Musculoskeletal disorders like osteoarthritis (OA) increase pain and reduce quality of life for millions of people worldwide, with 8 million people seeking treatment in the UK and hospital expenditures over $40 billion in the US alone. As a progressive degenerative condition, it is critical to detect and treat OA early, but there are currently few reliable biomarkers. It is known that joint injury can lead to OA-development, but it is unclear how injury causes early tissue structural damage to develop at the nano- and microscale in the bone-cartilage unit – and lead to OA. This project will discover the key damage and deformation processes initiated at the nanoscale in the tissue matrix of the bone-cartilage unit during injurious mechanical loading, and the dose-response thresholds at which nanoscale damage occurs. We will analyse the structural changes induced by injurious loads in cartilage and bone tissue of diarthroidal joints, using high-resolution micro- and nanoscale imaging techniques like X-ray micro-computed tomography (mCT), small-angle X-ray scattering (SAXS) and cryo-scanning-electron microscopy. These will be correlated to cellular markers of injury and inflammation. By developing a micro-compression rig to image bone-joint loading during CT- and SAXS measurements, we will obtain multiscale measurements of tissue strain-concentrations, enabling detection for the first time of nanoscale structural damage and the correlation with OA. The project will use state-of-the-art imaging and analysis techniques at Diamond Synchrotron (Harwell) and at QMUL and our collaborators. The project will elucidate biomechanical mechanisms which will help to discover novel nanoscale damage signatures of OA.