in-vitro-3d-cell-cultured-arterial-models-for-studying-vascular-drug

<em>In Vitro</em> 3D Cell-Cultured Arterial Models for Studying Vascular Drug Targeting Under Flow

The use of three-dimensional (3D) models of human arteries, which are designed with the correct dimensions and anatomy, enables the proper modeling of ...

Technion - IIT

Targeted drug delivery to diseased vasculature, such as atherosclerotic lesions, is a multistep process, which is based on the transport of drug carriers to a selected region and their deposition at the desired destination. Current modeling approaches, including microfluidics and animal models, fail to accurately simulate this multi-scale process in human arteries, where blood flow is dominant. Here we study particle deposition in endothelialized 3D reconstructed models of the human carotid bifurcation under physiological hemodyamic conditions. Our results showed that particle localization is highly dependent on vessel geometry and local flow features. Additionally, while strongly adhesive particles tend to adhere more profoundly at high-shear regions, associated with athero-thrombosis, enhanced deposition at vascular flow regions, associated with inflammation and plaque accumulation, e.g., recirculation flows, can be achieved using weakly adhesive particles. Moreover, pulsatile flow as well as presence of blood cells significantly reduce particle adhesion and affect their deposition pattern. These findings highlight the key role of vessel geometry, hemodynamics and particle characteristics in the optimizing vascular targeting nano-carriers.

Mapping deposition of particles in reconstructed models of human arteries.

Intracranial aneurysms frequently develop blood clots, plaque and inflammations, which are linked to enhanced particulate mass deposition. In this work, we propose a computational model for particulate deposition, that accounts for the influence of field forces, such as gravity and electrostatics, which produce an additional flux of particles perpendicular to the fluid motion and towards the wall. This field-mediated flux can significantly enhance particle deposition in low-shear environments, such as in aneurysm cavities. Experimental investigation of particle deposition patterns in  models of side aneurysms, demonstrated the ability of the model to predict enhanced particle adhesion at these sites. Our results showed a significant influence of gravity and electrostatic forces (greater than 10%), indicating that the additional terms presented in our models may be necessary for modelling a wide range of physiological flow conditions and not only for ultra-low shear regions. Spatial differences between the computational model and the experimental results suggested that additional transport and fluidic mechanisms affect the deposition pattern within aneurysms. Taken together, the presented findings may enhance our understanding of pathological deposition processes at cardiovascular disease sites, and facilitate rational design and optimization of cardiovascular particulate drug carriers.

Mark Epshtein

Department of Biomedical Engineering

Technion - IIT

In Vitro 3D Cell-Cultured Arterial Models for Studying Vascular Drug Targeting Under Flow