Myocardial infarction is the global leading cause of mortality (Go AS et al. 2014). Coronary artery occlusion is its main etiology and it is commonly treated by Coronary Artery Bypass Graft (CABG) surgery (Wilson CT 2007). The long-term outcome remains unsatisfactory (Benedetto U 2016) as the graft faces the phenomenon of restenosis during the post-surgery, which consists of re-occlusion of the lumen and usually requires secondary intervention even within one year after the initial surgery (Harskamp RE 2013). In this work, we propose an extensive study of the restenosis phenomenon by implementing two mathematical models previously developed by our group: a heuristic Dynamical System (DS) (Garbey M et al. 2013), and a stochastic Agent Based Model (ABM) (Garbey M et al. 2015). With an extensive use of the ABM, we retrieved the pattern formations of the cellular events that mainly lead the restenosis, especially focusing on mitosis in intima, caused by alteration in shear stress, and mitosis in media, fostered by alteration in wall tension. A deep understanding of the elements at the base of the restenosis is indeed crucial in order to improve the final outcome of vein graft bypass. We also turned the ABM closer to the physiological reality by abating its original assumption of circumferential symmetry. This allowed us to finely replicate the trigger event of the restenosis, i.e. the loss of the endothelium in the early stage of the post-surgical follow up (Roubos N et al. 1995) and to simulate the encroachment of the lumen in a fashion aligned with histological evidences (Owens CD et al. 2015). Finally, we cross-validated the two models by creating an accurate matching procedure. In this way we added the degree of accuracy given by the ABM to a simplified model (DS) that can serve as powerful predictive tool for the clinic.

Background. Peripheral artery disease (PAD) is an atherosclerotic disorder that leads to unpaired lumen patency through intimal hyperplasia and the build-up of plaques, mainly localized in areas of disturbed flow. Computational models can provide valuable insights in the pathogenesis of atherosclerosis and act as a predictive tool to optimize current interventional techniques. Our hypothesis is that a reliable predictive model must include the atherosclerosis development history. Accordingly, we developed a multiscale modeling framework of atherosclerosis that replicates the hemodynamic-driven arterial wall remodeling and plaque formation. Methods. The framework was based on the coupling of Computational Fluid Dynamics (CFD) simulations with an Agent-Based Model (ABM). The CFD simulation computed the hemodynamics in a 3D artery model, while 2D ABMs simulated cell, extracellular matrix (ECM) and lipid dynamics in multiple vessel cross-sections. A sensitivity analysis was also performed to evaluate the oscillation of the ABM output to variations in the inputs and to identify the most influencing ABM parameters.Results. Our multiscale model qualitatively replicated both the physiologic and pathologic arterial configuration, capturing histological-like features. The ABM outputs were mostly driven by cell and ECM dynamics, largely affecting the lumen area. A subset of parameters was found to affect the final lipid core size, without influencing cell/ECM or lumen area trends. Conclusion.The fully coupled CFD-ABM framework described atherosclerotic morphological and compositional changes triggered by a disturbed hemodynamics.

Background Bone-targeting radiotherapy with Radium-223 (Rad-223), a radioisotope emitting genotoxic alpha-radiation with limited tissue penetrance (∼100 µm), prolongs the survival of patients with metastatic prostate cancer (PCa). Confoundingly, the clinical response to Rad-223 is often followed by detrimental relapse and progression, and whether Rad-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. We hypothesized that limited radiation penetrance in situ defines outcome. Methods We tested Rad-223 overall response by PC3 and C4–2B human PCa cell lines in mouse bones (n = 5–18 tibiae per group). Rad-223 efficacy at subcellular resolution was determined by intravital microscopy analysis of dual-color fluorescent PC3 cells (n = 3–4 mice per group) in tissue-engineered bone constructs. In vivo data were fed into an in silico model to predict Rad-223 effectiveness in lesions of different sizes (1–27, 306 initial cells; n = 10–100 simulations) and the predictions validated in vivo by treating PCa tumors of varying sizes in bones (n = 10–14 tibiae per group). Statistical tests were performed by two-sided Student t test or by one-way ANOVA followed by Tukey’s post-hoc test. Results Rad-223 (385 kBq/kg) delayed the growth (means [SD]; comparison with control-treated mice) of PC3 (6.7 × 105[4.2 × 105] vs 2.8 × 106 [2.2 × 106], P = .01) and C4–2B tumors in bone (7.7 × 105 [4.0 × 105] vs 3.5 × 106 [1.3 × 106], P < .001). Cancer cell lethality in response to Rad-223 (385 kBq/kg) was profound but zonally confined along the bone interface compared with the more distant tumor core, which remained unperturbed (day 4; 13.1 [2.3%] apoptotic cells, 0–100 µm distance from bone vs 3.6 [0.2%], >300 µm distance; P = .01).In silico simulations predicted greater efficacy of Rad-223 on single-cell lesions (eradication rate: 88.0%) and minimal effects on larger tumors (no eradication, 16.2% growth reduction in tumors of 27 306 cells), as further confirmed in vivo for PC3 and C4–2B tumors. Conclusions Micro-tumors showed severe growth delay or eradication in response to Rad-223, whereas macro-tumors persisted and expanded. The relative inefficacy in controlling large tumors points to application of Rad-223 in secondary prevention of early bone-metastatic disease and regimens co-targeting the tumor core.

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.

In-stent restenosis (ISR) represents a major drawback of stented superficial femoral arteries (SFAs). Motivated by the high incidence and limited knowledge of ISR onset and development in human SFAs, this study aims to (i) analyze the lumen remodeling trajectory over 1-year follow-up period in human stented SFAs and (ii) investigate the impact of altered hemodynamics on ISR initiation and progression. Ten SFA lesions were reconstructed at four follow-ups from computed tomography to quantify the lumen area change occurring within 1-year post-intervention. Patient-specific computational fluid dynamics simulations were performed at each follow-up to relate wall shear stress (WSS) based descriptors with lumen remodeling. The largest lumen remodeling was found in the first post-operative month, with slight regional-specific differences (larger inward remodeling in the fringe segments, p < 0.05). Focal re-narrowing frequently occurred after 6 months. Slight differences in the lumen area change emerged between long and short stents, and between segments upstream and downstream from stent overlapping portions, at specific time intervals. Abnormal patterns of multidirectional WSS were associated with lumen remodeling within 1-year post-intervention. This longitudinal study gave important insights into the dynamics of ISR and the impact of hemodynamics on ISR progression in human SFAs.

Peripheral arterial occlusive disease is a chronic pathology affecting at least 8-12 million people in the USA, typically treated with a vein graft bypass or through the deployment of a stent in order to restore the physiological circulation. Failure of peripheral endovascular interventions occurs at the intersection of vascular biology, biomechanics, and clinical decision making. It is our hypothesis that the majority of endovascular treatment approaches share the same driving mechanisms and that a deep understanding of the adaptation process is pivotal in order to improve the current outcome of the procedure. The postsurgical adaptation of vein graft bypasses offers the perfect example of how the balance between intimal hyperplasia and wall remodeling determines the failure or the success of the intervention. Accordingly, this work presents a versatile computational model able to capture the feedback loop that describes the interaction between events at cellular/tissue level and mechano-environmental conditions. The work here presented is a generalization and an improvement of a previous work by our group of investigators, where an agent-based model uses a cellular automata principle on a fixed hexagonal grid to reproduce the leading events of the graft's restenosis. The new hybrid model here presented allows a more realistic simulation both of the biological laws that drive the cellular behavior and of the active role of the membranes that separate the various layers of the vein. The novel feature is to use an immersed boundary implementation of a highly viscous flow to represent SMC motility and matrix reorganization in response to graft adaptation. Our implementation is modular, and this makes us able to choose the right compromise between closeness to the physiological reality and complexity of the model. The focus of this paper is to offer a new modular implementation that combines the best features of an agent-based model, continuum mechanics, and particle-tracking methods to cope with the multiscale nature of the adaptation phenomena. This hybrid method allows us to quickly test various hypotheses with a particular attention to cellular motility, a process that we demonstrated should be driven by mechanical homeostasis in order to maintain the right balance between cells and extracellular matrix in order to reproduce a distribution similar to histological experimental data from vein grafts.

In-stent restenosis (ISR) is the major drawback of superficial femoral artery (SFA) stenting. Abnormal hemodynamics after stent implantation seems to promote the development of ISR. Accordingly, this study aims to investigate the impact of local hemodynamics on lumen remodeling in human stented SFA lesions. Ten SFA models were reconstructed at 1-week and 1-year follow-up from computed tomography images. Patient-specific computational fluid dynamics simulations were performed to relate the local hemodynamics at 1-week, expressed in terms of time-averaged wall shear stress (TAWSS), oscillatory shear index and relative residence time, with the lumen remodeling at 1-year, quantified as the change of lumen area between 1-week and 1-year. The TAWSS was negatively associated with the lumen area change (ρ = − 0.75, p = 0.013). The surface area exposed to low TAWSS was positively correlated with the lumen area change (ρ = 0.69, p = 0.026). No significant correlations were present between the other hemodynamic descriptors and lumen area change. The low TAWSS was the best predictive marker of lumen remodeling (positive predictive value of 44.8%). Moreover, stent length and overlapping were predictor of ISR at follow-up. Despite the limited number of analyzed lesions, the overall findings suggest an association between abnormal patterns of WSS after stenting and lumen remodeling.

Reductionist approaches, where individual pieces of a process are examined in isolation, have been the mainstay of biomedical research. While these methods are effective in highly compartmentalized systems, they fail to account for the inherent plasticity and non-linearity within the signaling structure. In the current manuscript, we present the computational architecture for tracking an acute perturbation in a biologic system through a multiscale model that links gene dynamics to cell kinetics, with the overall goal of predicting tissue adaptation. Given the complexity of the genome, the problem is made tractable by clustering temporal changes in gene expression into unique patterns. These cluster elements form the core of an integrated network that serves as the driving force for the response of the biologic system. This modeling approach is illustrated using the clinical scenario of vein bypass graft adaptation. Vein segments placed in the arterial circulation for treatment of advanced occlusive disease can develop an aggressive hyperplastic response that narrows the lumen, reduces blood flow, and induces in situ thrombosis. Reducing this hyperplastic response has been a long-standing but unrealized goal of biologic researchers in the field. With repeated failures of single target therapies, the redundant response pathways are thought to be a fundamental issue preventing progress towards a solution. Using the current framework, we demonstrate how theoretical genomic manipulations can be introduced into the system to shift the adaptation to a more beneficial phenotype, where the hyperplastic response is mitigated and the risk of thrombosis reduced. Utilizing our previously published rabbit vein graft genomic data, where grafts were harvested at time points ranging from 2 hours to 28 days and under differential flow conditions, and a customized clustering algorithm, five gene clusters that differentiated the low flow (i.e., pro-hyperplastic) from high flow (i.e., anti-hyperplastic) response were identified. The current analysis advances these general associations to create a model that identifies those genes sets most likely to be of therapeutic benefit. Using this approach, we examine the range of potential opportunities for intervention via gene cluster over-expression or inhibition, delivered in isolation or combination, at the time of vein graft implantation.