Table 2 Summary of Approaches for Lymphatic Tissue Engineering
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 | [58] |
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 | [160] | |
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 | [201] | |
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 | [202] | |
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 | [50] |
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 | ||
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 | ||
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 | [226] | |
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 | ||
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 | [239] |
Tail lymphedema treated with low-energy ESWT | Rat | -Increased expression of VEGF-C and bFGF -Decreased lymphedema | [240] | |
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 | [244] | |
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 | [245] | |
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] |