A predictive multiscale model of in-stent restenosis in femoral arteries: linking haemodynamics and gene expression with an agent-based model of cellular dynamics

Abstract

In-stent restenosis (ISR) is a maladaptive inflammatory-driven response of femoral arteries to percutaneous transluminal angioplasty and stent deployment, leading to lumen re-narrowing as consequence of excessive cellular proliferative and synthetic activities. A thorough understanding of the underlying mechanobiological factors contributing to ISR is still lacking. Computational multiscale models integrating both continuous- and agent-based approaches have been identified as promising tools to capture key aspects of the complex network of events encompassing molecular, cellular and tissue response to the intervention. In this regard, this work presents a multiscale framework integrating the effects of local haemodynamics and monocyte gene expression data on cellular dynamics to simulate ISR mechanobiological processes in a patient-specific model of stented superficial femoral artery. The framework is based on the coupling of computational fluid dynamics simulations (haemodynamics module) with an agent-based model (ABM) of cellular activities (tissue remodelling module). Sensitivity analysis and surrogate modelling combined with genetic algorithm optimization were adopted to explore the model behaviour and calibrate the ABM parameters. The proposed framework successfully described the patient lumen area reduction from baseline to one-month follow-up, demonstrating the potential capabilities of this approach in predicting the short-term arterial response to the endovascular procedure.

An intricate interplay between stent drug dose and release rate dictates arterial restenosis

“…Chen et al [49] adopted a similar framework but within coronary arteries and coupled WSS to a damage index through a linear interpolation which directly influenced the behaviour of constituents present in restenosis. In agreement with [33,34,45,48,50], greater neointimal thickness was observed in regions where WSS was low. Furthermore, Jansen et al [51] devised a multiscale bio-chemo-mechanical model of intimal hyperplasia, where haemodynamic indices are coupled to restenosis in an idealised artery through an influx of growth factors.…”

“…Models simulating computational fluid dynamics (CFD) following stent deployment have established a link between low wall shear stress (WSS < 0.5 Pa) and ISR outcome [34,[45][46][47]. For example, Corti et al [45] devised a multi-scale model framework applied to human femoral arteries, where WSS directly influenced the functionality of ECs, such that areas exposed to lower levels of WSS gave rise to increased renarrowing of the lumen [34,45,48]. Chen et al [49] adopted a similar framework but within coronary arteries and coupled WSS to a damage index through a linear interpolation which directly influenced the behaviour of constituents present in restenosis.…”

“…Furthermore, Jansen et al [51] devised a multiscale bio-chemo-mechanical model of intimal hyperplasia, where haemodynamic indices are coupled to restenosis in an idealised artery through an influx of growth factors. Although CFD is included within these models [34,45,49], the role of stent deployment on arterial healing is not considered, as is present in [19][20][21]25,38]; a feature ubiquitously linked to neointimal thickening [52,53].…”

“…[25,38]), we assume that damage induced by stent deployment is the predominant driver of the biological cascade of events that initiate the healing process. Alternative approaches in the literature include linking haemodynamic indices such as WSS to a damage index [49], a function describing endothelial dysfunction [45] or an influx of growth factors [51]. Damage, d (r, z, t), is modelled as a spatiotemporal variable mapped throughout the domain in response to the stresses present following stent expansion.…”

Predicting 1-year in-stent restenosis in superficial femoral arteries through multiscale computational modelling

“…However, these frameworks (i) are not patient-specific, (ii) do not include gene expression data, and (iii) do not simulate long-term arterial wall remodelling. Recently, Corti et al [7] have developed a patientspecific multiscale agent-based modelling framework of ISR in SFAs, integrating the effects of local haemodynamics and monocyte gene expression (accounting for systemic inflammation) on cellular dynamics and subsequent postintervention arterial wall remodelling. The framework consisted of a unidirectional coupling between a computational fluid dynamics (CFD) simulation (haemodynamics module) and an ABM of cellular dynamics (tissue remodelling module).…”