Chronic pain afflicts more than 50 million American adults and costs our nation an estimated $560 to $635 billion annually. Complex regional pain syndrome (CRPS) represents one of the most disabling and difficult-to- treat chronic pain conditions in clinical practice. Management of CRPS is one of the greatest challenges in the field of pain management. Novel and more efficacious treatment strategies are urgently needed to relieve the burden of pain, suffering, and disability caused by CRPS. To address this unmet need, we propose to develop a first-in-class, mechanism-guided, and cell-based treatment for CRPS using human mesenchymal stem cells (hMSCs). Based upon strong biological rationale and ample supporting data, we hypothesize that hMSC transplantation significantly improves the symptoms and distinctly modifies the disease processes of CRPS through neuroimmune-modulatory and analgesic effects of MSCs. In this bench-to-bedside translational investigation, we aim to generate clinical-grade hMSCs derived from the bone marrow, adipose, and umbilical cord tissues, to optimize hMSC treatment protocols in terms of source and dose of hMSCs, and to gain Investigational New Drug (IND) approval for clinical trials. We further aim to conduct a pilot clinical trial to determine the safety and efficacy of hMSC therapy in reducing pain and improving function in patients with CRPS. As an architype of neuropathic pain (NP) and a prototype of a new type of autoimmunity, CRPS is an ideal disease to study for innovative strategies to treat NP. The use of hMSCs represents a golden opportunity to treat CRPS and to advance this technology to human patients, which is strongly supported by our published and preliminary data. This project is innovative because the use of MSCs to treat CRPS has never been studied. We propose novel experimental designs to optimize the source and dose of MSC therapy through synergistic preclinical and clinical trials to determine the scientific rationale for future MSC treatment clinical trial protocols. The proposed pilot clinical trial represents the first-in-class and mechanism-guided human trial of a novel MSC treatment not only for CRPS, but also for other NP conditions. We will use the novel and sensitive in vitro assays we have developed to assess the neuroimmune modulatory properties of hMSCs, to serve as a measure of quality control, and to predict clinical outcomes of hMSC therapy. Our interdisciplinary team with complementary expertise in stem cell biology, pain management, pre-clinical testing, and outcomes research, is uniquely positioned to successfully implement this project. Successful completion of the project will deliver a safe, efficacious, non-addictive, and cost-effective treatment for patients with refractory CRPS. By addressing the unmet needs of CRPS patients through bench-to-bedside translation, this novel therapy promises to be a game- changer that would fundamentally shift the paradigm in the management of CRP...