Abstract

Effectiveness of ultrasound-and-microbubble mediated therapy depends on the acoustic response of microbubbles. In this study, the acoustic response of microbubbles in the absence and presence of cells is measured using integrated cavitation dose (ICD) over harmonics/ultraharmonics/broadband, and correlated with intracellular uptake of a fluorescent marker for varying peak-negative-pressures (PNPs). The ICD was independent of presence of cells. A PNP-threshold of 0.64 MPa was observed for microbubble’s inertial cavitation; stable cavitation (PNPs<0.64MPa) and inertial cavitation (PNPs≥0.64MPa) regimes were identified. Within inertial cavitation regime, a stronger correlation (R2>0.9) was observed between the ICD and FITC-positive cells, whereas, a weaker correlation, ranging from R2=0.59 at 3rd ultra-harmonic to R2 = 0.85 at 2nd ultra-harmonic, was observed under stable cavitation regime. The intracellular uptake, ICD and their correlation is dependent on microbubbles cavitation regime, indicating that ICD shows potential to predict bio-effects induced not only by inertial cavitation but also by stable cavitation of MBs.

Highlights

  • I would like to express my sincere gratitude to my supervisor, Dr Raffi Karshafian, who pushed me to be a better researcher and showed me how to apply my knowledge beyond the scope of academics

  • The acoustic behaviour of Definity® MBs was characterized in the absence and presence of cells at varying peak negative pressures (PNPs) using passive cavitation detection (PCD)

  • Acoustic response of MBs depends on the PNP and tends to shift from stable to inertial cavitation with increasing PNP

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Summary

CHAPTER 1: INTRODUCTION

Microbubbles (MBs), currently utilized clinically as ultrasound contrast agents in diagnostic applications, are shell encapsulated gas filled bubbles with less than 5 μm in diameter (Kiessling et al, 2012). Cavitation activities of a population of MBs under USMB therapeutic conditions and in the presence of cells may be different from that of a single MB in water alone or in the absence of cells. MBs emit harmonic and ultra-harmonic energy during stable cavitation and a broadband spectrum upon inertial cavitation (Hoff, 2001). Such cavitation activities of MBs has been quantified using Integrated Cavitation Dose (ICD), which was correlated with bio-effects (Lai et al, 2006; Chen et al, 2003). USMB induced intracellular uptake of a fluorescent molecule will be measured and correlated with stable and inertial cavitation of MBs. MBs’ acoustic response will be measured using Passive Cavitation Detection (PCD) method and quantified using Integrated Cavitation Dose (ICD) over the harmonics, ultra-harmonics, and broadband spectra

ULTRASOUND (US) PHYSICS
Ultrasound interaction with matter
MICROBUBBLES (MBs)
CHARACTERIZATION AND QUANTIFICATION OF MBs’ CAVITATION ACTIVITIES
US AND MBs MEDIATED THERAPEUTIC APPLICATIONS
THESIS OUTLINE
CHAPTER 2: MATERIALS AND METHODS
IN VITRO CELL MODEL
CELL PERMEABILITY
DEFINITY®, MICROBUBBLE AGENT
USMB EXPERIMENTAL SETUP
Data Acquisition
Inertial Cavitation PNP-threshold
CHAPTER 3: RESULTS
CHARACTERIZATION OF DEFINITY® MBs IN THE ABSENCE AND PRESENCE OF CELLS
EFFECTS OF PNP ON THE INTRACELLULAR UPTAKE
CORRELATION BETWEEN THE ICD OVER A RANGE OF FREQUENCIES AND INTRACELLULAR UPTAKE
MB ACOUSTIC BEHAVIOR IN THE ABSENCE AND PRESENCE OF CELLS
INTRACELLULAR UPTAKE AT VARYING PNPs
CORRELATION BETWEEN THE ICD AND INTRACELLUAR UPTAKE
Findings
CONCLUSIONS, FUTURE WORK AND LIMITATION
Full Text
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