ABSTRACT The ability to perform dynamic imaging of time-varying physiological processes in small animal models is critically needed to understand the progression of human disease and develop new therapies. Although dynamic imaging methods have been used to evaluate tumor vascular perfusion in small animal models, the available methods typically provide only two-dimensional (2D) spatial imaging, lack the precision needed for quantitative measurements, or suffer from other drawbacks. Photoacoustic computed tomography (PACT) can circumvent the limitations of existing methods and has been recognized as a promising tool for dynamic small animal imaging. By exploiting the optical absorption of hemoglobin or exogeneous contrast agents, dynamic PACT holds great potential for measuring important time-varying biomarkers such as tumor vascular perfusion and oxygenation and improving the assessments of anti-cancer and other therapies. While exciting, current dynamic PACT technologies for small animal imaging still possess several fundamental limitations. Many biological models require true 3D spatial imaging of time-varying physiological processes. However, most of the available dynamic PACT technologies have been designed to rapidly image two-dimensional (2D) slices. While fully 3D PACT imagers are available, most employ a tomographic measurement process in which a gantry containing acoustic transducers is rotated about the animal. This presents unmet challenges for dynamic image reconstruction because only a small number of tomographic views is available to reconstruct each temporal image frame. Moreover, the ability of the available image reconstruction methods to produce quantitatively accurate estimates of the wavelength-dependent optical properties of an object is largely unproven. For dynamic PACT to be established as a transformative preclinical imaging modality, there remains an urgent need for accurate new image reconstruction methods that can be deployed with widely available 3D imagers that use rotating gantries. The broad objective of this project is to directly address these challenges by developing novel and advanced dynamic PACT image reconstruction methods that permit both four-dimensional (4D) imaging (3D space + time) and five-dimensional (5D) multi-spectral imaging (3D space + time + wavelength). This will be game-changing and will enable, for the first time, high-resolution and quantitatively accurate 4D and 5D whole-body PACT imaging of small animal models with widely available PACT imagers that utilize rotating gantries. The specific aims of the project are: Aim 1. To develop 4D image reconstruction methods for dynamic PACT; Aim 2. To develop 5D image reconstruction methods for dynamic PACT; Aim 3. To refine and validate the proposed methods using well-characterized phantoms; Aim 4. To demonstrate and validate the proposed reconstruction methods in in-vivo studies.

PUBLIC HEALTH RELEVANCE STATEMENT The ability to perform dynamic imaging of time-varying physiological processes in small animal models is critically needed to understand the progression of human disease and develop new therapies. This research will transform photoacoustic tomography into what has been promised for several decades—a quantitative imaging modality for dynamic functional and molecular imaging. The developed computational technologies will find widespread application in preclinical medicine and have immediate and sustained positive impact on preclinical science.