Development of a Personalized 3D Carotid Model for Cerebral Vasculopathy Monitoring in Sickle Cell Disease

Abstract

Introduction Sickle cell disease (SCD) is the most prevalent and severe monogenic disorder due to a mutation in the b-globin gene, responsible for the production of an abnormal hemoglobin (HbS) which polymerizes under hypoxia. Cerebral vasculopathy (CV) generally appearing during childhood, is responsible for ischemic stroke, making SCD the first etiology of stroke in children and young adults. To date, several biological and hemodynamical determinants have been identified in CV development such as severe anemia and/or high intracranial vascular flow velocities (> 200 cm/s). Chronic blood exchange transfusion decreases the risk of stroke in children having a pathological Doppler. However some patients still have a progressive impairment despite conventional treatment highlighting the need for new therapeutic strategies and a better understanding of the physiopathology. Therefore, by developing a 3D carotid model reproducing exactly vascular parameters of a SCD patient, we aim to: (i) determine the mechanisms of CV development in SCD, (ii) find new therapeutic approaches and (iii) predict the risk of progression of CV. Materials and methods Three-dimensional reconstructions of the internal carotid, middle cerebral and anterior cerebral artery from SCD patients were generated from magnetic resonance angiograms (MIMICS & 3Matics software, Materialise). We performed 3D simulations of the Navier-Stokes equations in patient specific geometries, including the state-of-the-art techniques of Computational Hemodynamics (multiscale coupling, backflow stabilization - FeLiSCe software) and other factors - such as the increase of the ejection fraction or the drop of peripheral resistances). Blood viscosity was based on a SCD cohort. Hemodynamic properties such as flow velocities (TMMV) and wall shear stress (WSS) in different areas of modelled carotid were then computed according to flow variations. Modelled carotid was obtained by 3D printing according to computer design (CATIA software). The next steps will consist in 1/importing doppler parameters from patients in a programmable pump for flow assays with blood mimicking fluid to measure TMMV and WSS at different areas in carotid, 2/incorporating resting or activated platelets in BMF to evaluate impact of high WSS on platelets degranulation, 3/developing a flow co-culture of smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) on carotid wall. HUVECs and SMCs at different zones of the carotid undergoing high/low WSS and oscillatory flow will be analysed Preliminary results Our preliminary results suggest that the carotid inlet flow but not blood viscosity is responsible for the pathological intra cranial velocities (Figure 1A). At high carotid inlet flow, areas of high and low WSS appeared in children (Figure 1B), suggesting the existence of turbulent flow that could lead to arterial wall damages. Figure 2A shows a 3D printed carotid reproducing the exact SCD child's one. The material of artificial carotid is compatible with HUVECs culture (Figure 2B) and fluidic experiment at high inlet flow (Figure 2C). On Doppler ultrasonography, the velocities measured in different sections of carotid were comparable to patient's data and these velocities were modified according to variations of inlet flow values. Conclusions and perspectives By modification of input conditions, our 3D personalized model can predict high or low vascular velocities areas and will allow a better understanding of the pathophysiological processes involved at the interface between abnormal flow and cells on carotid wall. This innovative model could be a pertinent tool to evaluate individually effectiveness of new therapeutic strategies in SCD patients. Furthermore, this work may constitute a proof of concept that can be transposed to other diseases. Disclosures Verlhac: Addmedica, Paris: Other: Financial Support; Bluebird Bio: Consultancy. Bartolucci:AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.