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.

Histotripsy is a noninvasive mechanical ablation method that uses focused ultrasound to disintegrate target tissues into acellular homogenate through the generation of acoustic cavitation and is currently being developed for numerous clinical applications. Histotripsy uses high-pressure (>10 MPa), short-duration (<15 cycles) pulses to cause the rapid expansion and collapse of nuclei at the focus resulting in large applied stress and strain in the adjacent tissue. At a sufficiently high pressure above the target medium's intrinsic cavitation threshold and an adequate number of applied pulses, cavitation "bubble clouds" create precise lesions with high fidelity to the region of the focus. Despite advances in histotripsy, additional research is still needed to better understand the acoustic cavitation nucleation process and its effects on therapies using focused ultrasound. This understanding is critical to better predict and control pulse dose for more rapid and efficient ablation procedures, to reduce off-target cavitation events for safer focused ultrasound therapies, and to localize ablation for high-precision procedures near critical structures or treatments without active imaging guidance. In this dissertation, I investigate the nucleation and dynamics of ultrasonically generated acoustic cavitation for novel applications of focused ultrasound. My Ph.D. thesis focuses on (1) investigating the effect of histotripsy pulsing parameters on bubble cloud cavitation nucleation, bubble dynamics, and ablation efficiency, (2) investigating the effect of nuclei characteristics on the threshold for cavitation nucleation and resulting bubble dynamics for therapeutic applications, and (3) developing methods alter select characteristics and dynamics of acoustic cavitation by adjusting pulsing parameters to optimize ablation efficiency in conventional and nanoparticle-mediated histotripsy. The culmination of this thesis will advance our understanding of the nucleation and behavior of acoustic cavitation from pulsed focused ultrasound and develop innovative systems to improve the efficacy, efficiency, and safety of clinical focused ultrasound therapies. / Doctor of Philosophy / Histotripsy is a noninvasive focused ultrasound method that precisely destroys target tissues such as tumors through the acoustic generation of cavitation and is currently being developed for numerous clinical applications. Histotripsy uses high-pressure, short-duration pulsed soundwaves to cause the bubbles to rapidly expand and collapse within a precise region called the focus. This rapid cavitation results in large mechanical strain in the targeted tissue. With increasingly higher pressure, numerous bubbles form in the shape of cavitation "bubble clouds" that create lesions, closely matching their shape, in the target tissue after a sufficient number of pulses have been applied. Despite advances in histotripsy, additional research is still needed to better understand the initiation of the acoustic cavitation process in histotripsy and its effects on focused ultrasound therapies. This understanding is critical to better predict and control ablation procedures, improve procedure efficiency, reduce off-target cavitation events for safer focused ultrasound therapies, and further increase ablation precision for procedures near critical structures or treatments without active image guidance. In this dissertation, I investigate the initiation, growth, and collapse of ultrasonically generated acoustic cavitation for novel applications of focused ultrasound. My Ph.D. thesis focuses on (1) investigating the effect of histotripsy pulsing parameters on bubble cloud cavitation initiation, bubble growth and collapse, and treatment efficiency, (2) investigating the effect of particle characteristics on the threshold for cavitation initiation and resulting bubble behavior for therapeutic applications, and (3) adjusting pulsing parameters to optimize ablation efficiency in conventional and particle mediated histotripsy. The culmination of this thesis will advance our understanding of the initiation and behavior of acoustic cavitation from pulsed focused ultrasound and develop innovative systems to improve the efficacy, efficiency, and safety of clinically focused ultrasound therapies.

Peroxidase enzymes are of critical importance within the scientific community for their applications in biosensing assays. In a living system, natural peroxidases function as catalysts in the oxidation of peroxide (e.g., H2O2) - a harmful byproduct of aerobic processes and convert them into harmless compounds. Such an ability allows peroxidases to serve as labels in biosensing assays, where they are conjugated to antibodies and accurately produce a detection signal by catalyzing substrates. However, due to intrinsic limitations, namely instability, Peroxidase made of proteins substantially inhibit broader applications. Alternatively, nanoparticles produced from noble metals have been found to exhibit peroxidase-like abilities and, therefore, can be used as synthetic enzymes with the potential to replace their natural counterparts. Given that the stability of most peroxidase mimics is already much better than their natural counterparts, in this field, the principal challenge has been creating substantial improvements to the catalytic efficiency of the mimics. This study sought to create a cage-like nanostructure ( denoted as nanocages) consisting of two platinum group metals. This experiment uses Galvanic replacement as a mechanism to hollow all Nanocages formed. Galvanic replacement has been primarily demonstrated using coinage metals ( Ex. Ag and Au). This experiment seeks to show that this process is viable for other Nobel metals, as well. In particular, palladium cubes were used as scaffolds or sacrificed templates to induce the reaction with a precursor containing a secondary Nobel metal (Platinum, Rhodium, or Ruthenium). Once viable samples where produced and checked via TEM ( Transmission Electron microscope), the peroxidase-like activity was compared to the activity of a non-hollowed nanostructure of the same material composition using TMB colorimetric assay.

Electrolyte interactions with ligand functionalized gold nanoparticles (AuNPs) have broad implication to a wide range of applications in nanoparticle research field. Among a wide range of electrolytes, halides, nitrates, borohydrides, and sulfides are used to study the AuNP interfacial interactions. Although there are many studies on AuNP interactions with anionic species (halides, nitrates, borohydrides, and sulphides), there is limited information on AuNP interactions with metallic cations. Therefore, studying the nanoparticle interfacial interactions with both anionic and metallic cation species is highly important. The research reported here is focused on deepening the understanding of electrolyte interactions with ligand functionalized AuNPs in aqueous solutions. The stability of citrate-residues on AuNPs against ligand displacement has been controversial. In the first study, we demonstrated the direct experimental evidence for the simultaneous adsorption of both citrate-residues and solution impurities onto citrate-reduced AuNPs by using AuNPs synthesized with deuterated citrate in combination with the surface-enhanced Raman spectroscopic (SERS) analysis. The citrate-residues can be readily displaced from AuNPs by a wide range of specific and non-specific ligands including organosulfur and electrolytes. In the second study, we investigated the charge state and the mechanism of silver ion binding onto organothiol functionalized AuNPs. Mechanistic study reveals that silver binding onto AuNPs proceeds predominantly through reactive pathways with proton generations providing the first direct experimental evidence that Ag+ can disrupt the Au-S binding and enhance the mobility of the organothiols on AuNPs. Ligand displacement from AuNPs is important in a wide range of applications. Complete and non-destructive removal of ligands from AuNPs is important and challenging due to the strong Au-S binding and the steric hindrance imposed by ligand overlayer on AuNPs. In the final study, we investigated hydrogen sulphide (HS-), an anionic thiol as an effective ligand to induce complete and non-destructive removal of ligands from aggregated AuNPs. The new insights and methodologies presented in this dissertation are important for studying the electrolyte interfacial interactions with ligand functionalized AuNPs which have a broad impact on nanoparticle surface chemistry.

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