This proposal aims to understand and quantify the dynamics of microbubbles injected in the human circulation. These tiny bubbles, with sizes comparable to a red blood cell, are used toenhance ultrasound imaging and have been proposed as a vector for safe, non-intrusive drug delivery. The key physics that motivates this study is the presence of a net force on a bubble exerted by the application of ultrasound waves. This phenomenon, described by Bjerknes exactly a century ago, is being proposed as an important tool in the manipulation of microbubbles and microdroplets in many applications, specially in medicine. The coupling of this ?novel? force on the bubble with the well-known dynamics of bubbles and particles in non uniform flows must be understood before quantitative engineering design and analysis can be applied to the numerous medical diagnostic and therapeutic techniques been considered. The overarching theme of this proposal is the systematic study of the fundamental physics that control the dynamics (trajectory and volume oscillation) of bubbles in an environment dominated by a non-uniform, non-stationary velocity field, such as the one found in arteries and veins, and a high-amplitude, fast-changing pressure field, such as the one imposed by application of ultrasound. The motivation for this research is the use of microbubbles as Ultrasound Contrast Agents (UCAs) in certain areas of Diagnostic Ultrasound and the great potential that they present for new uses of Therapeutical Ultrasound, in particular in the area of targeted drug delivery. Intellectual Merit: The complex interactions of microbubbles with pulsatile flow and ultrasound waves present many open problems in the areas of multiphase flows and acoustics. The dynamics of microbubbles can be modeled by a Basset-Boussinesq-Oseen type equation, but the effect of the ultrasound-induced volume oscillations in the drag, lift and added mass terms need to be carefully studied. The coupling of the flow dynamics with the Bjerknes force exerted by the ultrasound field on the bubbles is also unknown. This proposal details a five year plan to study these problems, improve our understanding of the underlying physics and provide models that can guide applications and engineering design based on these processes. Broader Impacts: The ability to use ultrasound, a safe, non-invasive technique, to direct the motion of microbubbles towards certain regions of the circulation and to enhance their residence times in these areas will enable new therapies and diagnostic tools for a wide range of pressing medical problems such as intracraneal thrombolysis, targeted chemotherapy, myocardial perfusion and tumor vascularization assessment. The project goal will attract students from traditionally underrepresented groups into traditional fluid mechanics disciplines and help them make the link between quantitative engineering analysis and improved medical care. Age-adequate aspects of this research will be brought into the classroom for middle/high school, undergraduate and graduate students. A pulsatile flow kit will be prepared and presented to middle and high schools in the Seattle area in order to emphasize the importance of physics in medicine and biology and the increasing use of engineering quantitative tools in the design of medical procedures and devices. Undergraduates will learn, through lab session and involvement in the research, about the often confused concepts of unsteady flows, laminar vortices, flow separation and transition to turbulence, examples of which can be found in certain arteries. A specialized graduate course is been developed to introduce students to the complex fluid mechanics of the human circulation and the dynamics of microparticles (bubbles, droplets or cells) in unsteady, non uniform flows.
This project studied the motion of microbubbles under the effect of pulsatile flow and ultrasound pressure waves, in an effort to understand the way in which their trajectories can be steered when they are injected into the human arterial circulation. These microbubbles are FDA-approved as Ultrasound Contrast Agents to enhance the quality of ultrasound images in situations with low contrast, i.e. in echocardiography of the left ventricle wall, but have great potential to become targeted drug delivery vectors, bringing therapeutic molecules or genes to specific locations in the human body and depositing their load only where they are needed, such as at a tumor or a blood clot. The fundamental physics that determines the forces on the microbubbles when they are oscillating in volume, due to the pressure waves, has been investigated with experiments and theoretical modeling. A mechanism for coupling of the ultrasound to the force driving the microbubbles towards the arterial walls has been discovered. This mechanism can be exploited to drive in the direction of a target blood vessel and avoid them from spreading throughout the circulation. The fluid mechanics of blood flow in major arteries has also been studied in the project. Better understanding of the conditions that the microbubbles encounter in the complex anatomy and pulsatile flow in the human circulatory system has been achieved from a combination of computational flow modeling based on patient-specific medical imaging and actual measurements of the blood velocity in vivo with Doppler ultrasound. Blood flow in the carotid bifurcation, a common site for atherosclerosis, dialysis access arterio-venous fistulas, a common site of intimal hyperplasia, and intracranial arteries, a common site of thrombosis and aneurysms has been analyzed. Patient specific-models were used to simulate blood flow stresses, through Computational Fluid Dynamics, and mechanical stresses in the arterial or venous walls, through Fluid Structure Interaction simulations. In-vitro particle image velocimetry measurements have been conducted to validate the computational studies, including verification of model for endovascular treatment of aneurysms, such as coiling and stenting. The modeling of arterial flows have found that very high shear stresses in arteriovenous fistulae, induced by the tenfold increase in flow rate associated with the connection of arterial pressure to venous return flow, is localized in the anastomosis region. This effect, together with the chaotic flow that develops as the blood is forced to turn 180°, has been causally associated with endothelial dysfunction, denudation and intimal hyperplasia in in-vitro studies. Thus, design of better surgical alternatives, taking into account the patient’s anatomy and physiology, is promising to improve the outcome of this common surgery. The study of this same biomechanics problem with Fluid-Structure-Interaction simulations, proved that the level of shear stresses on the vascular wall is overestimated by rigid-wall simulations (CFD), up to 20%, but the faster simulations can be useful is screening patients at risk and selecting cases that require more accurate FSI studies of their surgery. The modeling of blood flow in the cerebral circulation has been used to predict the success of treatment of intracranial aneurysms. We were able to identify hemodynamic variables, namely peak wall shear stress inside the aneurysmal dome and circulation inside the aneurysmal sac, that correlate well with the success of treatment. Computational simulations of patient-specific blood flow in the intracranial circulation surrounding the aneurysm, before and immediately after the endovascular treatment (coiling and/or stenting) predict whether the current treatment will occlude flow into the aneurysm, providing relief from mechanical stresses on the vessel wall, at six months post-surgery. This could change the way clinical care is provided to patients, with better quality of life for patients under follow-up and better management of resources focusing on the patients who need them most. The diffusion of anticoagulants, i.e. heparin, from Central Venous Catheters in the human circulation has been studied, in vitro and in silico. We have shown that the leakage of heparin and other locking solutions used in these quasi-permanent catheters, is due to a combination of instillation losses, convective flow due to the pulsatility of flow near the catheter tip, in the Superior Vena Cava and, to a much lesser extent, diffusion. The different characteristic times for transport between convection at the catheter tip and diffusion inside the catheter (Re<<1) causes a complete depletion of the locking solution within ten cardiac cycles and a null concentration for the remainder of the interdialytic period (when the catheter is not being used). The diffusive flux of heparin from the back of the catheter towards the tip is insignificant compared to the convective flux that clears the tip. Thus, we have shown that the catheter locking procedure is ineffective, and that increasing the concentration of heparin in the locking solution, even by an order of magnitude, does not improve the outcome while putting the patients at significant risk of systemic heparinization.
