To enhance the functional image-guided capabilities in preclinical radiotherapy research, we developed fluorescence tomography (FT) and integrated it with a commercial bioluminescence tomography (BLT) system for small animal irradiators. We devised a novel method to achieve submillimeter accuracy in mapping the excitation sources and fluorescence data to the imaged animal surface. We expect to achieve approximately 1 mm accuracy in 3D target localization for in vivo tumor model. The multi-model FT/BLT-guided system will provide advanced image-guided capabilities to enhance preclinical radiotherapy research, particularly in cases where radiation is combined with other systemic treatments, thus expanding its applications beyond local therapy.
Bioluminescence tomography (BLT), as an available image-guided system for pre-clinical radiotherapy research, can localize in vivo tumors within high localization accuracy but it is still challenging to recover accurate structure information due to optical diffusion and ill-posed inverse problem. Recognition of this challenge led us develop novel reconstruction method, optimized spectral-derivative compressive sensing conjugate gradient algorithm. We will perform simulation and in vivo experiments to test BLT’s performance in reconstructing the target location and shape both in primary tumor or metastatic setting. We expect that our BLT-guided system will provide investigators quantitative tumor imaging to perform high precision radiation research.
The challenge to study radiotherapy for pre-clinical pancreatic ductal adenocarcinoma(PDAC) is lack of image-guided system providing strong soft-tissue contrast. Bioluminescence imaging is an attractive solution, but it is inadequate to localize movable PDAC at single projection. With these targeting uncertainties, large radiation beam is commonly used. Therefore, we innovated bioluminescence tomography(BLT) to guide conformal irradiation for PDAC. Our BLT could retrieve orthotopic PDAC volume within 0.5-2mm accuracy at 2-6mm depth, even tumor located at various locations at given study days. Our BLT offers unique opportunities to localize PDAC for conformal irradiation, reduce normal tissue toxicity, and therefore increase study reproducibility.
Significance: Bioluminescence imaging and tomography (BLT) are used to study biologically relevant activity, typically within a mouse model. A major limitation is that the underlying optical properties of the volume are unknown, leading to the use of a “best” estimate approach often compromising quantitative accuracy.
Aim: An optimization algorithm is presented that localizes the spatial distribution of bioluminescence by simultaneously recovering the optical properties and location of bioluminescence source from the same set of surface measurements.
Approach: Measured data, using implanted self-illuminating sources as well as an orthotopic glioblastoma mouse model, are employed to recover three-dimensional spatial distribution of the bioluminescence source using a multi-parameter optimization algorithm.
Results: The proposed algorithm is able to recover the size and location of the bioluminescence source while accounting for tissue attenuation. Localization accuracies of <1 mm are obtained in all cases, which is similar if not better than current “gold standard” methods that predict optical properties using a different imaging modality.
Conclusions: Application of this approach, using in-vivo experimental data has shown that quantitative BLT is possible without the need for any prior knowledge about optical parameters, paving the way toward quantitative molecular imaging of exogenous and indigenous biological tumor functionality.
A novel algorithm to simultaneously recover bioluminescence source location and optical parameters is developed. In-vivo studies show 30% improvement in localization error while also providing local total hemoglobin concentration.
While CBCT provides excellent guidance capability, it is less adept at localizing soft tissue targets growing in a low image contrast environment. To advance image-guided irradiation for soft tissue targets, we developed quantitative bioluminescence tomography(QBLT) for small animal radiation research platform(SARRP). We presented a comprehensive approach to systematically tackle the challenging of BLT for in vivo target delineation, quantify its uncertainties in localization, and demonstrate the practicality for radiation guidance. Our QBLT-guided system provides a unique opportunity for investigators to guide conformal irradiation for soft tissue targets. The accurate image-guidance is expected to increase rigorous and reproducibility of scientific discovery.
Genetically engineered mouse model(GEMM) that develops pancreatic ductal adenocarcinoma (PDAC) offers an experimental system to advance our understanding of radiotherapy (RT) for pancreatic cancer. Cone beam CT (CBCT)-guided small animal radiation research platform (SARRP) has been developed to mimic the RT used for human. However, we recognized that CBCT is inadequate to localize the PDAC growing in low image contrast environment. We innovated bioluminescence tomography (BLT) to guide SARRP irradiation for in vivo PDAC. Before working on the complex PDAC-GEMM, we first validated our BLT target localization using subcutaneous and orthotopic pancreatic tumor models. Our BLT process involves the animal transport between the BLT system and SARRP. We inserted a titanium wire into the orthotopic tumor as the fiducial marker to track the tumor location and to validate the BLT reconstruction accuracy. Our data shows that with careful animal handling, minimum disturbance for target position was introduced during our BLT imaging procedure(<0.5mm). However, from longitudinal 2D bioluminescence image (BLI) study, the day-to-day location variation for an abdominal tumor can be significant. We also showed that the 2D BLI in single projection setting cannot accurately capture the abdominal tumor location. It renders that 3D BLT with multipleprojection is needed to quantify the tumor volume and location for precise radiation research. Our initial results show the BLT can retrieve the location at 2mm accuracy for both tumor models, and the tumor volume can be delineated within 25% accuracy. The study for the subcutaneous and orthotopic models will provide us valuable knowledge for BLTguided PDAC-GEMM radiation research.
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