Quantitative Ultrasound Molecular Imaging in Large Blood Vessel Environments

Stroke is the fourth leading cause of death in the United States. The current standard of care for carotid atherosclerosis addresses the disease after the plaque has developed to the point at which it is detectable using anatomical-based imaging to measure luminal stenosis. Ultrasound molecular imaging, possessing the ability to image the molecular signature of early vascular inflammation, potentially decades prior to the formation of plaque, may enable more timely diagnosis and treatment of atherosclerosis and atherosclerotic risk. Additionally, it simultaneously meets the needs for rapid, low-cost, and radiation-free molecular marker detection that may facilitate clinical adoption. Unfortunately, existing ultrasound-based molecular imaging is limited to small blood vessel environments, and unable to measure molecular marker concentration in large blood vessels.
In the first part of the dissertation, the design, implementation, and validation of a new clinically translatable ultrasound molecular imaging strategy – modulated acoustic radiation force (ARF)-based imaging – is presented. This approach overcomes the limitations of current techniques such as complex and lengthy protocols and lack of quantitative measurements. The modulated ARF-based imaging was successfully implemented and validated in vitro in phantoms and in vivo in mice models. The proposed method demonstrated quantitative measurements of molecular marker concentration in vitro (measurements correlated with marker concentration, R2 > 0.94), and assessment of inflammatory response in mouse abdominal aorta in vivo (significant difference between targeted and various control groups, p < 0.0005). Significantly, the results showed rapid and reliable targeted molecular imaging measurements that are well-coordinated with existing ultrasound-based clinical work-flow, and thus amenable to translation to clinical usage.
In the second part of the dissertation, the characterization of an expanding-nozzle flow-focusing microfluidic device for the generation of monodisperse microbubbles is presented. Significantly, the characterization could facilitate real-time adjustment of microbubble diameter and production rate using microfluidic devices.