Rebuilding tissues involves the creation of a vasculature to supply nutrients and this in turn means that the endothelial cells (ECs) of the resulting endothelium must be a quiescent non-thrombogenic blood contacting surface. Such ECs are deployed on biomaterials that are composed of natural materials such as extracellular matrix proteins or synthetic polymers in the form of vascular grafts or tissue-engineered constructs. Because EC function is influenced by their origin, biomaterial surface chemistry and hemodynamics, these issues must be considered to optimize implant performance. In this review, we examine the recent in vivo use of endothelialized biomaterials and discuss the fundamental issues that must be considered when engineering functional vasculature.
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Figure 1. Strategies to endothelialize biomaterials
(a) Endothelialized vascular grafts for bypass surgery. Grafts are made of natural materials, such as collagen, or synthetic materials, such as Dacron®. They can be further modified to release soluble factors that encourage endothelium in-growth (shown on left) or be pre-endothelialized prior to implantation (shown on right) such that the endothelial cells in the graft merge with the in-growing endothelial cells from the host. (b) Scaffolds for vascularized constructs for tissue engineering. Some scaffolds rely on the controlled release or immobilization of pro-angiogenic factors to initiate host endothelial cell in-growth [–13] (shown on left) while others make use of specific internal geometric structures that act as spatial and organizational cues for infiltrating cells . Alternatively, pre-seeded scaffolds are cultured
in vitro prior to implantation in order to create a rudimentary internal vasculature (shown on the right). Upon implantation, the embedded endothelial cells are expected to connect (anastomose) with the host tissue in order to generate a perfusable construct. (c) Modular tissue engineering. Pre-seeded scaffolds can be used to produce larger tissue engineered constructs using a modular approach. Sub-millimeter-sized cylindrical scaffolds containing embedded therapeutic cells have their surfaces pre-seeded with endothelial cells. The modular scaffolds are then implanted directly or randomly packed into a larger container. Due to the random packing, an interconnecting, endothelial cell-lined void space capable of blood perfusion is created. Thus, a pre-vascularized construct capable of sustaining the embedded therapeutic cells is generated in vitro prior to implantation [6,19].
Figure 2. Endothelial cell sources and blood vessel structures
The lumen of the blood vessel contains an intact endothelium which carries blood. The blood contains plasma and cells such as erythrocytes, platelets and leukocytes. The structure of the vessel depends on its size and location within the vasculature. Larger vessels, such as arteries and arterioles, are surrounded by concentric layers of smooth muscle cells which aid in the maintenance of vascular tone and endothelial cell quiescence through, for example, a nitric oxide pathway . Smaller vessels, such as capillaries, lack smooth muscle and instead are surrounded by pericytes, which actively maintain vessel maturity and are thought now to be the source of mesenchymal stromal cells (refer to review by Corselli et al ). The source of the EC is an important consideration in this field.
Figure 3. Hemodynamics and its effect on endothelial cell phenotype
In a porous scaffold that contains a very tortuous network of pores, flow disturbances may arise which cause endothelial cell activation, loss of cell alignment and an increase in endothelium permeability (see also Text Box 2). As seen in the top right and bottom right images, endothelial cells in straight sections are aligned with the direction of flow. Flow disturbances (indicated by white swirls) are created by the separation of flow and thus occur when the vessel geometry undergoes rapid changes along its length (e.g. branches, obstructions, bends contractions and sudden expansions). These types of tortuous vessels are often seen in newly vascularized biomaterial implants
in vivo. As illustrated in the expansion region (top right image), cells are no longer aligned and are randomly oriented. Cells located within these disturbances also become more permeable (illustrated by green colour in the bottom left image) as their cell-cell junctions are disrupted through, for example, the dismantling of VE-cadherin junctions. Moreover, they become activated, which increases their cell adhesion molecule expression (dark blue dots). As the implant is remodeled by the endothelial cells and the surrounding host tissue, the vessel shape and structure can change over time, which creates further opportunity for changes in vessel geometry.
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Research Support, Non-U.S. Gov't
Endothelium / physiology*
Tissue Engineering / methods*