The evolution of vascular tissue engineering and current state of the art

Abstract

Dacron® (polyethylene terephthalate) and Goretex® (expanded polytetrafluoroethylene) vascular grafts have been very successful in replacing obstructed blood vessels of large and medium diameters. However, as diameters decrease below 6 mm, these grafts are clearly outperformed by transposed autologous veins and, particularly, arteries. With approximately 8 million individuals with peripheral arterial disease, over 500,000 patients diagnosed with end-stage renal disease, and over 250,000 patients per year undergoing coronary bypass in the USA alone, there is a critical clinical need for a functional small-diameter conduit [Lloyd-Jones et al., Circulation 2010;121:e46-e215]. Over the last decade, we have witnessed a dramatic paradigm shift in cardiovascular tissue engineering that has driven the field away from biomaterial-focused approaches and towards more biology-driven strategies. In this article, we review the preclinical and clinical efforts in the quest for a tissue-engineered blood vessel that is free of permanent synthetic scaffolds but has the mechanical strength to become a successful arterial graft. Special emphasis is given to the tissue engineering by self-assembly (TESA) approach, which has been the only one to reach clinical trials for applications under arterial pressure.

Fig. 1

a The workhorse of TESA: a sheet of HSFs. The sheets can become very robust depending on the culture time and conditions. b Sheet holding 500 g.

Fig. 2

a An age- and risk-matched human TEBV for implantation in the aorta of nude rats (ID 1.5 mm). b After 180 days in a nude rat, Verhoff-Masson staining reveals a collagen-rich (blue) and acellular IM as well as well-developed elastic lamellas in the ‘neo-media’ on the luminal side of the IM. The arrow indicates vasa vasorum in the ‘adventitia’. Scale bar = 20 μm. c SMC-specific α-actin staining of the vessel after 90 days confirms that the cells in the ‘neo-media’ are SMC-like cells. The arrow indicates cells around the IM that are positive, suggesting a phenotypic transformation of the implanted fibroblasts or a recruitment of cells from the surrounding tissue. Comparison of the thickness of the ‘neo-media’ in b and c shows that it does not thicken with time. Scale bar = 100 μm. d At the anastomotic region at 90 days, Movat staining shows a smooth interface (large arrow) and the difference in elastin (black) between the native aorta and the remodeling graft. Small arrows indicate sutures. Scale bar = 500 μm.

Fig. 3

Before beginning the clinical trials, we tested the resistance of the human grafts punctured in vitro under physiological pressure (a–c) versus an ePTFE graft (d–f). While both grafts seal well once the needle is inserted (a, d), the ePTFE graft leaks aggressively after removal of the 16-gauge hemodialysis needle while our graft self-seals like a native vessel. Note the poor compliance of the ePTFE around the needle in d. Leaking grafts are clinically difficult to manage because they require pressure to stop the bleeding, which can also cause graft thrombosis.

Fig. 4

Evolution of our tissue-engineered graft. We have followed a strategy that initially favors a positive clinical outcome over ease of production. Only when some level of clinical success is demonstrated do we introduce cost-effective design changes. If early results are confirmed in follow-up studies, we could produce an allogeneic, serum-free, off-the-shelf, and completely biological graft in about 10 weeks by using TBTE.