Abstract
After many years of research, small diameter, synthetic vascular grafts still lack the necessary biologic integration to perform ideally in clinical settings. Endothelialization of vascular grafts has the potential to improve synthetic graft function, and endothelial outgrowth cells (EOCs) are a promising autologous cell source. Yet no work has established the link between endothelial cell functions and outcomes of implanted endothelialized grafts. This work utilized steady flow, oscillatory flow, and tumor necrosis factor stimulation to alter EOC phenotype and enable the formulation of a model to predict endothelialized graft performance. To accomplish this, EOC in vitro expression of coagulation and inflammatory markers was quantified. In parallel, in non-human primate (baboon) models, the platelet and fibrinogen accumulation on endothelialized grafts were quantified in an ex vivo shunt, or the tissue ingrowth on implanted grafts were characterized after 1mth. Oscillatory flow stimulation of EOCs increased in vitro coagulation markers and ex vivo platelet accumulation. Steady flow preconditioning did not affect platelet accumulation or intimal hyperplasia relative to static samples. To determine whether in vitro markers predict implant performance, a linear regression model of the in vitro data was fit to platelet accumulation data—correlating the markers with the thromboprotective performance of the EOCs. The model was tested against implant intimal hyperplasia data and found to correlate strongly with the parallel in vitro analyses. This research defines the effects of flow preconditioning on EOC regulation of coagulation in clinical vascular grafts through parallel in vitro, ex vivo, and in vivo analyses, and contributes to the translatability of in vitro tests to in vivo clinical graft performance.
Highlights
Vascular grafts are an essential technology for treating cardiovascular disease, the dominant cause of death in our society
In the absence of flow, the morphology of endothelial outgrowth cells (EOCs) on ePTFE vascular grafts was typical of mature endothelial cells with elongation occurring in somewhat random orientation (Fig. 1A and S1A Fig.), but with the majority of the alignment seen in the circumferential direction (S2 Fig.)
Steady shear stress treatment caused a significant increase in endothelial nitric oxide synthase (eNOS) and CD39 gene expression by the EOCs compared to the oscillatory shear stress treatment
Summary
Vascular grafts are an essential technology for treating cardiovascular disease, the dominant cause of death in our society. Bypass grafts represent an important intervention to treat vessel blockage, with autologous saphenous vein or mammary artery tissues remaining the standard treatment for the past 30 years. Artificial materials are used when native tissues are unavailable; while these materials have the mechanical properties to withstand suturing and arterial blood forces, their compliance mismatch encourages intimal hyperplasia and leads to graft failure. Many of these materials lack the biologic capacity, predominantly due to the lack of endothelial-dependent regulatory functions, to integrate with the surrounding vessels leading to thrombosis. Various biologic materials are being used or developed for vascular grafts, but current clinical products still have considerable limitations in mechanical integrity, patient wait time, immune rejection, and patency [2]
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