF created gradient of VEGF
[160, 235]
IF applied to regenerating skin Mouse -Lymphatic vessels only formed in the direction of lymph flow [236]
Multichamber radial fluidic device that exposed LECs to IF In vitro -LECs formed multicellular, lumenized structures similar to natural lymphatic networks [200]
Extracorporeal Shockwave Therapy (ESWT) Ear lymphedema treated with low-energy shockwaves Rabbit -Increased expression of VEGF-C and VEGFR-3
-Decreased lymphedema
Tail lymphedema treated with low-energy ESWT Rat -Increased expression of VEGF-C and bFGF
-Decreased lymphedema
Scaffolds Collagen and fibrin-based hydrogels vascularized with LECs in vitro, then implanted Mouse -Functional vessels developed 15 days after implantation [220]
Engineered fibrin-binding VEGF-C (FB-VEGF-C) that is slowly released upon demand of infiltrating cells Mouse -FB-VEGF-C act synergistically with IF to drive lymphatic capillary morphogenesis in vitro
-Induce local lymphatic hyperplasia but do not remodel downstream collecting vessels
Nanofibrillar collagen scaffolds placed across lymphedema area to guide lymphatic regeneration Porcine -Increased number of lymphatic collectors in the proximity of scaffold
-Bioimpedance ratio improved, implying that functional lymphatic drainage was restored
Combinatorial Combinations of gelatin hydrogels, VEGF-C supplementation, and ESWT used to treat lymphedema Mouse -Greatest lymphatic vessel formation and greatest decrease in lymphedema resulted when all three approaches (hydrogels, VEGF-C, and ESWT) were combined [250]