Hollow, Perfusable Small-Diameter Tissue Engineered Vascular Grafts

Unmet Need
Cardiovascular disease, often called “heart disease,” refers to conditions that involve narrowed or blocked blood vessels that can lead to a heart attack. Approximately 43% of all cardiovascular disease cases involve coronary artery disease (CAD) and require coronary artery bypass surgery. Implantation of vascular grafts is the most common treatment, but involves a secondary surgical site to harvest donor grafts. Furthermore, patients with widespread vascular disease or previously harvested vessels lack suitable or durable donor tissue. Pediatric congenital cardiovascular defects (CCDs) is another condition that is commonly treated by implanting vascular grafts.  But congenital heart disease remains the leading source of death in newborns, in part because of the inability of synthetic grafts to grow as the child develops. Current tissue-engineered (TE) vascular grafts 1) do not enable sufficient perfusion, 2) do not adequately model the complex cellular and extracellular matrix (ECM) organization of vessels, 3) are associated with post-implantation challenges, including thrombogenicity, decreased elasticity, aneurysmal failure, and intimal hyperplasia, and/or 4) require extensive preparation techniques that impede commercial or clinical translation. Therefore, there is a need for implantable, perfusable vascular grafts that will mimic and grow alongside patients’ vascular tissue, have a clinically relevant shelf life, exhibit mechanical and cellular properties similar to native vessels, and minimize post-implantation complications. This need is compounded by the lack of an accurate TE vascular model for basic science research into endothelial cell dysfunction and tissue-engineered organs. Current TE vascular models fail to include the endothelium, preventing research into the endothelial basis of cardiovascular disorders, angiogenesis, and drug uptake (among other research areas).  These models also have poor perfusion capacity which impedes development of TE implantable organs.

Technology Overview
Fibrin scaffolds can be fabricated in the shape of a tube or sheet with microfibers that induce 3D curvature of endothelial cells in an aligned orientation, and enhance deposition of an organized ECM layer. The hollow fibrin microfiber tubes are able to withstand perfusion at various shear stresses with no fluid leakage, lending the graft greater perfusion capacity and durability. Cells, including endothelial and smooth muscle cells, can be seeded onto the scaffold and cultured in a wide range of bioreactors to develop a vascular structure that mimics native tissue. Compared to current vascular models which may take several weeks to months for clinical use, these acellular or endothelialized vascular grafts can be developed within 1 week. The scaffold also enables customization of the lumen diameter and wall thickness, adapting it for wide clinical usage. The graft’s tailored regenerative capacity overcomes many post-implantation challenges of arterial bypass grafts. Since the graft replicates the aligned endothelial cell layer and ECM of native vessels, it also offers more accurate characterization of vascular response that is valuable for in vitro research models.

Stage of Development
The inventors have developed a method and two prototype bioreactors, and conducted an in vivo animal study. Replacement of a neonate rat’s abdominal aorta by an acellular fibrin graft indicated that the graft was able to withstand aortic flow for 1 hour without bursting or leaking, suggesting successful in vivo implantation and demonstrating surgical utility. Long-term implantation of acellular and endothelialized grafts in a mouse abdominal aorta indicate substantial remodeling of the scaffold towards a healthy artery-like structure in vivo.
Publications
M.B. Elliott, et al.  “Regenerative and durable small-diameter graft as an arterial conduit.”  PNAS. 116 (26), pp. 12710-19 (June 25, 2019).
 

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