Computationally guided in-vitro vascular growth model reveals causal link between flow oscillations and disorganized neotissue

Abstract

Disturbed shear stress is thought to be the driving factor of neointimal hyperplasia in blood vessels and grafts, for example in hemodialysis conduits. Despite the common occurrence of neointimal hyperplasia, however, the mechanistic role of shear stress is unclear. This is especially problematic in the context of in situ scaffold-guided vascular regeneration, a process strongly driven by the scaffold mechanical environment. To address this issue, we herein introduce an integrated numerical-experimental approach to reconstruct the graft–host response and interrogate the mechanoregulation in dialysis grafts. Starting from patient data, we numerically analyze the biomechanics at the vein–graft anastomosis of a hemodialysis conduit. Using this biomechanical data, we show in an in vitro vascular growth model that oscillatory shear stress, in the presence of cyclic strain, favors neotissue development by reducing the secretion of remodeling markers by vascular cells and promoting the formation of a dense and disorganized collagen network. These findings identify scaffold-based shielding of cells from oscillatory shear stress as a potential handle to inhibit neointimal hyperplasia in grafts.

Effects of weaving parameters on the properties of completely biological tissue-engineered vascular grafts

“…Another intrinsic property of a woven TEVG is a wavy luminal surface. Flow oscillations and WSS are well-known for influencing cell behavior and in vivo remodeling [48,49]. In particular, low shear stress zones have been correlated with the development of intimal hyperplasia [50,51].…”

A bypass flow model to study endothelial cell mechanotransduction across diverse flow environments

“…S1 ). The completed medium was used as the perfusion medium which was mixed with 0.7 mg/ml Xanthan gum (Sigma-Aldrich) to increase the viscosity [ 19 , 33 ], and the medium was refreshed every day.…”

“…Conversely, disturbed flow with oscillatory and low WSS, is a pathological flow pattern, resulting in ECs loosing parallel alignment and elongation, and remodeling of cell-junctions. Contrary to laminar flow conditions, KLF2 expression is downregulated while inflammatory factors are upregulated in disturbed flow areas [ [17] , [18] , [19] , [20] ]. In addition, studies have shown that high RRT and OSI can predict a spectrum of pathological alterations and their occurrence in a disturbed flow area [ 9 ].…”

A realistic arteriovenous dialysis graft model for hemodynamic simulations

“…Hemodynamic metrics were defined to quantify disturbed flow and disturbed WSS in the anastomotic region. Although multiple hypotheses regarding the definition of disturbed WSS exist [ 27 ], here it was assumed that WSS outside the physiological range (0.1–7 Pa [ 28 ]), WSS sufficiently high to cause irreversible endothelial damage (>40 Pa [ 29 ]) and highly oscillatory WSS [ 30 ] were detrimental to graft longevity. Disturbed flow and non-physiological WSS were assessed over the total venous segment and in the venous perianastomotic region of all simulations.…”