Expanded autologous MSCs and biomaterials in non-unions: a European clinical trial
Philippe Rosset1,2, Philippe Hernigou3, Florian Gebhard4, Christian Ehrnthaller4, Nicola Baldini5, Enrique Gomez Barrena6, Pierre Layrolle1.
1Lab. Pathophysiology of bone resorption, Inserm U957, Nantes, France; 2Orthopedic and trauma surgery, CHRU Tours, Tours, France; 3Orthopedic and trauma surgery, APHP Hopital Henri Mondor, Créteil, France; 4Orthopaedic Trauma surgery, Ulm University, Ulm, Germany; 5Orthopedic and trauma surgery, Istituto Ortopedico Rizzoli, Bologna, Italy; 6Orthopedic and trauma surgery, UAM-Hospital La Paz, Madrid, Spain
Introduction: Bone is the most transplanted tissue in human with about 1 million procedures annually in Europe. Autologous bone grafting is the gold standard in bone regeneration but it requires a second surgery, is limited in quantity and often associated with painful complications. Synthetic calcium phosphate biomaterial in association with mesenchymal stem cells may be a potent alternative to autologous bone grafting. However, a definitive proof of clinical efficacy is lacking on mesenchymal stem cell (MSCs) therapy to regenerate bone. In this study, a prospective, multicenter, multinational Phase I/IIa interventional clinical trial was conducted under the EU-FP7 REBORNE Project to evaluate safety and early efficacy of autologous expanded MSCs loaded on biomaterial in non-union fractures.
Materials and Methods: The clinical trial (EudraCT 2011-005441-13) was sponsored by INSERM and included 30 recruited patients among 5 European centres in France, Spain, Germany, and Italy. Patients have diaphyseal and/or metaphysodiaphyseal fractures (femur, tibia, humerus) with non-union at 6 months. Starting from a bone marrow aspirate, several hundred millions of mesenchymal stem cells (MSC) were produced in 3 weeks in a culture medium containing human blood platelet lysate plasma. Cultured MSCs from autologous bone marrow was the Investigational Medicinal Product standardized in GMP facilities. After transportation, these cells were mixed for 60 min with biphasic calcium phosphate (BCP, CE and FDA approved, Biomatlante, France) granules in the surgical room at a dose of 20×106 cells per cm3 of biomaterial (total 200×106 MSC/10 cm3 per case). Autologous MSCs attached on the BCP granules were implanted at the fracture site in a single administration, after debridement of the non-union. Safety endpoints were determined by local and general complication rates and graded pain scores assessment. Early efficacy was controlled by determining the number of patients with clinically and radiologically proven bone healing at 12 and 24 weeks post-surgery.
Results and Discussion: On the basis of safety and efficacy demonstrated in several animal models,, this multi centre clinical trial has been approved by Medicinal agencies and Ethical committees in France, Germany, Spain and Italy in March 2013. Of 30 recruited patients, 28 patients received the treatment and completed the protocol up to 24 weeks. As shown in Figure 1, a closed diaphyseal femoral fracture due to a motorbike accident in 2009 was diagnosed non-union with associated pain. After debridement, autologous MSC/BCP was grafted at the fracture site. After 3 months, a callus was observed on radiographs. After 6 months, the patient had no pain with full weight and radiographs confirmed consolidation. Overall, no adverse effects related to cell therapy were detected. Two superficial infections associated to musculoskeletal flaps were solved with antibiotics. No pain with clinical consolidation was confirmed in 23/27 cases (85 %) at 6 months. Preliminary efficacy results with RX imaging corroborated 16/27 consolidations (59%) at 3 months. At 6 months, 20/26 consolidations (77%) were confirmed. One failure underwent reoperation at 6 months.
Figure 1: Radiographs of a non-union closed diaphyseal femoral fracture due to a motorbike accident and treated with autologous MSC/BCP. Note the fracture consolidation at 6 months.
Conclusions: This study reports evidence of bone regeneration of non-union fractures with autologous expanded MSC and BCP biomaterial in a multi centre European clinical trial. Preliminary results confirm feasibility, safety and efficacy at 3 and 6 months with the described procedure. Results seem comparable to autologous bone grafting.
Acknowledgements: Funding for this research was received from the European Commission Seventh Framework Programme (Grant agreement n° 241879) through the “Reborne” project.