Current orthopaedic treatments permit spontaneous bone regeneration to unite and heal 90% bone injuries. Non-union associates pain and disability, often requiring biological enhancement. Regenerative medicine research suggests to the general public that alternative treatments based on advanced therapy medicinal products (ATMP) are already available. However, early clinical trials only explore its potential benefit. Underreported results and absence of early trial confirmation in adequately powered prospective randomized clinical trials (RCT) indicate that evidence is not available to transfer any technique into routine clinical application. This ORTHOUNION Project was developed from FP7-Project (REBORNE). Its results confirmed 92% bone healing rate (Gómez-Barrena et al, 2016 submitted manuscript) with an autologous ATMP of GMP expanded bone marrow derived human MSC in non-unions, where the reported bone healing rate after surgery with standard bone autograft is 74%. Any further development requires adequately powered prospective RCTs. This will be the main aim of ORTHOUNION: to assess clinically relevant efficacy of an autologous ATMP with GMP multicentric production in a well-designed, randomized, controlled, three-arm clinical trial under GCP, versus bone autograft, gold-standard in fracture non-unions. A non-inferiority analysis will evaluate if cell dose can be lowered. ATMP has been authorized by the National Competent Authorities of the participating countries in 3 previous trials (REBORNE) and will be monitored by ECRIN-ERIC to ensure quality and credibility of RCT results. Secondary aims include innovative strategies to increase manufacturing capacity and lower costs to pave translation into routine clinical treatments, biomaterial refinement to facilitate surgery, personalized medicine supportive instruments for patient selection and monitoring, and health economic evaluation. Results in this project may help define the future of bone regenerative medicin

Bone fracture with delay or failure to heal is a condition with huge health impact. Although only a small proportion of long bone fractures evolve to non-union (5%), it is a first magnitude problem due to the number of new annual fractures and increasing incidence of complex fractures with high risk of non-consolidation, need for repeated procedures and years of patient disability. Bone autografts, autologous mesenchymal cells, or other complex interventions are used in this setting. The aim of this project is the development of a universal therapy for fractures with delay or failure to heal, aiming to a simple and wide access to allogenic cell therapy combined with biomaterial, in a broad number of patients. Rather than considering ATMP only as a last solution in established non-union fractures, this project advocates that the indication should be moved to an earlier timepoint. Patients will be treated with the combined ATMP as soon as the need for reoperation is identified due to delayed healing, with or without an added infectious component, to avoid long-term suffering for patients and their relatives, and prevent progression to more severe non-unions, with heavy personal, social and economic costs. This approach is aligned with the real needs of patients and better fits with the usual practice in the EU, where reoperations are performed at 6 months or before, in an attempt to accelerate bone healing and avoid complications. The project will establish a master cell bank for a wide allogenic production with donors selection criteria of bone formation potential. Necessary preclinical and clinical information to support the EU approval of a specific combined ATMP will be obtained. Open access to scientific and regulatory information will be available for other EU medical device companies and cell therapy producers, so in addition to direct clinical benefit to patients and healthcare providers, other developers of combined ATMP products will get benefit.