| Summary: | <p> Cerenkov luminescence (CL) is optical radiation induced by fast, charged, particles. In the biomedical setting, it is produced by all PET radionuclides and by radiotherapy beams.</p><p> The work presented in this dissertation, spanning some five years, has sought to both investigate the utility of Cerenkov luminescence imaging (CLI) in the biomedical setting and to push the boundaries by inventing ultrasound-modulated Cerenkov luminescence imaging (USCLI), a modality that potentially mitigates the scattering limit of resolution for CLI. </p><p> Clinical applications of CLI have focused on evaluating the potential of Cerenkov luminescence as a tool for guidance during brain tumor resection. Monte Carlo simulations of a brain phantom, along with an experimental analysis scheme, were developed to recapitulate a tumor margin assessment task. The brain phantom has optical properties derived from real brain tissues, and the simulation accounts for all physics of nuclear decay, charged particles, and optical photon propagation. The relative merits of the Cerenkov luminescence signal have been compared with other decay signals in the context of an intraoperative detection task. Considering two surgically-feasible implementations, imaging with a sensitive camera or intraoperative probe, CL objectively provides the most sensitive signal when the tumor remnant resides at superficial (<2 mm) depths. </p><p> CL-activated photodynamic therapy (PDT) was quantitatively explored, and progress was made toward resolving the quantitative dissonance between extraordinary published results and expected required dosimetry. Published <i> in vivo</i> results, which purport to positively demonstrate CL-activated PDT, are at least six orders of magnitude below the therapeutic threshold for PDT dosimetry. The results herein suggest that CL is unlikely to be the driver of the observed therapeutic results, and the mechanism behind these surprising results merits further investigation.</p><p> Finally, both the theory and instrumentation for USCLI, a new, high resolution imaging modality, were developed. USCLI uses ultrasound to modulate the CL signal and thereby shift the resolution-dependence from tissue optical properties to those of the ultrasound beam. Monte Carlo simulations were performed and positively demonstrate higher resolution CLI in a scattering media. Instrumentation to experimentally demonstrate and quantify ultrasound modulation of Cerenkov luminescence imaging were developed and characterized.</p><p>
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