Advancing In Silico Clinical Trials for Regulatory Adoption and Innovation.

The evolution of information and communication technologies has affected all fields of science, including health sciences. However, the rate of technological innovation adoption by the healthcare sector has been historically slow, compared to other industrial sectors. Innovation in computer modeling and simulation approaches has changed the landscape in biomedical applications and biomedicine, paving the way for their potential contribution in reducing, refining, and partially replacing animal and human clinical trials.

Carotid single- and dual-layer stents reduce the wall adhesion of platelets by influencing flow and cellular transport.

An ongoing thrombosis on a ruptured atherosclerotic plaque in the carotid may cause stroke. The primary treatment for patients with tandem lesion is stenting. Dual-layer stents have been introduced as an alternative to single-layer stents for elective and emergent carotid artery stenting.

FAIR compliant database development for human microbiome data samples.

Introduction: Sharing microbiome data among researchers fosters new innovations and reduces cost for research. Practically, this means that the (meta)data will have to be standardized, transparent and readily available for researchers. The microbiome data and associated metadata will then be described with regards to composition and origin, in order to maximize the possibilities for application in various contexts of research.

The need for systems thinking to advance Alzheimer's disease research.

Despite extensive research efforts to mechanistically understand late-onset Alzheimer's disease (LOAD) and other complex mental health disorders, curative treatments remain elusive. We emphasize the multiscale multicausality inherent to LOAD, highlighting the interplay between interconnected pathophysiological processes and risk factors. Systems thinking methods, such as causal loop diagrams and systems dynamic models, offer powerful means to capture and study this complexity.

The impact of cardiovascular diagnostics and treatments on fall risk in older adults: a scoping review and evidence map.

Background: We aimed to summarize the published evidence on the fall risk reducing potential of cardiovascular diagnostics and treatments in older adults.

Methods: Design: scoping review and evidence map.

Data Sources: Medline and Embase.

Exploring the potential impact of multi-factor precision interventions in Alzheimer's disease with system dynamics.

Numerous clinical trials based on a single-cause paradigm have not resulted in efficacious treatments for Alzheimer's disease (AD). Recently, prevention trials that simultaneously intervened on multiple risk factors have shown mixed results, suggesting that careful design is necessary. Moreover, intensive pilot precision medicine (PM) trial results have been promising but may not generalize to a broader population.

Image-based flow simulation of platelet aggregates under different shear rates.

Hemodynamics is crucial for the activation and aggregation of platelets in response to flow-induced shear. In this paper, a novel image-based computational model simulating blood flow through and around platelet aggregates is presented. The microstructure of aggregates was captured by two different modalities of microscopy images of in vitro whole blood perfusion experiments in microfluidic chambers coated with collagen.

Applying systems thinking to unravel the mechanisms underlying orthostatic hypotension related fall risk.

Orthostatic hypotension (OH) is an established and common cardiovascular risk factor for falls. An in-depth understanding of the various interacting pathophysiological pathways contributing to OH-related falls is essential to guide improvements in diagnostic and treatment opportunities. We applied systems thinking to multidisciplinary map out causal mechanisms and risk factors.

Simulating the multicausality of Alzheimer's disease with system dynamics.

Introduction: In Alzheimer's disease (AD), cognitive decline is driven by various interlinking causal factors. Systems thinking could help elucidate this multicausality and identify opportune intervention targets.

Methods: We developed a system dynamics model (SDM) of sporadic AD with 33 factors and 148 causal links calibrated with empirical data from two studies.

In silico thrombectomy trials for acute ischemic stroke.

Background And Objective: In silico trials aim to speed up the introduction of new devices in clinical practice by testing device design and performance in different patient scenarios and improving patient stratification for optimizing clinical trials. In this paper, we demonstrate an in silico trial framework for thrombectomy treatment of acute ischemic stroke and apply this framework to compare treatment outcomes in different subpopulations and with different thrombectomy stent-retriever devices. We employ a novel surrogate thrombectomy model to evaluate the thrombectomy success in the in silico trial.

Modelling collateral flow and thrombus permeability during acute ischaemic stroke.

The presence of collaterals and high thrombus permeability are associated with good functional outcomes after an acute ischaemic stroke. We aim to understand the combined effect of the collaterals and thrombus permeability on cerebral blood flow during an acute ischaemic stroke. A cerebral blood flow model including the leptomeningeal collateral circulation is used to simulate cerebral blood flow during an acute ischaemic stroke.

Impact of cardiovascular evaluations and interventions on fall risk in older adults: a protocol for a scoping review and evidence map.

Introduction: Cardiovascular disorders are increasingly recognised as important fall risk factors in older adults. Falls are a major public health problem in older adults, and therefore, effective interventions for reducing falls are essential for this population. Cardiovascular disease is a clinically relevant (but often overlooked) and potentially modifiable risk factor for falls.

The effect of stiffened diabetic red blood cells on wall shear stress in a reconstructed 3D microaneurysm.

Blood flow within the vasculature of the retina has been found to influence the progression of diabetic retinopathy. In this research cell resolved blood flow simulations are used to study the pulsatile flow of whole blood through a segmented retinal microaneurysm. Images were collected using adaptive optics optical coherence tomography of the retina of a patient with diabetic retinopathy, and a sidewall (sacciform) microaneurysm was segmented from the volumetric data.

Uncertainty quantification of a three-dimensional in-stent restenosis model with surrogate modelling.

In-stent restenosis is a recurrence of coronary artery narrowing due to vascular injury caused by balloon dilation and stent placement. It may lead to the relapse of angina symptoms or to an acute coronary syndrome. An uncertainty quantification of a model for in-stent restenosis with four uncertain parameters (endothelium regeneration time, the threshold strain for smooth muscle cell bond breaking, blood flow velocity and the percentage of fenestration in the internal elastic lamina) is presented.

Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart.

Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans.

The Effects of Micro-vessel Curvature Induced Elongational Flows on Platelet Adhesion.

The emerging profile of blood flow and the cross-sectional distribution of blood cells have far reaching biological consequences in various diseases and vital internal processes, such as platelet adhesion. The effects of several essential blood flow parameters, such as red blood cell free layer width, wall shear rate, and hematocrit on platelet adhesion were previously explored to great lengths in straight geometries. In the current work, the effects of channel curvature on cellular blood flow are investigated by simulating the accurate cellular movement and interaction of red blood cells and platelets in a half-arc channel for multiple wall shear rate and hematocrit values.

In silico trials for treatment of acute ischemic stroke: Design and implementation.

An in silico trial simulates a disease and its corresponding therapies on a cohort of virtual patients to support the development and evaluation of medical devices, drugs, and treatment. In silico trials have the potential to refine, reduce cost, and partially replace current in vivo studies, namely clinical trials and animal testing. We present the design and implementation of an in silico trial for treatment of acute ischemic stroke.

Applicability analysis to evaluate credibility of an in silico thrombectomy procedure.

Intra-arterial thrombectomy is a minimally invasive procedure in which an obstructing thrombus (clot) is removed using a minimally-invasive device: a stent-retriever. The stent-retriever is first deployed, and then the thrombus is removed during stent-retriever retraction. This procedure can be simulated using a detailed computational model.

Modelling the leptomeningeal collateral circulation during acute ischaemic stroke.

A novel model of the leptomeningeal collateral circulation is created by combining data from multiple sources with statistical scaling laws. The extent of the collateral circulation is varied by defining a collateral vessel probability. Blood flow and pressure are simulated using a one-dimensional steady state blood flow model.

Coupling one-dimensional arterial blood flow to three-dimensional tissue perfusion models for trials of acute ischaemic stroke.

An acute ischaemic stroke is due to the sudden blockage of an intracranial blood vessel by an embolized thrombus. In the context of setting up trials for the treatment of acute ischaemic stroke, the effect of a stroke on perfusion and metabolism of brain tissue should be modelled to predict final infarcted brain tissue. This requires coupling of blood flow and tissue perfusion models.

Biorheology of occlusive thrombi formation under high shear: in vitro growth and shrinkage.

Occlusive thrombi formed under high flow shear rates develop very rapidly in arteries and may lead to myocardial infarction or stroke. Rapid platelet accumulation (RPA) and occlusion of platelet-rich thrombi and clot shrinkage have been studied after flow arrest. However, the influence of margination and shear rate on occlusive clot formation is not fully understood yet.

Trials for Treatment of Acute Ischemic Stroke.

Despite improved treatment, a large portion of patients with acute ischemic stroke due to a large vessel occlusion have poor functional outcome. Further research exploring novel treatments and better patient selection has therefore been initiated. The feasibility of new treatments and optimized patient selection are commonly tested in extensive and expensive randomized clinical trials.