Diffuse optical tomography (DOT) and fluorescence molecule tomography (FMT) are emerging as important optical imaging tools for clinical and biomedical research. Two major outstanding challenge in DOT and FMT are i) the relatively low imaging resolution, which results from the high degree of photon scatter through biological tissue, and ii) the difficulty to image multiple fluorescent targets in deep tissue (“multiplexing”) due to the relatively narrow wavelength region within which light is less attenuated and effectively transmitted through bulk tissue.
In this dissertation, we explored the use of time-domain DOT and FMT imaging to address these problems. First, time-resolved (TR) measurement of early arriving photons from a pulse laser was studied as a method for improving resolution in diffuse optical imaging. The underlying concept is photons that arrive first (“early”) at a detector from a pulsed laser incident on bulk tissue have experienced fewer scattering events and taken relatively straight paths. We developed and tested a time-domain diffuse optical imaging system consisting of a femetosecond titanium: sapphire laser and fast, single photon avalanche photodiode (SPAD) detectors, that had an extremely fast temporal response time of 59 ps. We validated that the SPAD allowed measurement of photon-density sensitivity function that were 65\% narrower than the temporally un-gated case at very early times. This exceeded the performance achieved previously with photomultiplier-based systems and approached the theoretical maximum predicted by time-resolved Monte Carlo simulations. Following this work, we then developed a complete SPAD-based DOT scanner, in which an array of SPADs were used. We validated performance of the system in cylindrical and irregular shaped optical phantoms of approximately small animal size. We were able to accurately reconstruct the size and position of up to 4 absorbing inclusions in diffusive media for the first time, with increasing image quality at earlier times.
Next, we developed a time-resolved multiplexed fluorescence tomography system, which allowed us to measure extremely rich multi-spectral and temporal fluorescence data sets from diffusing media. In combination with a recently developed two-stage de-mixing and image reconstruction algorithm we are able to concurrently image as many as four (and in theory 5) red and near-infrared fluorophores with closely overlapping spectral and temporal profiles, doubling the information throughput of FMT systems. This instrument also allowed us to account for the wavelength-dependency of optical properties in bulk biological tissue, which is a major challenge in biological imaging. The unique multiplexing imaging capabilities of this technology will be promising to study multiple biological targets or activities simultaneously in a variety of application, such as tumor imaging, anticancer treatment, drug research, etc.
Advisor: Professor Mark Niedre
Professor Mark Niedre
Professor Charles DiMarzio
Professor Qianqian Fang