Endothelial Track Patterning for Directing Vascularization of Engineered Tissues

Abstract

Engineered organs may one day provide critical therapeutic relief to patients suffering from end-stage organ failure. However, generation of physiological vascular networks within organ-scale tissues that rapidly integrate upon in vivo remains a major challenge for clinical translation. Here, we address these challenges by patterning vascular promoting, endothelial collagen “tracks” that guide vessel assembly and improve integration with host circulation within engineered tissue constructs. First, we implant track-containing patches in mice and rats and find significant differences in vascularization and cardiac tissue engraftment, highlighting the often overlooked but crucial role that host biology plays in successful implantation of engineered tissues. We then sought to increase the architectural complexity of engineered vasculature within larger, physiologically relevant tissues and conduct a thorough evaluation of three-dimensional (3D) biofabrication approaches that prioritize sustaining viability of living cells during fabrication pipelines. Finally, we leverage a 3D biofabrication approach to develop a platform for fabricating complex branching track networks within centimeter scale tissues of many biomaterial matrices– achieving a 10-fold volume increase from all previous track containing tissues. When implanted in vivo, these tissues undergo volumetric vascularization, spanning entire tissue constructs, and significantly improve host integration. In all, the work presented here advances tissue engineering by evaluating and emphasizing the importance of host biology, and by developing scalable 3D vascularization methodologies, collectively moving the field closer to the reality of transplantable engineered human organs.