PROJECT SUMMARY / ABSTRACT The healthcare burden of fractures is exacerbated for patients who suffer from non-unions and delayed unions. Prediction of non-unions and development of new therapies stimulating bone growth is challenged by a lack of quantitative, non-invasive tests to simultaneously assess the two primary aspects of bone healing: (i) mineral density of the callus and fracture gap; and (ii) mechanical stability under weight-bearing. To address this challenge, we proposed to use a novel extremity cone-beam CT system (CBCT) that provides a unique capability of weight-bearing 3D imaging at high spatial resolution. This will allow measurement of the motion of bone fragments by estimating their displacement between weight-bearing and non-weight-bearing scans of the extremity. In addition, much like conventional CT, CBCT can perform bone mineral density (BMD) measurements of the fracture. To enable quantitative weight-bearing assessment of fracture repair on extremities CBCT, artifacts and image nonuniformity due to metal fixation hardware must be mitigated. The scientific premise of this work is that the effects of metal hardware can be minimized by a combination of novel Dual Energy (DE) techniques suitable for extremities CBCT and advanced model-based image reconstruction (MBIR) incorporating prior knowledge of the surgical hardware. DE imaging will provide a robust correction of the attenuation value inaccuracy due to beam hardening. Efficient, single-scan implementation of DE CBCT will be achieved using the innovative multi-source configuration on the extremities CBCT scanner. The Known-Component Reconstruction algorithm (KCR) will be used to address metal-induced photon starvation and nonlinear partial volume effects by exploiting prior knowledge of the shape and pose of the metal component. Inherent in this approach is a component registration step that will provide a precise estimate of implant deformation under weight-bearing, resulting in a novel approach to asses fracture stability. The following specific aims will be pursued: 1) Enable Dual Energy CBCT from multi-source CBCT data by means of an novel DE MBIR algorithm and optimized DE imaging protocols to yield detection of ~5% relative change in bone mineral density in phantoms; 2) Integrate prior knowledge of surgical hardware in MBIR DE reconstruction by exploiting accurate (~0.5 mm Target Registration Error) deformable 3D-2D registration of fracture fixation hardware to estimate component pose and deformation; 3) Perform clinical translation of the Known-Component DE algorithms in implanted cadaveric extremities under controlled load and in pilot patient study. Fracture patients will be imaged at 2, 4, 8 and 12 weeks post-fracture to demonstrate detection of changes in callus mineralization during fracture repair. This research will establish an innovative quantitative imaging approach for simultaneous, non-invasive assessment of two primary biomarkers of fracture repair: mi...