archives@tulane.edu / Acoustic droplet vaporization (ADV) is an attractive alternative to traditional hepatocellular carcinoma (HCC) treatments. ADV involves injecting microdroplets into the bloodstream which then accumulate in and around the tumor’s vasculature. Once accumulated, high-power ultrasound is used to vaporize the microdroplets into larger perfluoropentane gas microbubbles which occlude blood flow and induce necrosis of the tumor without harming healthy tissue like traditional HCC treatments. This study aims to optimize ADV treatment by improving the shell composition and surface architecture of microdroplets while ensuring the treatment remains safe. In order to ensure the treatment is as effective as possible, the microdroplets must have powerful binding capabilities, guaranteeing maximum microdroplet accumulation and treatment efficacy. The binding capabilities of three microdroplet shell compositions, created by adjusting the molar percentages of the three lipids found in the shell, were investigated and found to all have equal binding abilities. The surface architecture of these microdroplets were also altered to maximise binding capabilities. Microdroplets can have either an exposed-ligand or buried-ligand surface architecture. In microdroplets with a buried-ligand surface architecture, the attached tumor-targeting ligands are hidden within a layer of longer lipid chains which allow the microdroplets to evade the immune system and circulate within the bloodstream longer, increasing treatment efficacy. It was found that microdroplets with a buried-ligand surface architecture do not have comparable binding capabilities to microdroplets with an exposed-ligand surface architecture and are therefore not a viable alternative for use in ADV. Finally, the velocity required to dislodge perfluoropentane gas microbubbles was explored to determine if the gas microbubbles can remain adhered to the tumor’s vasculature to create a strong occlusion. Since perfluoropentane gas microbubbles occlude blood flow it is imperative that the microbubbles remain in the tumor’s vasculature and do not dislodge and accumulate in other parts of the body’s vasculature. By measuring the velocity and calculating the force necessary for dislodgement and comparing those values to those found in capillaries it was concluded that the perfluoropentane gas microbubbles can withstand the force of blood flow and remain lodged in capillaries. / 1 / Chloe Celingant-Copie

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Acoustic droplet vaporization (ADV) is a process in which a phase shift of a liquified droplet into a gaseous microbubble, is triggered using an ultrasonic wave. In contrast to utilizing conventional contrast agents in ultrasound, the phase change contrast agents used in ADV can extravasate into tumor tissue, and they offer a greater circulatory lifespan, thereby increasing the potential applications in which they can be utilized. In this project, the impact of different ultrasound parameters on the efficiency of ADV was investigated, using a programmable ultrasound system. Two different ultrasound sequences were designed, for imaging and vaporization of droplets. Furthermore, three different sets of experiments were performed. Firstly, the vaporization effect of different imaging voltages was investigated, whereby a setting of 15V was identified as an able voltage for the remaining experiments. Secondly, experiments concerning the effect of vaporizing frequency on the ADV efficiency were performed, including the use of single and dual frequencies. Lastly, different frequency settings were combined with varying the number of cycles, to assess how the choice of pulse length influences the vaporization. The results from the project indicate that no substantial difference in ADV efficiency is achieved when using different frequency settings for perfluoropentane droplets encapsulated by cellulose nanofibers. However, the results provide clear indications of the benefit of using longer pulse durations on the vaporization efficiency. In conclusion, further studies are required before ADV can be translated into a clinical setting.

Ultrasound-mediated drug delivery has been proposed as a safe and non-invasive method to achieve localized drug release. Drug-loaded microbubbles are injected in the vascular system and ultrasound waves are then used to localize and burst the microbubbles at a specific targeted area. The relatively large size of microbubbles however limits both their lifetime and their reach in the human body. Phase-change liquid droplets can extend the use of ultrasound contrast agents for localized drug delivery. Their smaller size provides several advantages. The droplets can reach smaller capillaries, such as those in tumors vasculature. Their lifetime is also considerably prolonged. Through the phenomenon of Acoustic Droplet Vaporization (ADV), triggered by ultrasound stimulation, the liquid-filled droplets experience a phase change and are converted into gas-filled microbubbles. The newly created microbubbles can then be disrupted by further stimulation and release their drug load in the tumor tissue. In this project, a protocol to image and burst perfluoropentane-based micro-sized droplets using a single transducer is developed using the Verasonics Ultrasound System. The pulse sequences are developed to allow close monitoring of the drug delivery by capturing a series of images before and after the vaporization or destruction of the droplets. The droplets response was assessed for different pulse voltages and durations. Mean pixel value was calculated for the regions of interest, using the images captured before and after delivery of the ultrasound pulse. Vaporization of the droplets can be achieved with low voltage (10V), whereas high voltage (50V) triggers their destruction. Combined with high voltage, pulse duration affects the rate at which droplets can be destructed.

The use of peruorocarbon lled droplets for use as Phase Changing Contrast Agents (PCCAs) is a promosing eld. These capsules also have potential to be used for mediated drug delivery. The phase change, which has given the capsules their name, is the process when the capsule transforms from a droplet into a bubble. This process is referred to as Acoustic Droplet Vaporization (ADV) and can be induced with the use of ultrasonic waves. In this study a new type of Perfluorpentane (PFC5) capsules which are stabilized with Cellulose Nano Fibers (CNF) have been evaluated for its potential as a PCCA. To investigate this potential a setup was designed in which the capsules could be exposed to ultrasound waves. Following the ultrasound exposure the capsules were visualized under a light transmission microscope. The experiments were conducted for dierent combinations of ultrasound parameters. For each combination eight volume distributions were created, in which two of them as reference cases were not exposed to ultrasound waves. Six cases with the ultrasound ring with different levels of acoustic power, resulting in peak negative pressures ranging from 0.144 to 0.291 MPa. The results showedfthat ADV could be observed when the frequency of the acoustic wave is 3.5 MHz, the pulse repetition frequency is 500 and the burst width is set to 12 cycles. The Peak Negative Pressure (PNP)-threshold for ADV is about 0.200 MPa. When the burst width is set to 8, ADV is also observed however to a lesser extent then when it is set to 12. These results indicate that the CNF-stabilized PFC5 capsules are promising droplets with a potential future as an alternative to currently used PCCAs.

The use of ultrasound contrast agents increases the information available for reconstruction during ultrasound imaging. Previously studied microbubbles, consisting of a gas core, are subject to limitations such as a short lifetime and a large size. Droplets with a liquid perfluorocarbon core that is stabilized by cellulose nanofibers eliminate these drawbacks, but require further investigation. By studying the frequency-dependent attenuation profile of the cellulose nanofiber coated perfluorocarbon droplets within an ultrasound field, information about the droplets as oscillators can be retrieved, enabling characterization of their physical properties. In this study, the frequency-dependent attenuation profile was experimentally acquired and compared between two concentrations, using flat transducers covering the frequency range of 1-15 MHz. The data collected in the time domain was processed and transformed into the frequency domain and the attenuation was calculated across the entire frequency range. Among the frequencies studied, the attenuation increases with frequency and covers the range of approximately 0.25-8.3 dB/cm and 0.01-3.3 dB/cm at the concentrations of 50 million droplets/ml and 10 million droplets/ml respectively. The attenuation reaches a minimum at 3 MHz within the highest concentration, compared to 4.43 MHz within the lowest. The increase of the attenuation with frequency is explained by the droplets not exhibiting large oscillations within the range covered. It is probable that the droplets do exhibit oscillations, due to a viscosity lower than that of water, but a resonance frequency is not found within the spectrum studied. This could be explained by a shell elasticity or a small droplet radius placing the resonance frequency outside of the spectrum studied, or high levels of damping broadening the resonance peak. Localizing the resonance frequency would enable characterization of these physical properties of the cellulose nanofiber shell as well as the perfluorocarbon liquid core of the droplets. The increase of the attenuation with frequency demonstrates that the droplets do not produce a maximized amount of scattering at a specific frequency within the range studied, which is observed among other oscillating particles implemented as ultrasound contrast agents. The attenuation is, however, larger than that of blood across all frequencies except for those among which the attenuation reaches its minimum. Potential errors that are affecting the results include droplet vaporization, the formation of flocs after the mechanical agitation has ceased, the experimental setup, the settings on the pulse generator, the sensitivity of the transducers and the processing code.

The first step on the way to understanding the complicated dynamics of spray is to study the behavior of isolated droplets. In many industrial and natural processes such as turbulent combustion, agricultural sprays, spray cooler, falling raindrops and cloud evolution the droplet is subjected to a chaotic unsteady external flow field. The interaction between the liquid and gaseous phases results in very intricate droplet dynamics like capillary instabilities, atomization, droplet collision and coalescence and vaporization, to name a few. In this dissertation, the focus is on shape oscillations, atomization and vaporization dynamics of pendant and sessile droplets. A droplet residing on a substrate which vibrates vertically at ultrasonic frequency will exhibit different modes of shape oscillation. The competition between capillary forces and inertia forces is basically responsible for these oscillations. However, when an acoustic force field is introduced asymmetrically around the droplet, we discover with the help of ultra high-speed imaging, a new droplet spreading phase. This new method of droplet manipulation could nd application in micro fluidics and lab-on-a-chip systems. By lading the droplet with nanoparticles, the spreading rate can be easily controlled. The spreading phase is followed by an atomization phase where surface ligaments grow to disintegrate into daughter droplets; the intensity of atomization is found to decrease with increase in fluid viscosity. The ability to control atomization characteristics of droplets by lading them with nanoparticles is a powerful technique that may be implemented in spray coolers and combustors to control the spray characteristics or combustion efficiency. Both the spreading and ligament dynamics have been theoretically simulated and the physics behind the observed trends is explained. The growth rate of the ligaments is found to be governed by Weber number modified to include the acoustic pressure level of the standing wave. The frequency of ligament breakup is found to decrease with fluid viscosity and this observation is adequately supported by a theory developed based on the evolution crater on the droplet surface. Turning now to the pendant droplets, by decomposing the droplet shape into Legendre modes, the shape oscillations exhibited by a droplet hanging from the junction of cross-wire placed at the center of an air jet is studied. Both high-speed imaging and hot-wire anemometry are employed. The driving force of oscillation of droplets subjected to the air jet is proved to be the inherent pressure fluctuations in the jet. The effect of surface tension, viscosity and Reynolds number on the shape oscillation level has been examined. The first experimental evidence of viscous attenuation of lower frequencies in a particular mode in glycerol/water mixture is reported. A theoretical model was developed to simulate the droplet shape oscillations induced by different ambient flow fields like pulsatile flow, vortical flow and flow with broadband energy spectrum. The time of interaction of the droplet with an eddy in the flow is found to be very crucial in determining the amplitude of oscillation of the droplet. The shorter the interaction time, the higher are the chances of the droplet oscillation being pushed into resonance. Finally, the heat transfer and droplet regression dynamics of pendant droplets in a hot air stream of various chemical compositions (like conventional fuels, alternative fuels and nanosuspensions) have been experimentally analyzed using high speed imaging. The droplet is deployed at the junction of cross-wire at the centre of a vertical air jet. A hybrid timescale has been proposed which incorporates the effects of latent heat of vaporization, saturation vapor pressure and thermal diffusivity. This timescale in essence encapsulates the different parameters that influence the droplet vaporization rate. The analysis further permitted the evaluation of the effect of various parameters such as surrounding temperature, Reynolds number, far-field vapor presence, impurity content and agglomeration dynamics (nanosuspensions) in the droplet.

Droplets as precursor are extensively applied in diverse fields of science and engineering. Various contributions are provided previously towards analysis of single phase and multi-phase droplets of single and multiple components. This thesis describes modelling of multi-phase (nano fluid) droplet vaporization. The evaporation of liquid phase along with migration of dispersed particles in two-dimensional plane within droplet is detailed using the governing transport equations along with the appropriate boundary and interface conditions. The evaporation model is incorporated with aggregate kinetics to study agglomeration among nano silica particles in base water. Agglomeration model based on population balance approach is used to track down the aggregation kinetics of nano particles in the droplet. With the simulated model it is able to predict different types of final structure of the aggregates formed as observed in experimental results available in literature. High spatial resolution in terms of agglomeration dynamics is achieved using current model. Comparison based study of aggregation dynamics is done by heating droplet in convective environment as well as with radiations and using different combination of heating and physical parameters. The effect of internal flow field is also analysed with comparative study using levitation and without levitation individually. For levitation, droplet is stabilized in an acoustic standing wave. It is also attempted to study the transformation of cerium nitrate to ceria in droplets when heated under different environmental conditions. Reaction kinetics based on modified rate equation is modelled along with vaporization in aqueous cerium nitrate droplet. The thermo physical changes within the droplet along with dissociation reaction is analysed under different modes of heating. The chemical conversion of cerium nitrate to ceria during the process is predicted using Kramers' reaction velocity equation in a modified form. The model is able to explain the kinetics behind formation of ceria within droplet at low temperatures. Transformation of chemical species is observed to be influenced by temperature and configuration of the system. Reaction based model along with CFD (computational fluid dynamics) simulation within the droplet is able to determine the rate of chemical dissociation of species and predict formation of ceria within the droplet. The prediction shows good agreement with experimental data which are obtained from literature.