The primary graft-related complication during the first clinical trial evaluating the use of tissue-engineered vascular grafts (TEVGs) was stenosis. We investigated the role of macrophages in the formation of TEVG stenosis in a murine model. We analyzed the natural history of TEVG macrophage infiltration at critical time points and evaluated the role of cell seeding on neovessel formation. To assess the function of infiltrating macrophages, we implanted TEVGs into mice that had been macrophage depleted using clodronate liposomes. To confirm this, we used a CD11b-diphtheria toxin-receptor (DTR) transgenic mouse model. Monocytes infiltrated the scaffold within the first few days and initially transformed into M1 macrophages. As the scaffold degraded, the macrophage infiltrate disappeared. Cell seeding decreased the incidence of stenosis (32% seeded, 64% unseeded, P=0.024) and the degree of macrophage infiltration at 2 wk. Unseeded TEVGs demonstrated conversion from M1 to M2 phenotype, whereas seeded grafts did not. Clodronate and DTR inhibited macrophage infiltration and decreased stenosis but blocked formation of vascular neotissue, evidenced by the absence of endothelial and smooth muscle cells and collagen. These findings suggest that macrophage infiltration is critical for neovessel formation and provides a strategy for predicting, detecting, and inhibiting stenosis in TEVGs.

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Vascular Tissue Engineering belongs to a rapidly expanding discipline. Tissue engineered vascular grafts (TEVG) have a broad range of clinical application extending from use as small diameter vascular grafts in adult peripheral vasculature to serving as large vessel conduits in pediatric cardiovascular surgery. Several approaches have been utilized by different groups to design these grafts. Preliminary outcomes are exceedingly promising. These grafts have demonstrated the ability to transform into living blood vessels with growth potential and while the underlying mechanisms remain to be elucidated, it has been shown that inflammatory pathways may play an important role. Small animal experiments, development of cell seeding techniques and the application of nanotechnology have all contributed vastly to our understanding of the mechanisms involved in TEVG remodeling. The application of nanomedicine in TEVG design continues to expand at a rapid rate and has provided some clues as to how vascular graft design can be pursued in the future. In this review we discuss the current state of the field of tissue engineered vascular grafts and how the principles of nanomedicine are being applied to aid in the design of second-generation grafts.

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