Local induction of lymphangiogenesis with engineered fibrin-binding VEGF-C promotes wound healing by increasing immune cell trafficking and matrix remodeling

Biomaterials. 2017 Jul;131:160-175. doi: 10.1016/j.biomaterials.2017.03.033. Epub 2017 Mar 25.


Lymphangiogenesis occurs in inflammation and wound healing, yet its functional roles in these processes are not fully understood. Consequently, clinically relevant strategies for therapeutic lymphangiogenesis remain underdeveloped, particularly using growth factors. To achieve controlled, local capillary lymphangiogenesis with protein engineering and determine its effects on fluid clearance, leukocyte trafficking, and wound healing, we developed a fibrin-binding variant of vascular endothelial growth factor C (FB-VEGF-C) that is slowly released upon demand from infiltrating cells. Using a novel wound healing model, we show that implanted fibrin containing FB-VEGF-C, but not free VEGF-C, could stimulate local lymphangiogenesis in a dose-dependent manner. Importantly, the effects of FB-VEGF-C were restricted to lymphatic capillaries, with no apparent changes to blood vessels and downstream collecting vessels. Leukocyte intravasation and trafficking to lymph nodes were increased in hyperplastic lymphatics, while fluid clearance was maintained at physiological levels. In diabetic wounds, FB-VEGF-C-induced lymphangiogenesis increased extracellular matrix deposition and granulation tissue thickening, indicators of improved wound healing. Together, these results indicate that FB-VEGF-C is a promising strategy for inducing lymphangiogenesis locally, and that such lymphangiogenesis can promote wound healing by enhancing leukocyte trafficking without affecting downstream lymphatic collecting vessels.

Keywords: Fibrin; Lymphatics; Regenerative medicine; VEGF-C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / drug effects
  • Cells, Cultured
  • Cloning, Molecular
  • Delayed-Action Preparations / metabolism*
  • Female
  • Fibrin / metabolism*
  • Humans
  • Leukocytes / cytology
  • Leukocytes / drug effects*
  • Lymphangiogenesis / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Protein Engineering
  • Vascular Endothelial Growth Factor C / administration & dosage
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor C / therapeutic use*
  • Wound Healing / drug effects*


  • Delayed-Action Preparations
  • Vascular Endothelial Growth Factor C
  • Fibrin