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Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial.

Servicio de Cirugía Ortopédica y Traumatología, Hospital Universitario La Paz-IdiPAZ and Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: enrique.gomezbarrena@uam.es. Service de Chirurgie Orthopédique et Traumatologique 2, Hôpital Trousseau, Université François-Rabelais de Tours, CHU de Tours, Tours, France. Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany. Orthopaedic Department, Hôpital Henri Mondor, InsermU955 and UPEC (University Paris-Est, Créteil), Créteil, France. Laboratory for Orthopaedic Pathophysiology and Regenerative Medicine, Istituto Ortopedico Rizzoli, and Dept. of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Orthopaedic Department, Hôpital Henri Mondor, InsermU955 and UPEC (University Paris-Est, Créteil), Créteil, France; Établissement Français du Sang, Paris, France. Établissement Français du Sang, Paris, France; STROMA Lab, UMR5273-INSERM U1031, Toulouse, France. Servicio de Hematología, Hospital Universitario Puerta de Hierro-Majadahonda, and Universidad Autónoma de Madrid, Madrid, Spain. Cell Factory, Center for Cellular Therapy and Cryobiology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy. Servicio de Cirugía Ortopédica y Traumatología, Hospital Universitario La Paz-IdiPAZ and Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. Victor Babes University of Medicine and Pharmacy, Timisoara, Romania. Laboratory of Cellular Therapies, Department of Medical and Surgical Sciences for Children & Adults, University - Hospital of Modena and Reggio Emilia, Modena, Italy. Institut for Transfusion Medicine, Ulm University, Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service and University Hospital Ulm, Ulm, Germany. INSERM U957, Lab. Pathophysiology of Bone Resorption, Faculty of Medicine, University of Nantes, Nantes, France.

Biomaterials. 2019;:100-108
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Abstract

BACKGROUND ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. METHODS Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. FINDINGS With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). INTERPRETATION Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. FUNDING EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).

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