Integrating engineered macro vessels with self-assembled capillaries in 3D implantable tissue for promoting vascular integration in-vivo.

A functional multi-scale vascular network can promote 3D engineered tissue growth and improve transplantation outcome. In this work, by using a combination of living cells, biological hydrogel, and biodegradable synthetic polymer we fabricated a biocompatible, multi-scale vascular network (MSVT) within thick, implantable engineered tissues. Using a templating technique, macro-vessels were patterned in a 3D biodegradable polymeric scaffold seeded with endothelial and support cells within a collagen gel. The lumen of the macro-vessel was lined with endothelial cells, which further sprouted and anastomosed with the surrounding self-assembled capillaries. Anastomoses between the two-scaled vascular systems displayed tightly bonded cell junctions, as indicated by vascular endothelial cadherin expression. Moreover, MSVT functionality and patency were demonstrated by dextran passage through the interconnected multi-scale vasculature. Additionally, physiological flow conditions were applied with home-designed flow bioreactors, to achieve a MSVT with a natural endothelium structure. Finally, implantation of a multi-scale-vascularized graft in a mouse model resulted in extensive host vessel penetration into the graft and a significant increase in blood perfusion via the engineered vessels compared to control micro-scale-vascularized graft. Designing and fabricating such multi-scale vascular architectures within 3D engineered tissues may benefit both in vitro models and therapeutic translation research.