Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Advances in imaging technologies have always been the major driving forces for the evolution of biomedical research. Compared with other modalities, optical imaging possesses several prominent merits. Because light interacts with tissue at the microscopic level through many distinct physical mechanisms, optical methods allow sensitive exploration of various aspects of the life down to the single-molecule level. From the technical perspective, optical systems utilize safe non-ionizing radiation, could be implemented at relatively low cost, also have the potential to be miniaturized for portable or endoscopic applications. As a result, optical imaging tools are playing an increasingly important role in both laboratorial research and clinical practice. Among them, photoacoustic imaging: PAI) and optical coherence tomography: OCT) are the two fastest growing branches. PAI measures the laser-induced acoustic wave, and produces high-resolution images of the optically absorbing features of tissue at multiple length-scales. OCT detects singly backscattered photons, and enables real-time high-resolution in vivo biopsy of tissue up to an optical transport mean-free-path. My doctoral research is focused on developing three novel optical imaging techniques based on the spirits of PAI and OCT. In the first part of this study, we established a new paradigm to visualize gene expression in vivo based on optical absorption. In the post-genomic era, we are now being challenged to develop novel molecular imaging methods to identify the functions of genes. PAI can detect specific molecules according to their characteristic absorption spectra, thus is a promising candidate for molecular imaging of gene expression. The full potential of photoacoustic molecular imaging still remains to be explored. For the first time, we demonstrated imaging gene expression by PAI in living mice and rats, using a chromogenic lacZ/X-gal reporter gene system. We demonstrated the expression of the lacZ reporter gene can be detected by PAI as deep as 5 cm inside tissue. In addition, we showcased that PAI could follow gene expression from the microscopic to the macroscopic level. This work represents one of the pioneering efforts to extend photoacoustic methods for molecular imaging. In the second part of this study, we developed a novel multimodal microscope, called the integrated photoacoustic and optical coherence microscope: iPOM), which combines PAI and OCT in a single imaging platform. PAI is predominantly sensitive to optical absorption, while OCT exploits optical scattering. By combining their naturally complementary imaging contrasts, iPOM can provide comprehensive information about biological tissue. We designed and built a reflection-mode prototype of iPOM, which fuses optical-resolution photoacoustic microscopy with spectral-domain optical coherence tomography. The potential applications of iPOM in studying cutaneous and ocular microcirculation, and tissue engineering were demonstrated. Finally, we invented a new optical tomography, named optical coherence computed tomography: optical CCT), which overcomes several major limitations of OCT. OCT relies on singly backscattered photons to obtain high-resolution images. Its image quality degrades fast with the increase of the depth, because the multiply scattered photons quickly become dominant at a penetration larger than 500 &mum. As a result, OCT can only effectively penetrate ~1 mm into highly scattering tissue like skin. In addition, OCT is mainly sensitive to optical scattering, which does not reflect the molecular content of tissue directly. Optical CCT measures both singly and multiply scattered photons using a low-coherence interferometer. We make use of both types of photons by adopting a model-based reconstruction algorithm. The light-tissue interaction model was established using the time-resolved Monte Carlo method. The optical properties of the tissue were reconstructed from measurements by solving the inverse radiative transport problem under the first Born approximation. As a result, optical CCT could image deeper than OCT, and provide extra molecule-specific contrasts, such as optical absorption. We designed and built the first optical CCT system. In experiments, absorbing inclusions of 100 &mum diameter were imaged with consistent quality through a 2.6-mm-thick: equivalent to ~3 transport mean-free-paths) tissue-mimicking phantom.
Li, Li, "Photoacoustic Reporter Gene Imaging And Optical Coherence Computed Tomography" (2010). All Theses and Dissertations (ETDs). 869.