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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - INSIST (IN-Silico trials for treatment of acute Ischemic STroke)

Teaser

Summary

Stroke is a major health problem in the Western world; 1.3 million Europeans have a first stroke each year, 30% die and 30% are left permanently disabled. One in 5 patients require long term institutional care, costing ~â‚¬38 billion per year in Europe. An acute ischemic stroke occurs when an artery supplying blood to the brain is blocked by a blood clot (thrombus), causing rapid loss of brain function. Treatment is limited to thrombolysis by clot-dissolving enzymes and thrombectomy by mechanical devices. As still 2 out of 3 patients become functionally dependent, further improvement of treatment is needed. The required clinical trials are extremely expensive.
In silico models of patient characteristics, pathophysiology and (effects of) treatment may be used to set up in silico clinical trials (â€œvirtualâ€ patients are â€œvirtuallyâ€ treated), potentially reducing, refining and partially replacing actual clinical trials. This will allow testing efficacy of new treatments, suitability for specific patient(s) populations, and provide tools for in silico proof of concept trial design modelling, resulting in faster and safer marketing of new drugs and devices.
There are 5 objectives (O1-5) outlined in the section below.

Work performed

O1: Virtual populations
The generated virtual population should contain individual patients closely resembling the real population, matching variations and covariations in e.g. demographic data, brain anatomy, location of the clot and clinical presentation. Three statistical approaches were evaluated, relevant parameters selected and actual data included, resulting in first versions of this model, based on 1488 patients and 11 clinical and imaging parameters. A first version of a public web application was created.
We have applied and developed image analysis procedures, developed pipelines for extracting arterial geometries from the 3D voxel images and analysed position and size of the final infarct in relation to the location of the clot. Clot composition and permeability are crucial for treatment and outcome. We extensively analysed clot composition, ultrastructure and biomechanics (~500 thrombi) to generate a clot database and investigated the relation between imaging characteristics and composition (input to O2-O4).
O2: thrombosis & thrombolysis
We found that actual flow through the clot is needed for effective thrombolysis, underlining the importance of the imaging and composition data above. A sensitivity analysis helped to strongly reduce the complexity of the biochemical model and identify the crucial role of natural lysis inhibitors.
A second approach was based on a full 3D geometry of the clot as obtained from O1. We simulated individual packages of enzymes moving through the clot and interacting with its constituents. Analysis allowed reduction to a â€˜two speciesâ€™ model for adequate prediction of clot lysis, given patient-specific composition and architecture, qualitatively resembling experimental data in flow chambers.
We started modelling thrombosis and will combine both models. The second approach allows inclusion of local differences in clots in patients, providing the required link between clot imaging data and prediction of patient outcome.
O3: thrombectomy
Thrombectomy involves guiding, employing and retracting a stent retriever through a complex arterial geometry, without damaging the vascular wall or losing fragments that may cause downstream occlusions. Modelling requires a firm base for prediction of flow and pressure profiles and the effect of a clot on these. Using imaging data from 50 patients (O2), we generated patient-specific geometries and developed and applied a new procedure for optimizing suitability for finite element analysis of hemodynamics and wall forces including the mechanical properties of the vascular wall, clot and blood.
Clot properties were studied using synthetic clots of various compositions (+/- thrombolytics). Mechanical tests provided nonlinear stress-strain relations to which the above mechanical models can be fitted. Fracture properties were studied. Clot properties and interaction with the vascular wall were used to predict clot location.
Initial thrombectomy models were developed. Based on computational load we chose mesoscopic simulation of individual elements and finite elements analysis with structure-fluid interaction. We modelled geometry and mechanics of two devices, with actual tests serving as input for validation. An initial meta-model was created predicting outcome on the basis of clot and vessel characteristics and a first run of thrombectomy simulations predicted the actual procedure within the expected limits.
O4: perfusion defects & tissue damage
Acute stroke reduces local tissue perfusion, which may culminate in tissue death. We modelled this process in finite elements with data from literature and INSIST. A simplified tissue health model was developed including the interaction of vessels and tissue, requiring high-quality surface segmentation of the brain. The massive amount of brain vessels was modelled as a continuum, describing local perfusion on the basis of Darcy flow through a porous medium. This approach is now extended to a multi-compart

Final results

INSIST has the potential to reduce size and duration of randomized clinical trials, leading to a more effective human clinical trial design, significant reduction in animal testing, lower development costs, shorter time to market for new medical products and improving prediction of human risk for new biomedical products. INSIST also aims to enforce the credibility of in silico clinical trials, relying upon regulatory acceptance of in silico computational modelling for decision-making and pre-market submissions. The population method, which allows generating libraries of virtual patients, for re-use in pre- and post-competitive testing of biomedical products, with both deep clinical and imaging data on acute ischemic stroke will provide a lucrative data source for ischemic stroke related research.