Growing a living blood vessel: insights for the second hundred years

Abstract

Cardiovascular disease continues to be the leading cause of death worldwide, and the prevalence of cardiovascular disease has reached epidemic proportions worldwide. Not surprisingly this has led to an increasing number of vascular procedures annually. Unfortunately, the success of these procedures over time continues to limit their long-term effects. Biomedical engineering approaches to improve upon current prosthetic grafts, developing new prosthetic grafts, and creating tissue engineered blood vessels for clinical application offer hope of improving the durability of vascular interventions and improving patients' treatment for cardiovascular disease.

Figure 1. Mechanisms of endothelial cell ingrowth

1. Circulating endothelial cells and endothelial progenitor cells can be recruited from the bloodstream to areas of endothelial injury or exposed graft; however in general this does not lead to complete endothelialization. 2. Endothelial cell migration and/or proliferation from the anastomotic edges is generally limited to 1–2cm. 3. However transinterstitial capillary ingrowth from the adventitia or peri-graft tissue can promote endothelialization at multiple sites circumferentially along the length of the graft.

Figure 2. Transmural Induction of Endothelialization by FGF-1 on Prosthetic Graft

Fibrin glue delivery of exogenous FGF-1 promotes ePTFE endothelialization. The untreated control is pictured on the left side at 117x, and the FGF-1 treated graft is seen on the right at 486x. The treated graft demonstrates robust capillary in-growth and cellular coverage not seen in the control graft. “Reprinted from the Journal of Surgical Research, Vol. 57; JL Gray, SS Kang, GC Zenni, DU Kim, PI Kim, WH Burgess, W Drohan, JA Winkles, CC Haudenschild, HP Greisler; FGF-1 affixation stimulates ePTFE endothelialization without intimal hyperplasia, pp. 600, 602; 1994, with permission from Elsevier.”

Figure 3. Three Dimensional in vitro Induction of a Capillary Network

Co-cultured aggregates of vascular smooth muscle cells and endothelial cells embedded within a 3-dimensional fibrin hydrogel demonstrate directed invasion towards one another. This spatial control of vascular network development can also be modified to include many aggregates increasing its complexity and vascular network. 4x magnification.

Figure 4. Directed differentiation of Endothelial and Vascular Smooth Muscle Cells in 3-D Co-culture

Directed spatial differentiation of an endothelial cell lined (red) tubule from an aggregate of endothelial cells with surrounding vascular smooth muscle cells (green) in 3-D co-culture after VEGF-165 treatment. 4x magnification.