Bone is the most frequently transplanted tissue with about 1 million procedures annually in Europe. Autologous bone transplantation is the primary procedure for regenerating large bone defect in patients, but is limited in quantity and leads to complications at the second surgical site. Bone tissue engineering that associates mesenchymal stem cells (MSC), synthetic scaffolds and molecular signals may become an alternative to bone grafts in orthopaedic and maxillofacial surgery. The objectives of the European project REBORNE are to perform clinical trials using cultured cells and advanced biomaterials triggering bone healing in patients. Four clinical studies aiming at demonstrating the safety and efficacy of this advanced therapy medicinal products (ATMPs) have been approved in several European Countries and are currently underway. Pre-clinical studies that have supported the approval of these trials will be presented. After receiving informed consent from patients, 30 ml of bone marrow was aspirated from the iliac crest. MSC were cultured in medium containing human platelet lysate. After 3 weeks of culture, cell therapy units were capable of producing about 400 million of clinical grade MSC. The culture conditions and quality controls were standardised to ensure the consistency of the ATMP across European blood transfusion centres. The optimal MSC dosage for bone formation was first determined by implantation of biphasic calcium phosphate (BCP) granules in ectopic sites of nude mice. MSC/BCP achieved ectopic bone formation with bone marrow territories. Cells of both host and human origin contributed to bone formation. The dose was then scaled up to clinically relevant sizes and transportation of fresh MSC was validated. Bioactivity and engraftment were also studied by bioluminescence imaging (BLI) of Luciferase expressing MSC and in situ hybridization using the human-specific repetitive Alu sequence. Critical sized bone defects were successfully repaired in skull of mice, femurs of rats and metatarsus of sheep using MSC and BCP. MSC were produced, transported, mixed with BCP biomaterial and implanted, mimicking the clinical scenario where large bone defects are regenerated. To date, 28 patients with non-union long bone fractures and 14 patients with osteonecrosis of the femoral head have been successfully treated in France, Spain, Germany and Italy.
Disclosure: The authors declared no competing interests. This work was supported by the grant (HEALTH-2009-1.4.2-241879) from the 7th Framework Programme of the European Commission (www.reborne.org).