Team:Harvard/Background
Background
Vascular grafts are used to provide alternative routes to stenosed or obstructed vessels in treatment of cardiovascular disease. This type of surgery is very common — for example, in the United States, more than 400,000 bypass graft surgeries for the coronary artery are performed per year. Most commonly, grafts are autologous, taken from the patient’s saphenous vein, or arteries such as the internal thoracic artery or radial artery. However, autologous grafts have hardly acceptable multi-year patency rates, donor site morbidity, and simply limited availability (e.g. in patients undergoing a second vascular graft surgery).
Tissue-engineered vascular grafts (TEVGs) offer the potential of an ideal vascular graft, compared to autologous or synthetic (e.g. polymer-only) grafts. Though several fabrication methods exist, generally fabrication involves seeding a patient’s endothelial or endothelial progenitor cells on a scaffold in vitro, culturing for several weeks, and re-implanting, where the scaffold eventually (depending on the material) degrades and leaves only tissue.
The most common complications correlated with graft failure are the development of: thromboses, intimal hyperplasia (where smooth muscle cells migrate inward and narrows the vessel), infection, and atherosclerosis. Wall shear stress (WSS) rises drastically with the narrowing of a vessel, and so abnormally high wall shear stress is caused by thrombus formation.
Alternatively, abnormally low wall shear stress (< 0.5 Pa), which may occur near bifurcations where laminar (sheetlike) flow becomes disturbed or oscillatory flow, can be causal to intimal hyperplasia as well as atherosclerosis.
With these relationships between wall shear stress and graft failures, we envisioned that a system that could sense various levels of wall shear stress and have a distinct, modular response to each could have therapeutic implications for TEVGs.
For example, some of a patient’s cells used to fabricate the scaffold could be engineered with our receptor-response system to respond to abnormally high shear stress (via activation of a receptor) with secretion of a clot-busting protein, such as tPA. Conversely, to respond to abnormally low shear stress, activation of a low-threshold shear stress sensitive receptor could be linked to expression of a repressor for genes that negatively regulate factors which exacerbate low shear stress (such as nitric oxide production), or a protein drug for atherosclerosis.
These cells may eventually be replaced by surrounding tissue, or lose their engineered constructs, but ideally after long enough to decrease patency loss rates.
[1] Pashneh-Tala, S., Macneil, S., & Claeyssens, F. (2016). The Tissue-Engineered Vascular Graft—Past, Present, and Future. Tissue Engineering Part B: Reviews, 22(1), 68–100. doi: 10.1089/ten.teb.2015.0100 [2] Donadoni, F., Pichardo-Almarza, C., Bartlett, M., Dardik, A., Homer-Vanniasinkam, S., & Díaz-Zuccarini, V. (2017). Patient-Specific, Multi-Scale Modeling of Neointimal Hyperplasia in Vein Grafts. Frontiers in Physiology, 8. doi: 10.3389/fphys.2017.00226