Exploring the link between disturbed flow and endothelial cell function in an in vitro arteriovenous fistula model

Acta Biomaterialia, vol. 213, pp. 328–340

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.

Authors 11

1. Zhuotao Xiao Aachen

   Leiden University · Leiden University Medical Center · First Affiliated Hospital of Soochow University

   Affiliation as printed

   Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden 2333, ZA, Netherlands; Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China

2. Nicholas A. White Aachen

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden 2333, ZA, Netherlands; Department of BioMechanical Engineering, Delft University of Technology, Delft 2628, CN, Netherlands

3. Jun Wen

   Southwest University of Science and Technology

   Affiliation as printed

   Department of Computer Science and Technology, Southwest University of Science and Technology, Mianyang 621010, China

4. Rudmer J. Postma Aachen Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden 2333, ZA, Netherlands

5. Wendy M.P.J. Sol Aachen Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden 2333, ZA, Netherlands

6. Bernard M. van den Berg Aachen Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden 2333, ZA, Netherlands

7. Anton Jan van Zonneveld Aachen Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden 2333, ZA, Netherlands

8. Huybert J. F. van de Stadt Aachen Department of Medical Technology

   Leiden University Medical Center

   Affiliation as printed

   Department of Medical Technology, Design & Prototyping, Leiden University Medical Center, Leiden 2333, ZA, Netherlands

9. Asad M. Mirza

   Florida International University

   Affiliation as printed

   Department of Biomedical Engineering, Florida International University, Miami, FL, 33199, United States

10. Roel Bijkerk Aachen Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden 2333, ZA, Netherlands

11. Joris I. Rotmans corresponding Aachen Department of Internal Medicine (Nephrology) & The Einthoven Laboratory for Vascular and Regenerative Medicine

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden 2333, ZA, Netherlands. Electronic address: j.i.rotmans@lumc.nl