[unreadable] Osteoarthritis (OA), or degenerative joint disease, is the most common form of joint diseases. It is a slowly progressing disease, and a major cause of morbidity in the population over 50, affecting more than 40 million Americans. It also imposes considerable expense on the health care system. While there is currently no cure for this disease, recent studies have shown that the progression of articular damage may be modified by medical or surgical intervention if the disease is detected early. These studies coupled with recent developments in gene therapy have generated substantial demand for noninvasive techniques for detecting early changes in the joints, when intervention is likely to have its greatest effect. X-ray radiography is excellent for imaging hard tissues and has been a routine modality for examining OA, primarily for advanced OA stages. The limitation of x-ray is its incapability for imaging soft tissues in the joints as well as its incapability for obtaining physiological information related to the functioning of OA. Diffuse optical tomography (DOT) is a promising method for detecting changes in cartilage and inflammation process in synovium. It can also provide information about the functioning and progression of OA. However, DOT has limited spatial resolution comparing to x-ray. To overcome this limitation, in this application we propose a combined x-ray/DOT approach so that we can use the x-ray images as structure guidance for DOT reconstruction. We aim to advance 3D DOT imaging of joint tissue co-registered with 3D x-ray tomosynthesis. Our specific aims include (1) investigation of several tomosynthetic reconstruction methods for 3D x-ray imaging, (2) development of algorithms for segmentation of 3D xray images, (3) development of 3D rendering environment, (4) advanced DOT reconstruction methods including automatic adaptive meshing scheme, parallel computing and a higher-order diffusion model, (5) design, construction and testing of a combined digital x-ray/optical imaging system for 3D imaging of joint tissue, (6) evaluation and optimization of this system using tissue phantom experiments, and (7) testing and evaluation of the combined xray/ optical imaging system in human subjects. If successful, the proposed mulfi-modality imaging method will have a major impact on the ability to make an early and appropriate therapeutic intervention, routinely monitor the progression/clinical outcome and assist in evaluating new treatment modalities. [unreadable] [unreadable]