de Saint Victor M, Carugo D, Barnsley L C, Owen J, Coussios C-C, Stride E
Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Oxford OX3 7DQ, United Kingdom.
Phys Med Biol. 2017 Sep 5;62(18):7451-7470. doi: 10.1088/1361-6560/aa858f.
Ultrasound and microbubbles have been shown to accelerate the breakdown of blood clots both in vitro and in vivo. Clinical translation of this technology is still limited, however, in part by inefficient microbubble delivery to the thrombus. This study examines the obstacles to delivery posed by fluid dynamic conditions in occluded vasculature and investigates whether magnetic targeting can improve microbubble delivery. A 2D computational fluid dynamic model of a fully occluded Y-shaped microarterial bifurcation was developed to determine: (i) the fluid dynamic field in the vessel with inlet velocities from 1-100 mm s (corresponding to Reynolds numbers 0.25-25); (ii) the transport dynamics of fibrinolytic drugs; and (iii) the flow behavior of microbubbles with diameters in the clinically-relevant range (0.6-5 µm). In vitro experiments were carried out in a custom-built microfluidic device. The flow field was characterized using tracer particles, and fibrinolytic drug transport was assessed using fluorescence microscopy. Lipid-shelled magnetic microbubbles were fluorescently labelled to determine their spatial distribution within the microvascular model. In both the simulations and experiments, the formation of laminar vortices and an abrupt reduction of fluid velocity were observed in the occluded branch of the bifurcation, severely limiting drug transport towards the occlusion. In the absence of a magnetic field, no microbubbles reached the occlusion, remaining trapped in the first vortex, within 350 µm from the bifurcation center. The number of microbubbles trapped within the vortex decreased as the inlet velocity increased, but was independent of microbubble size. Application of a magnetic field (magnetic flux density of 76 mT, magnetic flux density gradient of 10.90 T m at the centre of the bifurcation) enabled delivery of microbubbles to the occlusion and the number of microbubbles delivered increased with bubble size and with decreasing inlet velocity.
超声和微泡已被证明在体外和体内均可加速血栓溶解。然而，这项技术的临床应用仍然有限，部分原因是微泡向血栓的递送效率低下。本研究探讨了闭塞血管中流体动力学条件对递送造成的障碍，并研究了磁靶向是否可以改善微泡递送。建立了一个完全闭塞的Y形微动脉分支的二维计算流体动力学模型，以确定：(i) 入口速度为1-100 mm/s（对应雷诺数0.25-25）时血管内的流体动力学场；(ii) 纤溶药物的运输动力学；(iii) 临床相关直径范围（0.6-5 µm）内微泡的流动行为。在定制的微流控装置中进行了体外实验。使用示踪颗粒表征流场，并使用荧光显微镜评估纤溶药物的运输。对脂质壳磁性微泡进行荧光标记，以确定它们在微血管模型中的空间分布。在模拟和实验中，均在分支的闭塞分支中观察到层流涡旋的形成和流体速度的突然降低，这严重限制了药物向闭塞处的运输。在没有磁场的情况下，没有微泡到达闭塞处，而是被困在第一个涡旋中，距离分支中心350 µm以内。被困在涡旋中的微泡数量随着入口速度的增加而减少，但与微泡大小无关。施加磁场（在分支中心处的磁通密度为76 mT，磁通密度梯度为10.90 T/m）可使微泡递送至闭塞处，并且递送的微泡数量随着气泡大小的增加和入口速度的降低而增加。
