Co-registration of Bioluminescence Tomography and Anatomical Imaging Modalities for Cell Tracking and Source Quantification

Bioluminescence tomography (BLT) is a molecular imaging tool that provides three-dimensional, quantitative reconstructions of bioluminescent sources in vivo. A main limitation of BLT to date, however, has been a lack of validation and demonstrated utility in preclinical research. An approach employing a fusion of BLT with other, well-established imaging modalities was used in this work to validate results obtained with BLT and improve the performance of source quantification. In the first chapter of this thesis, a method was developed to co-register BLT to magnetic resonance (MR) and computed tomography (CT) anatomical data for tracking cell transplants using a specialized animal holder. Using a luciferase-expressing tumor model in mice, MRI was shown to be superior at locating cells while BLT provided a more sensitive measure of cell proliferation. A multimodal approach incorporating BLT can therefore provide a better understanding of cell dynamics in vivo in preclinical research than with anatomical imaging alone. In the second chapter of this thesis, anatomical MRI and CT images were segmented to provide hard spatial priors to quantify the power of calibrated luminescent sources implanted in mice. To do this, a finite element (FEM) implementation of the diffusion approximation was used as a forward model for light propagation and validated through a phantom experiment. Source powers quantified using hard prior information showed a 65% reduction in average deviation compared to traditional BLT using four spectral bins and comparable performance to eight bins. BLI imaging times using hard spatial priors were reduced by 16-fold and 100-fold compared to the four- and eight-bin BLT methods, respectively. Together with the results of the first chapter, these results show value in incorporating data from other imaging modalities into BLT

Co-Registration of Bioluminescence Tomography, Computed Tomography, and Magnetic Resonance Imaging for Multimodal In Vivo Stem Cell Tracking

We present a practical approach for coregistration of bioluminescence tomography (BLT), computed tomography (CT), and magnetic resonance (MR) images. For this, we developed a customized animal shuttle composed of nonfluorescent, MR-compatible Delrin plastic that fits a commercially available MR surface coil. Mouse embryonic stem cells were transfected with the luciferase gene and labeled with superparamagnetic iron oxide nanoparticles. Cells were stereotaxically implanted in the mouse brain and imaged weekly for 4 weeks with bioluminescent imaging (IVIS Spectrum CT scanner) and magnetic resonance imaging (MRI; 11.7 T horizontal bore scanner). Without the use of software coregistration, in vitro phantom studies yielded root-mean-square errors of 7.6 × 10−3, 0.93 mm, and 0.78 mm along the medial–lateral (ML), dorsal–ventral (DV), and anterior–posterior (AP) axes, respectively. Rotation errors were negligible. Software coregistration by translation along the DV and AP axes resulted in consistent agreement between the CT and MR images, without the need for rotation or warping. In vivo coregistered BLT/MRI mouse brain data sets showed a single diffuse region of bioluminescent imaging photon signal and MRI hypointensity. Over time, the transplanted cells formed tumors as histopathologically validated. Disagreement between BLT and MRI tumor location was greatest along the DV axis (1.4 ± 0.2 mm) than along the ML (0.5 ± 0.3 mm) and the AP axes (0.6 mm) because of the uncertainty of the depth of origin of the BLT signal. Combining the high spatial anatomical information of MRI with the cell viability/proliferation data from BLT should facilitate preclinical evaluation of novel therapeutic candidate stem cells