The major problem preventing the development of tissue engineered replacements for failing organs is the inability to adequately vascularize tissues created in vitro. Intact organs contain a highly complex and ordered three-dimensional network of arterioles, capillaries and venules that allow for the efficient exchange of oxygen and nutrients. Unfortunately, the complexity of vascular patterning makes attempts to engineer an in vitro vascular system daunting if not unfeasible with our current knowledge. Even if significant advances were to allow for the creation of functional microvascular beds in vitro, it is difficult to envision how such constructs could later be physiologically integrated into a patient. This proposal approaches tissue engineering from a novel perspective: by utilizing a pre-existing microvasculature as the scaffold for engineered tissue growth. Within the human body there exist numerous microvascular beds, commonly utilized for reconstructive procedures, with contain all the necessary organization and patterning that we are struggling to recreate. These microvascular beds are expendable and removable and may provide a practical, biologic framework of vessels upon which functional tissues maybe created in the near future. This proposal will examine the feasibility of long-term survival and growth of these microvascular tissue beds within a custom designed bioreactor system. Once the techniques are developed to maximize the viability of microvascular beds ex vivo, we will apply well established biologic techniques to augment both the surface area of the vasculature and the parenchymal cell mass supplied by it. Specifically, we will attempt to maintain and expand the microvascular bed and establish a stable resident population of differentiated end-organ cells by introducing pluripotent stem cells within the bioreactor system. Finally, we will return these engineered constructs to experimental animals using standard microvascular techniques and determine whether such cells remain persistently associated in vivo. It is our hope that at the conclusion of these experiments we will have engineered a rudimentary neo-organ that circumvents the two major obstacles to organ level tissue engineering: the creation of a microvascular network and the ability to be reintegrated to the host.
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