Measurement and Correlation of Acoustic Cavitation with Cellular and Tissue Bioeffects
Hallow, Daniel Martin
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Targeted intracellular delivery is a goal of many novel drug delivery systems to treat site-specific diseases thereby increasing the effectiveness of drugs and reducing side effects associated with current drug administration. The development of ultrasound-enhanced delivery is aimed at providing a targeted means to deliver drugs and genes intracellularly by utilizing ultrasound s ability to non-invasively focus energy into the body and generate cavitation, which has been found to cause transient poration of cells. To address some of the current issues in this field, the goals of this study were (i) to develop a measurement of cavitation to correlate with cellular bioeffects and (ii) to evaluate the ability of ultrasound to target delivery into cells in viable tissue. In addition, this study sought to exploit the shear-based mechanism of cavitation by (iii) developing a simplified device to expose cells to shear stress and cause intracellular uptake of molecules. This study has shown that broadband noise levels of frequency spectra processed from cavitation sound emissions can be used to quantify the kinetic activity of cavitation and provide a unifying parameter to correlate with the cellular bioeffects. We further demonstrated that ultrasound can target delivery of molecules into endothelial and smooth muscle cells in viable arterial tissue and determined approximate acoustic energies relevant to drug delivery applications. Lastly, we developed a novel device to expose cells to high-magnitude shear stress for short durations by using microfluidics and demonstrated the ability of this method to cause delivery of small and macromolecules into cells. In conclusion, this work has advanced the field of ultrasound-enhanced delivery in two major areas: (i) developing a real-time non-invasive measurement to correlate with intracellular uptake and viability that can be used as means to predict and control bioeffects in the lab and potentially the clinic and (ii) quantitatively evaluating the intracellular uptake into viable cells in tissue due to ultrasound that suggest applications to treat cardiovascular diseases and dysfunctions. Finally, by using shear forces generated in microchannels, we have fabricated a simple and inexpensive device to cause intracellular uptake of small and large molecules, which may have applications in biotechnology.