Exploring the link between disturbed flow and endothelial cell function in an in vitro arteriovenous fistula model
Zhuotao Xiao (Leiden University Medical Center, The First Affiliated Hospital of Soochow University)
Nicholas A. White (Leiden University Medical Center, TU Delft - Medical Instruments & Bio-Inspired Technology)
Jun Wen (Southwest University of Science and Technology)
Rudmer J. Postma (Leiden University Medical Center)
Wendy M.P.J. Sol (Leiden University Medical Center)
Bernard M. van den Berg (Leiden University Medical Center)
Anton Jan van Zonneveld (Leiden University Medical Center)
Huybert J.F. van de Stadt (Leiden University Medical Center)
Asad Mirza (Florida International University)
Roel Bijkerk (Leiden University Medical Center)
Joris I. Rotmans (Leiden University Medical Center)
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Abstract
Background The disturbed flow contributes to juxta-anastomotic intimal hyperplasia (IH) in arteriovenous fistulas (AVFs). This study developed an in vitro method aiming to understand the hemodynamic impact on endothelial cells (ECs) in AVFs. Methods A tubular bifurcation AVF model was constructed, and the disturbed flow was induced near the bifurcation by pulsatile flow. Hemodynamics was simulated using computational fluid dynamics (CFD) and visualized as 2D contour plots. Human Umbilical Vein Endothelial Cells (HUVECs) were cultured on a tailored polycarbonate membrane (PCM) and placed in the model. HUVECs on the PCM allowed precise mapping to the hemodynamic plots. Results CFD identified four regions: the outer wall with high time-averaged wall shear stress (TAWSS MAX) and transverse wall shear stress (TransWSS MAX), the inner wall with low and oscillatory wall shear stress (L/O), and the pulsatile flow (PF). HUVECs in PF were aligned in the direction of flow. The cells in other regions showed more focal adhesion junctions and fewer glycocalyces. HUVECs on inner wall had the lowest expression of Krüppel-like factor 2 and endothelial nitric oxide synthase, while the outer wall showed the highest expression of platelet-derived growth factor and transforming growth factor-β. Conclusions We developed an in vitro AVF model and validated the effects of different hemodynamic profiles on ECs by matching CFD plots with cell positions on a tailored PCM. This study shows that the in vitro AVF model can be a promising tool to assess the impact of interventions aimed at improving ECs function in AVFs. Statement of Significance In Vitro Model Development : An innovative in vitro model was developed to simulate arteriovenous fistula conditions, allowing for direct assessment of endothelial cell behavior under varied hemodynamic conditions. Linking Hemodynamics to Cell Response : The research successfully correlated computational fluid dynamics results with specific endothelial cell positions, facilitating a clearer understanding of the impact of hemodynamics on cell morphology and function. Arteriovenous Fistula Failure Understanding : The study enhances the understanding of arteriovenous fistula failure mechanisms, specifically the role of intimal hyperplasia caused by disturbed flow.
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