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Creation of Thick Prevascularized Implantable Tissues


Engineered thick tissues require rapid blood perfusion upon implantation for survival. We have previously described a method to prevascularize (in vitro development of a vascular network) engineered tissues with endothelial cells and mural cells prior to implantation. That strategy has the potential to overcome the limitation of oxygen delivery by diffusion, and thus increase post-implantation survival rate. Pericytes are recruited to facilitate vessel maturation and stabilization during the formation of blood vessels. We hypothesized that the introduction of pericytes into the prevascularized tissue would enhance vessel formation and stimulate host anastomosis. Fibrin tissues were prevascularized by co-culturing human placental pericytes with endothelial colony forming cell-derived endothelial cells (ECFC-EC) from cord blood and normal human lung fibroblasts (NHLF) for 7 or 14 days in vitro. Tissues were then subcutaneously implanted to the dorsal side of SCID mice and retrieved 7 days later. Tissues with a low pericyte-fibroblast ratio developed a vessel network that was well-perfused with host circulation after 7 days in vivo culture. In contrast, pericytes alone or with a high pericyte-fibroblast ratio failed to develop significant in vitro vessel networks, and did not anastomose with the host circulation. Our results suggest that a low pericyte-fibroblast ratio can enhance the in vivo perfusion of engineered tissues.

Additionally, we designed and constructed a model to control oxygen diffusion during both in vitro and in vivo culture using biocompatible Poly (methyl methacrylate) (PMMA) and low-density polyethylene (LDPE). Tissues were prevascularized in the devices without limiting oxygen diffusion in vitro for 7 days. Once tissues were implanted into the host, tissue access to oxygen was limited to a small opening facing the host skin side. Oxygen could diffuse through this opening, or be transported by convection following anastomosis with host vasculature. After 7 days, tissues were explanted. Blood perfusion is observed around the access point, but not the entire tissues, which is consistent with blood clotting following anastomosis.

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