CAREER: Evaluating the distribution of bubble nuclei for acoustic cavitation in tissues

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A major concern in every ultrasound application, such as fetal imaging, is acoustic cavitation (the creation, oscillation, and collapse of bubbles in an ultrasound field) because bubbles can damage tissues. In clinical ultrasound imagers, the risk is lessoned by requiring machines to display the mechanical index, which is a measure of the likelihood of cavitation. Yet therapeutic applications of ultrasound make use of acoustic cavitation to break kidney stones or destroy cancerous tissues. Acoustic cavitation arises from nucleation of bubbles, but no one understands what constitutes a bubble nucleus in human tissues and how these bubble nuclei might be influenced by certain diseases that deposit minerals in tissues. Thus, the overall goals of the project are to understand what constitutes a bubble nucleus in healthy tissues and to develop ultrasound to sensitively detect changes in bubble nuclei that occur when minerals are deposited in tissues. This research will provide a basis for developing an interactive classroom activity kit specifically designed to enhance the scientific interest and literacy of children, as well as educate graduate students from all disciplines on scientific communication and outreach, thereby increasing the societal impact of this work beyond what one scientist or lab can do on their own.The Investigator’s long-term career goal is to become a leader in bubble nucleation and acoustic cavitation in biological tissues. Toward this goal, the goal of this CAREER project is to improve the safety of diagnostic and therapeutic ultrasound by determining where bubble nuclei exist in tissues for acoustic cavitation. Using a combination of experimentation and modeling, the Research Plan is organized under three objectives. The FIRST Objective is to evaluate the distribution of bubble nuclei that can undergo acoustic cavitation in healthy biological structures (rat skeletal muscle, hepatocyte, and mammary cells) with varying hydrophobicity and mechanical properties. Studies are designed to test the hypothesis that acoustic cavitation will occur predominantly extracellularly, with increased acoustic cavitation occurring in a mechanically malleable extracellular matrix. Expected results include: 1) identification of whether bubble nuclei exist predominantly intracellularly or extracellularly in 2D and 3D cell culture; 2) evaluation of the effects of mechanical properties in collagen gels and decellularized extracellular matrix on the distribution of bubble nuclei; and 3) an improved metric for the likelihood of cavitation based on a bubble dynamics and fracture model. The SECOND Objective is to determine the effect of biomineralization on the distribution of bubble nuclei for diseases including atherosclerosis (cholesterol crystals), gout (uric acid crystals), heterotopic ossification (calcium phosphate) and breast microcalcifications (calcium oxalate). Studies are designed to test the hypothesis that all forms of pathological biomineralization will have stabilized crevice microbubbles isolated to the surface of the minerals. Expected results include: 1) an understanding of the distribution of bubble nuclei on lab-grown crystals; 2) an evaluation of the effects of surface tension on the distribution of bubble nuclei in lab-grown crystals; and 3) a determination of how the mineral deposition by cells in pathological biomineralization influence the distribution of bubble nuclei. The THIRD Objective is to develop the color Doppler ultrasound twinkling artifact for sensitive detection of mineral deposition through acoustic cavitation. The distribution of bubble nuclei in healthy and mineralized tissues from the first two objectives will be leveraged to improve the color Doppler ultrasound twinkling artifact for detection of all forms of mineralization including gout, atherosclerosis, heterotopic ossifications, breast microcalcifications and kidney stones. Studies are designed to test the hypothesis that crystal composition and the surrounding environment will influence the Doppler imaging protocols for optimal detection of each form of pathological biomineralization. Expected results include: 1) Doppler imaging protocols to enhance twinkling specific to each identified form of pathological biomineralization and 2) prediction of the crystal composition from the raw Doppler ultrasound signals. The results from this fundamental research will provide the first connection between all forms of pathological biomineralization – namely that stabilized crevice microbubbles are present after mineralization occurs and may even cause cells to revert to the diseased or mineral-depositing state.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.