Multiscale Computational Modeling of Vascular Adaptation: A Systems Biology Approach Using Agent-Based Models

Abstract

The widespread incidence of cardiovascular diseases and associated mortality and morbidity, along with the advent of powerful computational resources, have fostered an extensive research in computational modeling of vascular pathophysiology field and promoted in-silico models as a support for biomedical research. Given the multiscale nature of biological systems, the integration of phenomena at different spatial and temporal scales has emerged to be essential in capturing mechanobiological mechanisms underlying vascular adaptation processes. In this regard, agent-based models have demonstrated to successfully embed the systems biology principles and capture the emergent behavior of cellular systems under different pathophysiological conditions. Furthermore, through their modular structure, agent-based models are suitable to be integrated with continuum-based models within a multiscale framework that can link the molecular pathways to the cell and tissue levels. This can allow improving existing therapies and/or developing new therapeutic strategies. The present review examines the multiscale computational frameworks of vascular adaptation with an emphasis on the integration of agent-based approaches with continuum models to describe vascular pathophysiology in a systems biology perspective. The state-of-the-art highlights the current gaps and limitations in the field, thus shedding light on new areas to be explored that may become the future research focus. The inclusion of molecular intracellular pathways (e.g., genomics or proteomics) within the multiscale agent-based modeling frameworks will certainly provide a great contribution to the promising personalized medicine. Efforts will be also needed to address the challenges encountered for the verification, uncertainty quantification, calibration and validation of these multiscale frameworks.

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

“…Previous cellular-scale ABMs were successfully integrated with molecular/tissue scale continuum-models to investigate the arterial response to haemodynamic and mechanical stimuli post-stenting [33][34][35][36][37][38][39][40][41][42][43]. However, applications to patient-specific scenarios are lacking and multi-omics data have never been included within these models [6]. The present study constitutes the first attempt to include patient gene expression data in a multiscale agent-based modelling framework of vascular adaptation.…”

“…The lack of a thorough understanding of ISR mechanobiological mechanisms has fostered extensive in vitro , in vivo and in silico research aimed at providing insights into the process. In this context, in silico multiscale models inspired by systems biology principles have been recently proposed to investigate the underlying mechanisms of ISR [6]. Different modelling strategies, based on continuum (e.g.…”

“…[7,8]) and/or discrete (e.g. [9]) approaches, have been adopted [6]. Among these, multiscale agent-based modelling frameworks, integrating both continuous- and agent-based approaches, has emerged as promising tools being able to (i) include components across molecular, cellular and tissue scales, and (ii) capture the dynamic interplay of mechanobiological events responding to stent implantation [6].…”

“…ISR and vascular adaptation processes are driven by complex, multifactorial and multiscale networks of events involving feedback mechanisms, cause-effect relationships and mutual interactions of components at different spatio-temporal scales, from molecular (e.g. gene pattern alteration) to cellular and tissue/organ ones [6]. Among the heterogeneous factors favouring ISR, the vessel wall damage-related inflammatory response induced by stent implantation and the stent-related haemodynamic alteration play significant roles [4].…”

“…The available multiscale frameworks have mainly described the cellular events and the subsequent arterial wall remodelling triggered by the intervention-induced damage and/or haemodynamic alteration in idealized vessel geometries [6]. However, patient-specific applications are lacking.…”