TOWARD CLINICAL TRANSLATION OF MICROVASCULAR ULTRASOUND IMAGING: ADVANCEMENTS IN SUPERHARMONIC ULTRASOUND TECHNOLOGY

Ultrasound imaging is perhaps the safest, most affordable, and most available biomedical imaging modality. However, it suffers from poor specificity for cancer detection, particularly in breast cancer, which affects one in eight women and leads to a high incidence of unnecessary biopsies from inconclusive screening. It is well-known that malignant cancers are accompanied by abnormal angiogenesis, leading to tortuous and disorganized vasculature. Acoustic angiography, a microvascular contrast-enhanced ultrasound technique, was developed to visualize and harness this aberrant vasculature as a biomarker of malignancy. This technique applies a dual-frequency superharmonic strategy to isolate intravascular microbubble contrast from the surrounding tissue with low-frequency transmit and high-frequency receive, resulting in high-resolution microvascular maps. Preclinically, acoustic angiography has been a valuable tool for differentiating tumors from healthy tissue by quantifying vascular features like tortuosity. The preclinical success of this technique is attributed to the single-element dual-frequency transducers used, which provide contrast sensitivity and focal depth best suited for imaging small animals at high microbubble doses. In an exploratory clinical study in which these transducers were used to image the human breast, imaging depth, low sensitivity, and motion artifacts significantly degraded image quality. For acoustic angiography to be successfully translated to clinical use, the technique must be optimized for clinical imaging. In this dissertation, we explore three ways in which acoustic angiography may be improved for the clinic. First, we evaluate microbubble contrast agents to determine the composition that maximizes superharmonic generation. The results indicate that lipid-shelled microbubbles with perfluorocarbon cores, like the commercial agent, DEFINITY, produce the greatest superharmonic signal. Then, we present a novel transducer, a stacked dual-frequency array, as the next-generation device for acoustic angiography and demonstrate improvements in imaging depth and sensitivity up to 10 mm and 13 dB, respectively. We go on to apply this device in a clinical pilot study and elucidate the challenges that remain to be overcome for clinical acoustic angiography. Finally, we propose custom simulations for superharmonic imaging and identify optimal frequency combinations for imaging at depths up to 8 cm, which can be used to design dedicated clinical dual-frequency arrays in the future.Doctor of Philosoph

Investigations of the Cavitation and Damage Thresholds of Histotripsy and Applications in Targeted Tissue Ablation.

Histotripsy is a noninvasive ultrasound therapy that controls acoustic cavitation to mechanically fractionate soft tissue. This dissertation investigates the physical thresholds to initiate cavitation and produce tissue damage in histotripsy and factors affecting these thresholds in order to develop novel strategies for targeted tissue ablation. In the first part of this dissertation, the effects of tissue properties on histotripsy cavitation thresholds and damage thresholds were investigated. Results demonstrated that the histotripsy shock scattering threshold using multi-cycle pulses increases in stiffer tissues, while the histotripsy intrinsic threshold using single-cycle pulses is independent of tissue stiffness. Further, the intrinsic threshold slightly decreases with lower frequencies and significantly decreases with increasing temperature. The effects of tissue properties on the susceptibility to histotripsy-induced tissue damage were also investigated, demonstrating that stiffer tissues are more resistant to histotripsy. In the second part of this dissertation, the feasibility of using histotripsy for targeted liver ablation was investigated in an intact in vivo porcine model, with results demonstrating that histotripsy was capable of non-invasively creating precise lesions throughout the entire liver. Additionally, a tissue selective ablation approach was developed, where histotripsy completely fractionated the liver tissue surrounding the major hepatic vessels and gallbladder while being self-limited at the boundaries of these critical structures. In the final part of this dissertation, a novel ablation method combining histotripsy with acoustically sensitive nanodroplets was developed for targeted cancer cell ablation, demonstrating the potential of using nanodroplet-mediated histotripsy (NMH) for targeted, multi-focal ablation. Studies demonstrated that lower frequency and higher boiling point perfluorocarbon droplets can improve NMH therapy. The role of positive and negative pressure on cavitation nucleation in NMH was also investigated, showing that NMH cavitation nucleation is caused directly from the peak negative pressure of the incident wave, similar to histotripsy bubbles generated above the intrinsic threshold. Overall, the results of this dissertation provide significant insight into the physical mechanisms underlying histotripsy tissue ablation and will help to guide the future development of histotripsy for clinical applications such as the treatment of liver cancer.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113591/1/evlaisav_1.pd

Noninvasive Thrombolysis Using Histotripsy Pulsed Ultrasound Cavitation Therapy.

Histotripsy is a noninvasive ultrasound therapy that utilizes short, high-amplitude, focused ultrasound pulses to mechanically reduce targeted tissue structures to liquid debris by acoustic cavitation. In this work, the physical mechanisms of histotripsy and its application as a method of thrombolysis were investigated. Cavitation activity which causes tissue breakdown during histotripsy was studied by high-speed photography. It was found that cavitation clouds form due to scattering of shock waves in a focused ultrasound pulse from individual inertial cavitation bubbles. The scattered shock is a large tensile wave which expands clusters of cavitation bubbles when the tensile pressure is greater than a measured threshold of approximately 30 MPa. The interaction of this cavitation with tissue and cells was explored with a phantom containing agarose and red blood cells to measure cavitation-based mechanical damage. The observations indicated that cell lysis may be achieved by bubble-induced tensile strain upon expansion, causing membrane rupture. Based on these studies, focused histotripsy therapy transducers were designed to controllably generate cavitation clouds in the vasculature for performing thrombolysis. Transducers were integrated with ultrasound imagers to provide feedback for targeting and monitoring progress of treatment. Rapid thrombolysis was observed when histotripsy was applied to clots in-vitro, and the resulting debris was mainly subcellular and unlikely to cause embolism. Additionally, it was observed that histotripsy can attract, trap, and destroy free clot fragments in a vessel phantom. Based on these observations, a noninvasive embolus trap (NET) was developed, acting as a filter to prevent embolism during the thrombolysis procedure. An in-vivo porcine model of deep-vein thrombosis was used to evaluate the safety and efficacy of the histotripsy thrombolysis technique. These experiments demonstrated the feasibility of the treatment and suggest histotripsy can achieve rapid clot breakdown in a controlled manner.Ph.D.Biomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91496/1/adamdm_1.pd

Imaging Sensors and Applications

In past decades, various sensor technologies have been used in all areas of our lives, thus improving our quality of life. In particular, imaging sensors have been widely applied in the development of various imaging approaches such as optical imaging, ultrasound imaging, X-ray imaging, and nuclear imaging, and contributed to achieve high sensitivity, miniaturization, and real-time imaging. These advanced image sensing technologies play an important role not only in the medical field but also in the industrial field. This Special Issue covers broad topics on imaging sensors and applications. The scope range of imaging sensors can be extended to novel imaging sensors and diverse imaging systems, including hardware and software advancements. Additionally, biomedical and nondestructive sensing applications are welcome

Instantaneous Ultrasonic Assessment of Urinary Bladder Volume

It is well known that bladder dysfunction is associated with a number of clinical conditions requiring treatment. In many of these cases it is important to accurately determine the volume of the bladder. Under other conditions such as post-operative recovery, where there is temporary loss of bladder sensation and/or loss of the normal voiding mechanism, over distension of the bladder has to be avoided. Under those conditions voiding by catheter introduction is carried out. The main goal of this project was to obtain the relationship between the detected harmonic components and the urine volume present in the bladder

Nanoscale Materials As Contrast Agents For Cavitation-Based High Intensity Focused Ultrasound Imaging and Thrombolytic Therapy

High intensity focused ultrasound (HIFU) can interact with nanoscale colloids in order to produce both an imaging and therapeutic effect on in vitro models of disease via mechanical forces associated with cavitation. My doctoral research has focused on the ability of HIFU to nucleate cavitating bubbles, which themselves have important imaging and therapeutic properties, from nanoscale particulate matter. The first part of this dissertation will show that insonation of a suspension of microbubbles yields a nanoparticle-rich suspension. This suspension can then interact with HIFU to produce further cavitation events, substantially changing the overall therapeutic efficacy of the microbubble suspension. Next, I will consider a hydrophobic mesoporous silica nanoparticle (hMSN) system in which the ability of the hMSNs to generate cavitation events from incident HIFU waves is dictated by the phase behavior of the phospholipids that stabilize the hMSNs in aqueous media. Lastly, I will apply these phospholipid coated hMSNs towards a thrombolytic therapy model and show that these phospholipid-coated hMSNs break down thrombi more effectively than competing strategies, as well as how these nanoparticles can reduce the microembolic load generated from clot lysis.</p

Ultrasound-Responsive Cavitation Nuclei for Therapy and Drug Delivery

Therapeutic ultrasound strategies that harness the mechanical activity of cavitation nuclei for beneficial tissue bio-effects are actively under development. The mechanical oscillations of circulating microbubbles, the most widely investigated cavitation nuclei, which may also encapsulate or shield a therapeutic agent in the bloodstream, trigger and promote localized uptake. Oscillating microbubbles can create stresses either on nearby tissue or in surrounding fluid to enhance drug penetration and efficacy in the brain, spinal cord, vasculature, immune system, biofilm or tumors. This review summarizes recent investigations that have elucidated interactions of ultrasound and cavitation nuclei with cells, the treatment of tumors, immunotherapy, the blood–brain and blood–spinal cord barriers, sonothrombolysis, cardiovascular drug delivery and sonobactericide. In particular, an overview of salient ultrasound features, drug delivery vehicles, therapeutic transport routes and pre-clinical and clinical studies is provided. Successful implementation of ultrasound and cavitation nuclei-mediated drug delivery has the potential to change the way drugs are administered systemically, resulting in more effective therapeutics and less-invasive treatments

Sonoporation with phase-shift nanoemulsions: an in vitro study

Acoustic cavitation (i.e. acoustically stimulated microbubble activity) has gained interest in the biomedical community due to its ability to locally concentrate mechanical forces inside the body. Biological structures in close proximity experience stresses that temporally disrupt their normal function and allow passage of material that would otherwise be impermeable. Examples include blood-brain barrier disruption, enhanced penetration of drugs into tumors, disruption of the blood vessel endothelium, and permeabilization of cell membranes (i.e. sonoporation). The goal of this thesis was to investigate a new class of acoustic cavitation nuclei for sonoporation called phase-shift nanoemulsions (PSNE). Ultrasound can be used to nucleate, or phase-shift PSNE into microbubbles with a process termed acoustic droplet vaporization (ADV). Specifically, the focus was to use PSNE for delivery of small interfering RNA (siRNA) to an in vitro cell suspension using sonoporation. Small interfering RNA is an exogenous RNA molecule and has gained increased attention due to its ability to knockdown specific proteins central to disease progression. Results showed that siRNA delivery with PSNE is possible with high uptake efficiency (i.e. ratio of the number of cells with uptake to the number of cells originally). Uptake was highly dependent on the amount of acoustic cavitation activity generated from PSNE. The acoustic emissions from individual PSNE were explored to understand the microbubble dynamics following ADV. Results showed that PSNE immediately undergo an explosive growth and collapse at the ADV threshold, and the maximum size of the microbubble depends on the ultrasound frequency. This led to the hypothesis that the sonoporation efficiency with PSNE is governed by the choice of frequency. Lower frequencies were shown to expand microbubbles to larger maximum radii, which in turn caused more energetic collapses leading to cell death. This explains the lower uptake efficiencies at lower frequencies (39.45% at 1 MHz and 46.62% at 2.5 MHz), compared to the relatively high uptake efficiency at 5 MHz (66.81%). In general, uptake efficiencies > 50% have rarely been achieved with current sonoporation methods and these results are a significant improvement. PSNE could also serve as a unique platform for numerous other therapeutic ultrasound applications that utilize the mechanical effects of acoustic cavitation. The frequency-dependent control over the microbubble dynamics following ADV could provide a way to tune the level of stress experienced by biological structures.2017-02-17T00:00:00