The diagnosis of osteoarthritis (OA) is based on clinical, laboratory, and imaging findings. Although diagnostic imaging is widely practiced, observations gained through diagnostic imaging do not necessarily reflect the patient’s experience of pain, which is the most important presenting feature in the clinical syndrome of OA. In fact, studies have estimated that less than 50% of individuals with radiographic knee OA report knee pain. The determinants of pain in OA are not well understood, but multiple interactive pathways are involved including psycho-social and physical components. From a biological perspective, neuronal activity in nociceptive pathways is responsible for signal generation that is interpreted in the brain as pain. Extracellular acidification in tissues has been recognized for many years now as a major factor involved in pain. Protons can directly activate cation channels, such as acid-sensing ion channels (ASICs), and have become increasingly recognized over the past two decades as being involved in the initiation, modulation, and sensitization of pain messages. In fact, an acidic milieu alone, without structural tissue damage, is sufficient to decrease nociceptor threshold sensitivity and potentiate the pain matrix. Recently, a unique molecular imaging method, termed acidoCEST magnetic resonance imaging (MRI), was introduced. This MRI technique uses a clinically approved X-ray/computed tomography contrast agent as a probe to measure local extra-cellular pH through the chemical exchange saturation transfer (CEST) effect. Joints are ideal targets for the acidoCEST technique since relatively large volumes and concentrations of iodinated contrast are routinely and safely used during clinical arthrography. The acidoCEST-UTE sequence combines the acidoCEST technique with an ultrashort echo time (UTE) acquisition to quantify the pH-sensitive CEST effect in musculoskeletal structures with long T2 (including cartilage, synovium, and muscles) and short T2 (including menisci, ligaments, capsule, and tendons). A minimally-invasive method to measure extracellular pH could potentially provide a visual map of the chemistry involved in pain. In our first aim, we seek to optimize and accelerate the acidoCEST-UTE technique in phantoms and assess sensitivity to pH throughout a range of experimental conditions. In our second aim, we translate our technique to patients who will undergo total knee arthroplasty and to patients without knee pain. We hypothesize that our technique will provide a minimally-invasive method to measure extracellular pH and will provide superior correlations with clinical scores and immunohistochemical evaluation of ASICs compared with conventional structural MRI evaluation. Ultimately, successful execution of the proposed study will provide information on the nociceptive system in and around the joint, enable visualization of painful internal structures, and facilitate diagnostic and management decision-making in clini...