Focused ultrasound therapy can be enhanced with microbubbles by thermal and cavitation effects. However, localization of treatment becomes difficult as bioeffects can occur outside of the target region. Spatial control of gas bubbles can be achieved with acoustic vaporization of perfluorocarbon droplets. This study was undertaken to determine the acoustic parameters for bubble production by droplet vaporization and how it depends on the acoustic conditions and droplet physical parameters. Droplets of varying sizes were sonicated in vitro with a focused ultrasound transducer and varying frequency and exposure. Simultaneous measurements of the vaporization and inertial cavitation thresholds were performed. The results show that droplets cannot be vaporized at low frequency without inertial cavitation occurring. However, the vaporization threshold decreased with increasing frequency, exposure and droplet size. In summary, we have demonstrated that droplet vaporization is feasible for clinically-relevant sized droplets and acoustic exposures.

Focused ultrasound therapy can be enhanced with microbubbles by thermal and cavitation effects. However, localization of treatment becomes difficult as bioeffects can occur outside of the target region. Spatial control of gas bubbles can be achieved with acoustic vaporization of perfluorocarbon droplets. This study was undertaken to determine the acoustic parameters for bubble production by droplet vaporization and how it depends on the acoustic conditions and droplet physical parameters. Droplets of varying sizes were sonicated in vitro with a focused ultrasound transducer and varying frequency and exposure. Simultaneous measurements of the vaporization and inertial cavitation thresholds were performed. The results show that droplets cannot be vaporized at low frequency without inertial cavitation occurring. However, the vaporization threshold decreased with increasing frequency, exposure and droplet size. In summary, we have demonstrated that droplet vaporization is feasible for clinically-relevant sized droplets and acoustic exposures.

acase@tulane.edu / Cancer’s response to mechanical vibration via high-intensity focused ultrasound and disruptive chemical agents (Mechanochemical Disruption) was examined in vitro and in vivo. We demonstrated that mechanochemical disruption of cellular structures induced phenotypic alterations in surviving tumor cells that prevented cancer progression. Mechanochemical disruption inhibited uncontrolled proliferation, tumorigenicity, metastatic development, and re-sensitized multiple cancer types to chemical treatment via alterations in protein expression and impediment of pro-survival signaling. Our study identified a novel curative therapeutic approach that can prevent the development of aggressive cancer phenotypes. / 1 / hakm murad

No description available.

The rising incidence of small, asymptomatic renal tumours discovered usmg abdominal imaging during the investigation of unrelated symptoms has fuelled the desire for new therapies which avoid surgical excision. Extracorporeal High Intensity Focused Ultrasound (HIFU) was proposed as one of these modalities but so far clinical research has been ,~." inconclusive. The present work was designed to improve these clii teal outcomes through the conduct of further clinical trials, laboratory based research and the translation of new technology into existing HIFU devices. A Phase II clinical trial of patients (n=13) with newly diagnosed <4cm renal tumours (clinical stage T1a) was designed, peer reviewed and received ethical approval (Ox REC 09/H0606104). Ten of 13 patients underwent renal HIFU using a clinical HIFU device (Model JCIJC200, HAIFU, China). One patient could not be treated due to poor tumour visualisation after anaesthesia and two patients could not be treated as they became unwell before or during anaesthesia. Histological evidence of HIFU ablation in either tumour or normal renal parenchyma was seen in all ten patients. Evidence of sub-total tumour ablation was seen in 8/10 of patients. Grade 1 «50%), 2 (50-90%) & 3 (90-99%) ablation was achieved in 4/10, 3/1 0 & 3/1 0 patients respectively but complete (100%) tumour ablation was not possible. HIFU treatment caused minimal morbidity - no Grade III- V (Clavien-Dindo) complications related to HIFU treatment occurred. Grade I skin pain and induration was seen in 9/1 0 patients; Grade II skin pain occurred in a single patient. Patient demographics, imaging and tumour characteristics were used to design parameters to improve patient selection for renal HIFU. The tumour location, thickness of peri-nephric fat and renal nephrometry score were useful predictors of successful screening for treatment. Page /ii Dr R. W Ritchie Nutiield Department of Surgical Sciences - TT 2012 Abstract Diligent use of these factors could limit unnecessary treatments and Improve ablation outcomes. , It is well known that ultrasound imaging of small renal masses can be challenging. Ultrasound imaging often deteriorates further during HIFU as the abdominal wall and fat tissues swell and cause increased attenuation. This loss of imaging quality was clearly demonstrated in this clinical trial and resulted in the early termination of treatment, before ,#,J' ... ~ .•.. endpoints were reached, in a number of cases. The current clinical method for monitoring the success of HIFU ablation using hyperecho analysis of B-mode ultrasound images is also questionable. Laboratory based studies using ex-vivo bovine liver subjected to HIFU confirmed that hyperecho monitoring had low sensitivity, predictive values and overall accuracy. A novel method of HIFU monitoring - passive mapping of the emissions received from acoustic cavitation activity and other sources of non-linearity during HIFU treatment - is believed to represent a significant opportunity to improve feedback. This technique uses the passively received signature of cavity activity which, when time-reversed, gives high- resolution images of the precise location of the activity. Laboratory-based ex-vivo work, using a commercially available ultrasound system (z.one, Zonare, USA), demonstrates its superiority over hyperecho monitoring. Indeed, thresholds could be applied to successfully predict HIFU ablation with high sensitivity and specificity. This technique was successfully translated into the clinical setting through the design of a Passive Acoustic Mapping (P AM) device. Custom-built receiving elements were applied without limiting the function of the existing HIFU devices. Both pre-clinical and ethically- Page [iii Dr R. W Ritchie Nuffield Department of Surgical Sciences - TT 2012 Abstract approved clinical studies demonstrated its safe integration without significant impact on the device energy output or treatment accuracy. Using similar passive beamfonning algorithms, acoustic cavitation activity was successfully mapped and corresponded with the location of thermal ablation in both ex-vivo tissue phantoms and during clinical HIFU therapy. ,~-' It is believed that the development of new patient selection paral~~tel's will elimil?ate target those patients who are most suitable for renal HIFU - small tumours, minimal peri-nephric fat & low nephrometry score .. The use of P AM will lead to a significant improvement in the efficacy of treatment. It can be successfully applied to existing devices and predicts the location and extent ofHIFU ablation with greater accuracy that existing techniques.

Regensburg, Univ., Diss., 2008

Despite the prevalence of CNS disorders, treatment options for CNS disorders fall woefully behind treatment options for other systemic disorders. This is due to the presence of the blood brain barrier (BBB) acting as an obstacle, preventing foreign substances from entering the brain. A newly developed and innovative biomedical procedure attempts to bypass the BBB in the delivery of therapeutics by using focused ultrasound (FUS) to disrupt and temporarily open the BBB. The use of FUS-facilitated BBB opening is able to target specific tissue for noninvasive, localized BBB penetration. As the technique is experimental and in it's nascent stage of development, there are only a few studies that investigate its abilities in delivering treatments directly to the brain. The studies involve delivery of large, hydrophilic molecules that traditionally would not be able to bypass the BBB and enter the brain, and analysis of CNS concentrations of the molecules after FUS treatment, as well as the therapeutic successes. Results of FUS the studies are promising and the results demonstrate that the procedure is able to significantly increase drug concentrations in the brain, increase survival rates in animal models, decrease tumor growth, and decrease tumor margins and volume. The potential and power of FUS should be further explored as the future of CNS disorder treatments.

The deposition of ultrasonic energy in tissue can cause tissue damage due to local heating. For pressures above a critical threshold, cavitation will occur in tissue and bubbles will be created. These oscillating bubbles can induce a much larger thermal energy deposition in the local region. Traditionally, clinicians and researchers have not exploited this bubble-enhanced heating since cavitation behavior is erratic and very difficult to control. The present work is an attempt to control and utilize this bubble-enhanced heating. First, by applying appropriate bubble dynamic models, limits on the asymptotic bubble size distribution are obtained for different driving pressures at 1 MHz. The size distributions are bounded by two thresholds: the bubble shape instability threshold and the rectified diffusion threshold. The growth rate of bubbles in this region is also given, and the resulting time evolution of the heating in a given insonation scenario is modeled. In addition, some experimental results have been obtained to investigate the bubble-enhanced heating in an agar and graphite based tissue- mimicking material. Heating as a function of dissolved gas concentrations in the tissue phantom is investigated. Bubble-based contrast agents are introduced to investigate the effect on the bubble-enhanced heating, and to control the initial bubble size distribution. The mechanisms of cavitation-related bubble heating are investigated, and a heating model is established using our understanding of the bubble dynamics. By fitting appropriate bubble densities in the ultrasound field, the peak temperature changes are simulated. The results for required bubble density are given. Finally, a simple bubbly liquid model is presented to estimate the shielding effects which may be important even for low void fraction during high intensity focused ultrasound (HIFU) treatment.

A complete understanding of high-intensity focused ultrasound-induced temperature changes in tissue requires insight into all potential mechanisms for heat deposition. Applications of therapeutic ultrasound often utilize acoustic pressures capable of producing cavitation activity. Recognizing the ability of bubbles to transfer acoustic energy into heat generation, a study of the role bubbles play in tissue hyperthermia becomes necessary. These bubbles are typically less than 50μm. This dissertation examines the contribution of bubbles and their motion to an enhanced heating effect observed in a tissue-mimicking phantom. A series of experiments established a relationship between bubble activity and an enhanced temperature rise in the phantom by simultaneously measuring both the temperature change and acoustic emissions from bubbles. It was found that a strong correlation exists between the onset of the enhanced heating effect and observable cavitation activity. In addition, the likelihood of observing the enhanced heating effect was largely unaffected by the insonation duration for all but the shortest of insonation times, 0.1 seconds. Numerical simulations were used investigate the relative importance of two candidate mechanisms for heat deposition from bubbles as a means to quantify the number of bubbles required to produce the enhanced temperature rise. The energy deposition from viscous dissipation and the absorption of radiated sound from bubbles were considered as a function of the bubble size and the viscosity of the surrounding medium. Although both mechanisms were capable of producing the level of energy required for the enhanced heating effect, it was found that inertial cavitation, associated with high acoustic radiation and low viscous dissipation, coincided with the the nature of the cavitation best detected by the experimental system. The number of bubbles required to account for the enhanced heating effect was determined through the numerical study to be on the order of 150 or less.

Histotripsy is a non-invasive and non-thermal focused ultrasound therapy that can be used to ablate tissue within the body while overcoming many of the limitations of thermal ablation. Histotripsy utilizes short-duration, high pressure ultrasound pulses to create a cavitation bubble cloud of numerous rapidly expanding and collapsing bubbles, which cause mechanical stress on the targeted region. Histotripsy contains multiple subtypes including intrinsic threshold, shock scattering, and boiling histotripsy, where intrinsic threshold histotripsy utilizes single cycle pulses focused to a single point to create a bubble cloud from the peak negative pressure (p- ≥ 25 MPa for water-based tissues). Nanoparticle-mediated histotripsy (NMH) uses perfluorocarbon-filled nanoparticles to create bubble clouds at lower pressures than that of the intrinsic threshold of histotripsy. Prior studies have shown that nanodroplets (NDs) and nanocone clusters (NCCs) both reduce the cavitation threshold, but further investigation on different parameters to optimize treatments have not fully been studied. Additional research is needed for the characterization of these nanoparticles with different pulsing parameters such as cycle number and frequency in order to better predict and understand the mechanisms underlying NMH. In this thesis, I investigate the ability of new nanodroplets and nanocone clusters to reduce histotripsy cavitation threshold with NMH. I also investigate the effect that multi-cycle pulsing parameters have on NMH and stable bubble formation from acoustic droplet vaporization (ADV) for nancone clusters. The culmination of this thesis will advance our understanding of the behavior of acoustically-active nanoparticles when exposed to varied pulsing schemes and frequencies. This knowledge will allow for the further investigation of more efficient, effective, and safe methods for clinical focused ultrasound therapies. / Master of Science / Histotripsy is a non-invasive and non-thermal focused ultrasound therapy that can be used to destroy targeted tissue within the body. Histotripsy is currently being developed for non-invasive and non-thermal cancerous tissue destruction with the first-in-man trial having been conducted within the last year for the treatment of liver tumors. Histotripsy utilizes high-pressure, short-duration pulses focused to a single region to create a cloud of bubbles that are rapidly expanding and collapsing which causes mechanical damage to the targeted cells. Nanoparticle-mediated histotripsy (NMH) has been developed to utilize nanoparticles to reduce the pressure needed to induce cavitation. Despite many studies and advances in histotripsy, there are many areas within the topic that need additional research to better understand the capabilities of the treatment method. This additional research is crucial in allowing for the development of new nanoparticles, faster treatment times, and new parameters that could allow for more precision near critical structures. In this thesis, I investigate the ability of new nanoparticles to reduce histotripsy cavitation threshold with NMH. I also investigate the effect that multi-cycle pulsing parameters have on NMH and stable bubble formation for nanoparticles. The culmination of this thesis will advance our understanding of the behavior of acoustically-active nanoparticles when exposed to varied pulsing schemes and frequencies. This knowledge will allow for the further investigation of more efficient, effective, and safe methods for clinical focused ultrasound therapies.