Coupling one-dimensional arterial blood flow to three-dimensional tissue perfusion models for in silico 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 in silico 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. A one-dimensional intracranial blood flow model and a method to couple this to a brain tissue perfusion model for patient-specific simulations is presented. Image-based patient-specific data on the anatomy of the circle of Willis are combined with literature data and models for vessel anatomy not visible in the images, to create an extended model for each patient from the larger vessels down to the pial surface. The coupling between arterial blood flow and tissue perfusion occurs at the pial surface through the estimation of perfusion territories. The coupling method is able to accurately estimate perfusion territories. Finally, we argue that blood flow can be approximated as steady-state flow at the interface between arterial blood flow and tissue perfusion to reduce the cost of organ-scale simulations

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, n

A simplified mesoscale 3D model for characterizing fibrinolysis under flow conditions

One of the routine clinical treatments to eliminate ischemic stroke thrombi is injecting a biochemical product into the patient’s bloodstream, which breaks down the thrombi’s fibrin fibers: intravenous or intravascular thrombolysis. However, this procedure is not without risk for the patient; the worst circumstances can cause a brain hemorrhage or embolism that can be fatal. Improvement in patient management drastically reduced these risks, and patients who benefited from thrombolysis soon after the onset of the stroke have a significantly better 3-month prognosis, but treatment success is highly variable. The causes of this variability remain unclear, and it is likely that some fundamental aspects still require thorough investigations. For that reason, we conducted in vitro flow-driven fibrinolysis experiments to study pure fibrin thrombi breakdown in controlled conditions and observed that the lysis front evolved non-linearly in time. To understand these results, we developed an analytical 1D lysis model in which the thrombus is considered a porous medium. The lytic cascade is reduced to a second-order reaction involving fibrin and a surrogate pro-fibrinolytic agent. The model was able to reproduce the observed lysis evolution under the assumptions of constant fluid velocity and lysis occurring only at the front. For adding complexity, such as clot heterogeneity or complex flow conditions, we propose a 3-dimensional mesoscopic numerical model of blood flow and fibrinolysis, which validates the analytical model’s results. Such a numerical model could help us better understand the spatial evolution of the thrombi breakdown, extract the most relevant physiological parameters to lysis efficiency, and possibly explain the failure of the clinical treatment. These findings suggest that even though real-world fibrinolysis is a complex biological process, a simplified model can recover the main features of lysis evolution.</p

Thrombolysis: Observations and numerical models.

This perspective paper considers thrombolysis in the context of ischemic strokes, intending to build eventually a numerical model capable of simulating the thrombolytic treatment and predicting patient outcomes. Numerical modeling is a scientific methodology based on an abstraction of a system but requires understanding their spatio-temporal interactions. However, although important, the current knowledge on thrombolysis is fragmented in contributions from which it is difficult to obtain a complete picture of the process, especially in a clinically relevant setup. This paper discusses, from a general point of view, how to develop a numerical model to describe the evolution of a patient clot under the action of a thrombolytic drug. We will present critical, yet fundamental, open questions that have emerged during this elaboration and discuss original experimental observations that challenge some of our current knowledge of thrombolysis.info:eu-repo/semantics/publishe

Stable Free-Standing Lipid Bilayer Membranes in Norland Optical Adhesive 81 Microchannels

We report a simple, cost-effective, and reproducible method to form free-standing lipid bilayer membranes in microdevices made with Norland Optical Adhesive 81 (NOA81). Surface treatment with either alkylsilane or fluoroalkylsilane enables the self-assembly of stable 1,2-diphytanoyl-sn-glycero-3-phosphocholine 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (DPPC) membranes. Capacitance measurements are used to characterize the lipid bilayer and to follow its formation in real-time. With current recordings, we detect the insertion of single α-hemolysin pores into the bilayer membrane, demonstrating the possibility of using this device for single-channel electrophysiology sensing applications. Optical transparency of the device and vertical position of the lipid bilayer with respect to the microscope focal plane allows easy integration with other single-molecule techniques, such as optical tweezers. Therefore, this method to form long-lived lipid bilayers finds a wide range of applications, from sensing measurements to biophysical studies of lipid bilayers and associated proteins.Accepted Author ManuscriptBN/Marie-Eve Aubin-Tam La

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. We propose an event-based modelling approach for the simulation of a disease and injury, where changes to the state of the system (the events) are assumed to be instantaneous. Using this approach we are able to combine a diverse set of models, spanning multiple time scales, to model acute ischemic stroke, treatment, and resulting brain tissue injury. The in silico trial is designed to be modular to aid development and reproducibility. It provides a comprehensive framework for application to any potential in silico trial. A statistical population model is used to generate cohorts of virtual patients. Patient functional outcomes are also predicted with a statistical model, using treatment and injury results and the patient's clinical parameters. We demonstrate the functionality of the event-based modelling approach and trial framework by running proof of concept in silico trials. The proof of concept trials simulate the same cohort of patients twice: once with successful treatment (successful recanalisation) and once with unsuccessful treatment (unsuccessful treatment). Ways to overcome some of the challenges and difficulties in setting up such an in silico trial are discussed, such as validation and computational limitations

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. The leptomeningeal collateral vessels provide significant flow during a stroke. The pressure drop over an occlusion predicted by the model ranges between 60 and 85 mmHg depending on the extent of the collateral circulation. The linear transport of contrast material was simulated in the circulatory network. The time delay of peak contrast over an occlusion is 3.3 s in the model, and 2.1 s (IQR 0.8–4.0 s) when measured in dynamic CTA data of acute ischaemic stroke patients. Modelling the leptomeningeal collateral circulation could lead to better estimates of infarct volume and patient outcome

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. The collateral circulation is varied to capture the collateral scores: absent, poor, moderate and good. Measurements of the transit time, void fraction and thrombus length in acute ischaemic stroke patients are used to estimate thrombus permeability. Estimated thrombus permeability ranges between 10-7 and 10-4 mm2. Measured flow rates through the thrombus are small and the effect of a permeable thrombus on brain perfusion during stroke is small compared with the effect of collaterals. Our simulations suggest that the collaterals are a dominant factor in the resulting infarct volume after a stroke