Lymphatic dysfunction is associated with the progression of many cardiovascular 
disorders due to their role in maintaining tissue fluid homeostasis. Promoting 
new lymphatic vessels (lymphangiogenesis) is a promising strategy to reverse 
these cardiovascular disorders via restoring lymphatic function. Vascular 
endothelial growth factor (VEGF) members VEGF-C and VEGF-D are both potent 
candidates for stimulating lymphangiogenesis, though maintaining spatial and 
temporal control of these factors represents a challenge to developing efficient 
therapeutic lymphangiogenic applications. Injectable alginate hydrogels have 
been useful for the controlled delivery of many angiogenic factors, including 
VEGF-A, to stimulate new blood vasculature. However, the utility of these 
tunable hydrogels for delivering lymphangiogenic factors has never been closely 
examined. Thus, the objective of this study was to utilize ionically 
cross-linked alginate hydrogels to deliver VEGF-C and VEGF-D for potential 
lymphangiogenic applications. We demonstrated that lymphatic endothelial cells 
(LECs) are sensitive to temporal presentation of VEGF-C and VEGF-D but with 
different responses between the factors. The greatest LEC mitogenic and 
sprouting response was observed for constant concentrations of VEGF-C and a high 
initial concentration that gradually decreased over time for VEGF-D. 
Additionally, alginate hydrogels provided sustained release of radiolabeled 
VEGF-C and VEGF-D. Finally, VEGF-C and VEGF-D released from these hydrogels 
promoted a similar number of LEC sprouts as exogenously added growth factors and 
new vasculature in vivo via a chick chorioallantoic membrane (CAM) assay. 
Overall, these findings demonstrate that alginate hydrogels can provide 
sustained and bioactive release of VEGF-C and VEGF-D which could have 
applications for therapeutic lymphangiogenesis.