UC San Diego

Medical imaging requires the perturbation of biological tissues with external radiation. Clinically, acoustic and optical methods (e.g., ultrasonography, fluorescence imaging) are attractive because they are non-ionizing and offer real-time acquisition with high resolution. Photoacoustic imaging is an emerging hybrid modality that combines the contrast of optics with the penetration of ultrasound. This dissertation presents novel strategies for the detection of aberrant biomarkers through the application of high-frequency ultrasonography, optical methods (i.e., visible/near-infrared absorbance, fluorescence, scattering) and photoacoustic imaging, with primary focuses in periodontal disease and protease detection. First, the preclinical field of photoacoustic imaging is reviewed across various disease areas for image-guided therapy, surgery, and drug delivery. The second chapter describes research advances in photoacoustic imaging specifically for drug delivery. The third chapter reviews progress to date in photoacoustic imaging for dental and oral health applications. In the fourth chapter, the clinical value of high-resolution ultrasonography is demonstrated for noninvasive and chairside measurement of anatomic periodontal metrics in a pilot case control study. Next, this work is extended to imaging the periodontal pocket in a healthy human case study using photoacoustic imaging with a food-grade contrast agent. Chapter six describes the application of a modality-independent algorithmic method for reducing motion artifacts that commonly arise during 3D photoacoustic/ultrasound imaging of the oral environment. Chapter seven describes the chemical development of a modular and activatable contrast agent that produces photoacoustic and fluorescent signal upon proteolytic cleavage by leveraging the intramolecular coupling of dye-peptide conjugates. This work is validated with trypsin as a model protease and subcutaneous photoacoustic imaging of the probe in mice. In chapter eight, the design is honed for targeting proteolytic gingipains secreted by the periodontal pathogen, Porphyromonas gingivalis, with demonstrated photoacoustic imaging of the gingipain-activated probe in ex vivo swine jaws and fluorescent activation in gingival crevicular fluid samples collected from human subjects with periodontal disease. In chapter nine, the dissertation concludes with a foray into the characterization of protein aggregates associated with Alzheimer’s disease. It is demonstrated that multispectral nanoparticle tracking analysis can utilize light scattering at multiple wavelengths to measure the nanoscale distribution of amyloid-β aggregates (size and concentration) in vitro, without interfering dyes and in real time.