UC Irvine

As one of the most sensitive in vivo molecular imaging modalities, fluorescence imaging has great potential to play an important role in preclinical and clinical studies. Indeed, in vivo fluorescence optical imaging extends across a wide range of applications, from cellular to organ levels. Unfortunately, in organ level applications, fluorescence imaging suffers from low spatial resolution due to the high scattering nature of biological tissue, especially in deep tissue (>1cm). Extensive effort has been spent to improve the spatial resolution of fluorescence tomography (FT). However, approaches such as integrating FT with other anatomic imaging modalities such as Magnetic Resonance Imaging (MRI) or computed tomography (CT) do not perform well if the fluorescent agent distribution within the medium cannot be defined in the anatomical image. There are also several techniques that attempt to modulate fluorescence signals using ultrasound to achieve higher spatial resolution. However, low modulation efficiency and extremely low signal to noise ratio (SNR) are the two primary factors that make the implementation of these techniques difficult.

Consequently, the poor spatial resolution and subsequent low quantitative accuracy are the main obstacles preventing the widespread use of this powerful technique in pre-clinical and clinical settings. To overcome these limitations, the goal of this thesis is to develop an entirely new approach termed, “Temperature-modulated fluorescence tomography (TM-FT)”, that can provide high resolution images at depths up to 6 cm without sacrificing the exceptional sensitivity of FT. In this innovative approach, FT is combined with temperature activatable fluorescence molecular probes (ThermoDots) and high intensity focused ultrasound (HIFU) which can provide localized heating of the tissue (only 3-5 °C) with high spatial resolution. The small size of the focal spot (~1.4 mm) allows imaging the distribution of these temperature sensitive agents with not only high spatial resolution but also high quantitative accuracy.

This thesis will present the development of the first TM-FT system prototype including the instrumentation and system design, image reconstruction algorithm, and ThermoDots probe development. The feasibility of this method to provide superior spatial resolution and high quantitative accuracy is validated using simulations and experimentally demonstrated in phantom and ex vivo tissue.