Abstract Osteoarthritis (OA) is one of the most prevalent diseases in the US, affecting over 50 million Americans with an annual cost of more than $60 billion per year. The major public health issues associated with OA are likely to become even more important as our society ages. OA is considered a whole joint disease with pathologic changes that often involve all of the constituent joint tissues. Of increasing interest is the region of the osteochondral junction (OCJ), which encompasses the tissues between the deep uncalcified layers of cartilage and the marrow spaces of the trabecular bone. It includes the deep radial uncalcified cartilage, tidemark, calcified cartilage (CC), and subchondral bone (SCB) plate. While these tissues are avascular in the normal joint, in OA, osteoclasts are activated and form channels through the subchondral bone plate, allowing blood vessels and nerves to extend from the marrow into deep cartilage. This is associated with a cascade of abnormalities, including local inflammation and upregulation of metalloproteinase activity, extracellular matrix degradation, reduction of cartilage load-bearing capacity, and degenerative change. The OCJ may change dramatically in OA, and these changes may be relevant in its pathogenesis. Magnetic resonance imaging (MRI) is widely used to directly and non-invasively evaluate articular cartilage and plays an important role in the clinical diagnosis and treatment of OA. However, MRI of the OCJ region is difficult due to the short mean transverse relaxation times (i.e., short T2 or T2*) of deep radial uncalcified articular cartilage, calcified cartilage, and subchondral bone, which result in little or no signal when conventional pulse sequences are used. In this study we aim to develop 3D adiabatic inversion recovery prepared ultrashort echo time Cones (3D IR-Cones) techniques for direct volumetric morphological imaging and quantitative mapping of the OCJ, to validate the signal sources, and finally develop translational 3D IR-Cones techniques for OCJ imaging in vivo. In Aim 1 we will further develop and validate 3D IR-Cones techniques for morphological and quantitative imaging of the OCJ in osteochondral samples from cadaveric human knee joints (n=10). We will investigate the effect of spatial resolution, long T2 suppression, RF power, and gradient strengths, as well as T1, T2*, and proton density weightings in OCJ imaging on a 3T Bruker small-bore scanner and a clinical 3T scanner, respectively. We will correlate morphological and quantitative Cones findings with µCT and histology. In Aim 2 we will develop translational 3D IR-Cones techniques for morphological and quantitative imaging of the OCJ in knee joints of healthy volunteers (n=10) and patients subject to total knee replacement (n=10). The excised osteochondral samples from relatively normal (n=10) and more degenerated regions (n=10) will be re-scanned with clinical and 3D IR-Cones sequences, followed by µCT imaging and histo...