Physicochemical regulation of endothelial sprouting in a 3D microfluidic angiogenesis model

J Biomed Mater Res A. 2013 Oct;101(10):2948-56. doi: 10.1002/jbm.a.34587. Epub 2013 Apr 5.


Both physiological and pathological tissue remodeling (e.g., during wound healing and cancer, respectively) require new blood vessel formation via angiogenesis, but the underlying microenvironmental mechanisms remain poorly defined due in part to the lack of biologically relevant in vitro models. Here, we present a biomaterials-based microfluidic 3D platform for analysis of endothelial sprouting in response to morphogen gradients. This system consists of three lithographically defined channels embedded in type I collagen hydrogels. A central channel is coated with endothelial cells, and two parallel side channels serve as a source and a sink for the steady-state generation of biochemical gradients. Gradients of vascular endothelial growth factor (VEGF) promoted sprouting, whereby endothelial cell responsiveness was markedly dependent on cell density and vessel geometry regardless of treatment conditions. These results point toward mechanical and/or autocrine mechanisms that may overwhelm pro-angiogenic paracrine signaling under certain conditions. To date, neither geometrical effects nor cell density have been considered critical determinants of angiogenesis in health and disease. This biomimetic vessel platform demonstrated utility for delineating hitherto underappreciated contributors of angiogenesis, and future studies may enable important new mechanistic insights that will inform anti-angiogenic cancer therapy.

Keywords: VEGF; angiogenesis; collagen; gradient; microfluidics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Count
  • Cell Culture Techniques
  • Chemical Phenomena*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / growth & development*
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Microfluidics / methods*
  • Models, Biological*
  • Neovascularization, Physiologic* / drug effects
  • Vascular Endothelial Growth Factor A / pharmacology


  • Vascular Endothelial Growth Factor A