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Self-assembly of prevascular tissues from endothelial and fibroblast cells under scaffold-free, nonadherent conditions.

ABSTRACT: To advance the emerging field of bioengineered prevascularized tissues, we investigated factors that control primary vascular network formation in scaffold-free, high-density cell suspension-derived tissues. Fabricating primary vascular networks in a scaffold-free system requires endothelial cells (ECs) and extracellular matrix (ECM)-producing cells that act together to elaborate a permissive matrix. We report findings on the effects to vascular patterning induced by altering the ratio of human endothelial to human fibroblast cells. Analysis revealed that a 1:4 ratio of ECs to fibroblasts resulted in the synthesis of an ECM permissive for organization of primary vascular networks that recapitulated the pattern of primary vascular networks observed in vivo. Importantly this work highlighted the significance of tension in the organization of vascular networks in prevascularized tissues. To our knowledge our in vitro studies are the first to demonstrate the formation of two distinct vascular patterns in an initially homogenous culture system. Specifically, we demonstrate that within our constructs, vascular networks formed with distinct directional orientations that reflect self-assembly-mediated tension. Further, our studies demonstrate that treatment of prevascularized tissues with matrix-promoting factors such as transforming growth factor beta 1 (TGF?1) increases tissue strength without altering vascular network patterning. Together, the ability to generate prevascularized tissues from human cells in scaffold-free systems and the ability to enhance the strength of the constructs with matrix-promoting factors represent advances to the potential translational utility of prevascularized tissues both as subcutaneous implants and in surgical scenarios requiring the application of tension to the tissue construct.

SUBMITTER: Czajka CA

PROVIDER: S-EPMC4293139 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Project description:Vascularization remains a substantial limitation to the viability of engineered tissue. By comparing in vivo vascularization dynamics of a self-assembled prevascular endothelial-fibroblast model to avascular grafts, we explore the vascularization rate limitations in implants at early time intervals, during which tissue hypoxia begins to affect cell viability. Scaffold-free prevascular endothelial-fibroblast constructs (SPECs) may serve as a modular and reshapable vascular bed in replacement tissues. SPECs, fibroblast-only spheroids (FOS), and silicone implants were implanted in 54 Sprague Dawley rats and harvested at 6, 12, and 24?h (n?=?5 per time point and implant type). We hypothesized that the primary endothelial networks of the SPECs allow earlier anastomosis and increased vessel formation in the interior of the implant compared to FOS and silicone implants within a 24?h window. All constructs were encapsulated by an endothelial lining at 6?h postimplantation and SPEC internal cords inosculated with the host vascular network by this time point. SPECs had a significantly higher microvascular area fraction and branch/junction density of penetrating cords at 6-12?h compared with other constructs. In addition, SPECs demonstrated perivascular cell recruitment, lumen formation, and network remodeling consistent with vessel maturation at 12-24?h; however, these implants were poorly perfused within our observation window, suggesting poor lumen patency. FOS vascular characteristics (microvessel area and penetrating cord density) increased within the 12-24?h period to represent those of the SPEC implants, suggesting a 12?h latency in host response to avascular grafts compared to prevascular grafts. Knowledge of this temporal advantage in in vitro prevascular network self-assembly as well as an understanding of the current limitations of SPEC engraftment builds on our theoretical temporal model of tissue graft vascularization and suggests a crucial time window, during which technological improvements and vascular therapy can improve engineered tissue survival.

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Self-assembly of prevascular tissues from endothelial and fibroblast cells under scaffold-free, nonadherent conditions.

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