Engineering three-dimensional lymphatic vasculature on-chip through biochemical and mechanical stimulus

Abstract

In this thesis, we developed a microfluidic-based platform for the generation of physiologically relevant 3D lymphatic capillaries. This tissue engineering platform allowed us to probe the vascularization dynamics of lymphatic endothelial cells under a highly controlled microenvironment and isolate the effects of biochemical and biophysical inputs. Under this precise control over local extracellular factors, we studied the angiogenic response of lymphatic endothelial cells to different soluble pro-angiogenic factors, which accordingly induced different sprout formation dynamics . We also controlled the vascularization behaviors of lymphatics by modulating the intrinsic composition of the extracellular matrix. Finally, we explored the influence of mechanical stimuli, more specifically interstitial flow, on the formation of lymphatic sprouts to which we observe a dependency on the synergistic stimulus from the presence of pro-angiogenic factors while inducing interstitial flow. In summary, these results elucidate the physiological process of lymphatic angiogenesis and explores the individual contribution of local cues in the cellular microenvironment during this vascular morphogenesis phenomenon. Additionally, the development of this platform has potential applications for physiological studies regarding lymphatic function, regenerative medicine and drug development for lymphatic-associated diseases..