Abstract
Arterial thrombosis is the main instigating factor of heart attacks and strokes, which result in over 14 million deaths worldwide every year. The mechanism of thrombosis involves factors from the blood and the vessel wall, and it also relies strongly on 3D vessel geometry and local blood flow patterns. Microfluidic chip-based vascular models allow controlled in vitro studies of the interaction between vessel wall and blood in thrombosis, but until now, they could not fully recapitulate the 3D geometry and blood flow patterns of real-life healthy or diseased arteries. Here we present a method for fabricating microfluidic chips containing miniaturized vascular structures that closely mimic architectures found in both healthy and stenotic blood vessels. By applying stereolithography (SLA) 3D printing of computed tomography angiography (CTA) data, 3D vessel constructs were produced with diameters of 400 μm, and resolution as low as 25 μm. The 3D-printed templates in turn were used as moulds for polydimethylsiloxane (PDMS)-based soft lithography to create microfluidic chips containing miniaturized replicates of in vivo vessel geometries. By applying computational fluid dynamics (CFD) modeling a correlation in terms of flow fields and local wall shear rate was found between the original and miniaturized artery. The walls of the microfluidic chips were coated with human umbilical vein endothelial cells (HUVECs) which formed a confluent monolayer as confirmed by confocal fluorescence microscopy. The endothelialised microfluidic devices, with healthy and stenotic geometries, were perfused with human whole blood with fluorescently labeled platelets at physiologically relevant shear rates. After 15 minutes of perfusion the healthy geometries showed no sign of thrombosis, while the stenotic geometries did induce thrombosis at and downstream of the stenotic area. Overall, the novel methodology reported here, overcomes important design limitations found in typical 2D wafer-based soft lithography microfabrication techniques and shows great potential for controlled studies of the role of 3D vessel geometries and blood flow patterns in arterial thrombosis.
Highlights
Arterial thrombosis is the main cause of heart attacks and strokes, which together cause over 14 million deaths worldwide every year.[1]
By applying stereolithography (SLA) 3D printing of computed tomography angiography (CTA) data, 3D vessel constructs were produced with diameters of 400 μm, and resolution as low as 25 μm
The walls of the microfluidic chips were coated with human umbilical vein endothelial cells (HUVECs) which formed a confluent monolayer as confirmed by confocal fluorescence microscopy
Summary
Arterial thrombosis is the main cause of heart attacks and strokes, which together cause over 14 million deaths worldwide every year.[1] Thrombosis is a complex process, which is instigated by multiple factors, both genetic and acquired: blood-borne factors, vessel wall dysfunction and fluid dynamical effects. Animal models are the most popular experimental tool to study the pathophysiology of thrombosis in laboratory settings. While animal models mimic the mechanistic multifactorial complexity found in arterial thrombosis, they do not fully recapitulate human physiology or human disease. Rodent platelet biology[2] and coagulation dynamics[3] display inter-species differences, and mice arteries typically undergo wall shear stresses that are an order of magnitude higher[4] than those in humans. Thrombosis in mice can only be instigated in the largest arteries by using
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