195. MELTING THE NANOSTRUCTURED LIPID SURFACE OF MICROBUBBLES TO INCREASE ULTRASOUND-MODULATED FLUORESCENCE FOR DEEP TISSUE OPTICAL IMAGING

Department: NanoEngineering
Faculty Advisor(s): Sadik Esener
Award(s): Rudee Outstanding Award | Department Best Poster

Primary Student
Name: Carolyn Elizabeth Schutt
Email: cschutt@ucsd.edu
Phone: 858-534-7607
Grad Year: 2013

Abstract
Optical imaging in a highly scattering medium is effective only at very shallow depths limiting its use for diagnostic imaging. By combining optical and acoustic modalities, high-contrast, physiologically-relevant optical information at higher spatial resolutions can be achieved. The main limitation is that tissue scattering results in poor signal-to-background ratios especially in deeper tissues. To overcome these challenges, we developed a novel microbubble contrast agent coated with phospholipid and surface-loaded with a self-quenching fluorophore. Upon ultrasound exposure, the microbubble expands and contracts, generating changes in the fluorophore surface density and producing a fluorescence intensity modulation ('blinking'). The modulation can be extracted from a strong non-modulated light background, increasing detection sensitivity. It was initially observed that <10% of the microbubbles showed the desired fluorescence modulation. To make this imaging scheme viable for in-vivo applications, this fraction must be increased to reduce the number of nonfunctional microbubbles. The microbubble surfaces were studied using structured illumination super-resolution microscopy to observe the structural distribution of lipids and surface-loaded lipophilic dye created through natural lipid partitioning. It was found that after manufacturing, the dye mostly partitioned into isolated islands less than 500 nm in size on the surface of the microbubble. Even though these microbubbles expanded and contracted upon ultrasound exposure, the islands remained tightly packed and failed to significantly change the quenching distance between fluorophores. The microbubble surfaces were heated to melt the lipid monolayer causing the fluorophores to distribute more evenly over the surface of the microbubble. Subsequent rapid cooling solidified the lipids in this distributed state. In contrast, slow cooling allowed the lipids time to reform the dense fluorophore islands. The melting and quick cooling process increased the fraction of modulating microbubbles to over 50%. The ability to optically image deep tissue effectively has important implications for cancer diagnosis, especially for breast cancer. Fluorescence imaging provides a safe, inexpensive means to analyze tumor-associated conditions including angiogenesis and hypoxia, potentially leading to substantially better diagnostic accuracy versus traditional x-ray mammography. This would enhance accurate early identification of malignant breast lesions, reducing the current number of false positive diagnoses and potentially preventing thousands of unneeded biopsies. The enhanced early detection diagnostic accuracy provided by this technology could lead to increased patient survival rates.

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