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Page 8 of 14 Heng et al. Vessel Plus 2023;7:31 https://dx.doi.org/10.20517/2574-1209.2023.97

[25]
remain at the endothelium . CFD analysis of these parameters using human patient data from the venous
external support trial (VEST) has revealed distinct flow patterns associated with external support
devices [26-28] . While TAWSS (determined by mean diameter and flow rate) was shown to be expectedly
similar between stented and unstented vein grafts, unstented SVGs demonstrated high OSI values
correlating with the development of diffuse intimal hyperplasia . Depending on overall graft topography,
[27]
OSI can differ significantly between grafts with equivalent TAWSS, and thus, the modern understanding of
vein graft remodeling has expanded to emphasize the importance of improving overall graft geometry,
rather than diameter modulation alone.

Beyond hemodynamic insights, computational methodologies have also been applied to the development of
predictive models to simulate the adaptive capacity of veins and identify mechanisms of maladaptation in
bypass grafts. In 2015, Ramachandra et al. introduced a growth and remodeling (G&R) framework of vein
graft adaptation using constrained mixture theory to integrate existing knowledge of fluid dynamics with
cell-mediated responses of vascular wall elements (collagen, elastin, and SMCs) . In these cell-mediated
[29]
G&R models, simulated veins were subjected to a range of combined pressure and flow in arterial
circulation to identify the upper and lower bounds of vein adaptability. Repeated computational testing with
this model has suggested that gradual mechanical loading over 8 days rather than abrupt change seen in
clinical practice greatly increased the adaptive capacity of veins , a finding that has inspired biodegradable
[30]
[31]
designs of modern vein graft sheaths .
Molecular gene expression in vein graft remodeling
While changes in EC and SMC proliferation along with matrix deposition have long been appreciated in
vein graft remodeling, studies of molecular gene expression in grafted veins have uncovered specific
proteins and chemical pathways driving these pathologic adaptations. In response to arterial pressurization,
vein graft SMCs have been shown to undergo loss of differentiation via downregulation of the
Notch1/Ephrin-B2 (arterial marker) and Notch4/Ephrin-B4 (venous marker) pathways, and additionally
switch from a contractile to synthetic phenotype with markedly decreased SM22α and calponin
[32]
expression . Endothelial dysfunction also ensues with persistent downregulation of endothelial nitric oxide
synthase (eNOS). Following alterations in cell proliferation, matrix metalloproteinases (MMPs) and tissue
inhibitors of these enzymes (TIMPs) have also been shown to drive ECM remodeling, with upregulation of
MMP-2, MMP-9, TIMP-1, and TIMP-2. In comparison to unsupported vein grafts, external stenting
appears to attenuate ECM remodeling and fibrosis by counteracting the upregulation of plasminogen
activator inhibitor-1 (PAI-1) and transforming growth factor beta II (TGFβ2). Additionally, heatmaps of
differential gene expression between wrapped and non-wrapped vein grafts have also identified
downregulation of collagen 11A1 (COL11A1) and thrombospondin-4 (THBS4) as atheroprotective
mechanisms of external supports, as well as decreased fibrillin 2 (FBN2) and LIM domain only 7 (LMO7)
[31]
corresponding to decreases in maximum wall thickness .
Modern therapies to prevent vein graft failure
Contemporary iterations of external vein graft stents have leveraged advancements in biomaterials
engineering and fabrication techniques to build on historical techniques and evolving knowledge of vein
graft remodeling mechanisms [Figure 3]. Reminiscent of the “finger trap” concept first proposed in seminal
work by Parsonnet et al., recent expandable stent devices have been made using braided cobalt-chromium
alloy fibers in order to produce kink-resistant external supports capable of conforming to a variety of vessel
diameters [20,33] . Likewise, efforts to minimize long-term foreign body reactions from non-degradable stents
have led to the exploration of biodegradable materials including poly L-lactide- ε-caprolactone (75/25)
[35]
copolymer (P (LA/CL)) mesh and poly(ester urethane)urea (PEUU) , the latter of which has been
[34]
electrospun directly onto sheep saphenous veins to produce patient-specific external graft support .
[36]