DESCRIPTION (provided by applicant): This BIRT project should integrate novel cellular imaging technologies, developed through our parental R01 project, with an advanced understanding of the pathogenesis of corticosteroid-induced osteonecrosis through our new co-investigator Dr. Sakamoto (Professor of Pediatrics) and new stem cell therapies for osteonecrosis, developed by our new co-investigator Dr. Goodman (Professor of Orthopedic Surgery). Therapy-induced osteonecrosis is a major source of morbidity in patients with leukemia and lymphoma. Recently, surgical core decompression coupled with delivery of bone marrow derived stem cells has shown promising results to repair the necrotic bone. The overall goal of our BIRT project is to utilize cell tracking tools, developed by our parent R01 grant, for n vivo detection of stem cell transplants in osteonecrotic bone and to correlate stem cell engraftment with bone regeneration outcomes. In a bench-to-bedside approach, we propose to use the FDA-approved iron supplement ferumoxytol to label mesenchymal stem cells (MSC) in the bone marrow of patients before a decompression surgery, and then follow the engraftment of bone marrow derived MSC after transplantation into osteonecrotic bone with serial MR imaging studies. We hypothesize that MR tracking of stem cells in osteonecrotic bone will enable differentiation of successful and failed cell therapies, as determined by reconstitution or progressive collapse of the affected bone. This will enable in vivo detection of complications of the engraftment process at a point in evolution, which is early enough for repeated surgeries or other corrective actions. Results will help to establish an immediately clinically applicable imaging test for early detection of MSC graft failure and generate important feasibility data for clinical translation of stem cell tracking technologies. Since we address a generalized novel concept of image-guided therapy, results might not only impact patients with stem cell transplants for osteonecrosis treatment but also patients with a variety of other stem cell therapies.

PUBLIC HEALTH RELEVANCE: There are currently about 380,000 survivors of childhood cancer and 126,752 survivors of childhood leukemia and lymphoma. 15-47% of these patients develop an osteonecrosis as a result of high dose corticosteroid therapy. Through a new collaboration with pediatric oncologists and orthopedic surgeons, we propose to utilize cell tracking tools, developed through our parent R01 grant, to monitor new stem cell therapies for the treatment of corticosteroid-induced osteonecrosis in cancer survivors. In a bench-to-bedside approach, we propose to use the FDA-approved iron supplement ferumoxytol to label bone marrow derived mesenchymal stem cells (MSC) before their transplantation into osteonecrotic bone, and then follow MSC engraftment with serial magnetic resonance imaging studies. This immediately clinically applicable stem cell imaging test could become a powerful technology to diagnose success or failure of stem cell transplants in osteonecrotic bone in patients, monitor engraftment non-invasively and predict bone repair outcomes.