Early detection of cancer metastasis at a synthetic pre-metastatic niche using inverse spectroscopic optical coherence tomography


Cancer progression is a complex process, leading to metastatic spread of primary tumor cells that colonize distant vital organs and mortality if not stopped. Since clinical strategies to stem this progression are still being developed, it is of great importance to detect this end stage metastatic spread as early as possible when the burden of the disease is still manageable by currently available treatments. The pre-metastatic niche describes a local tissue microenvironment where changes in chemokine signaling and immune cell recruitment allow for homing to and metastatic colonization of a specific organ site. An emerging approach to detect metastasis at its earliest stages is through the use of an implanted biomaterial scaffold to mimic this pre-metastatic niche and recruit circulating metastatic cells, lessening metastatic burden in organs and allowing for minimally invasive detection at a subcutaneous location. Using inverse spectroscopic optical coherence tomography (ISOCT), a novel optical spectral tomographic imaging technique, changes in nanoscale structure of the scaffold site in mice have been measured and correlated with presence of metastatic disease. This dissertation describes the development of ISOCT for early detection of metastasis via measurement of the scaffold in vivo and elucidates the milieu of cancer-associated restructuring effects detected with this technique. Laboratory models of carcinogenesis determined ISOCT sensitivity to both extracellular matrix crosslinking and its subsequent effect on proliferative and structural phenotype of cancer cells. A dual-bandwidth ISOCT benchtop instrument and an ISOCT probe housed in a hypodermic needle were developed to address the challenge of imaging and measurement of a scaffold through the skin. Studies of scaffold structure determined increased cancer-associated fibrosis, dysregulated angiogenesis, and differences in scaffold-resident cell population and structure to be the prevailing changes in scaffold structure that allow for potential metastasis screening with ISOCT. Separate development and application of partial wave spectroscopic microscopy for gold nanoparticle imaging, tracking, and spectral analysis allowed for spectral classification of gold nanoparticles based on cellular internalization, with potential for future application to enhancing ISOCT contrast. Development of ISOCT measurement techniques and processing algorithms enabled novel application to imaging and measurement of optical, ultrastructural, and chemical properties in living corals.

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