Osteoarthritis (OA) is a common debilitating and painful disease with a high prevalence in the U.S.. Because pain is the most prominent symptom of OA, it is unfortunate that there are no consistently effective OA pain treatments devoid of deleterious consequences, leaving surgery as the only long-term option. Cyclooxygenase products such as prostaglandin E2 appear to play a prominent role in the pain associated with acute injury and the early stages of OA, given the analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs). However, there is a general loss of efficacy of these drugs with time. These observations serve as the basis for the central hypothesis of this proposal, which is that the mediators underlying chronic OA pain are distinct from those underlying acute OA pain and involve plasticity in both the afferents innervating the joint as well as the tissues within the joint. In this new study, the Lin team and collaborators propose to add neural cells to innervate bone, synovium and fat pad in the tissue chip to enable the pain-relevant studies, in particular the identification of mechanisms underlying pain as it transitions from the acute to chronic state.