After addressing all regulatory demands, the partners have obtained ethical and medicinal agency approvals to conduct a multi-centric randomised clinical trial across Europe through a voluntary harmonisation procedure in October 2019. Personal data protection led to the production and use of a secured web platform called electronic clinical research form (eCRF) that ensured monitoring, traceability and quality of the data according to clinical good practices.
The clinical study was sponsored by the University of Bergen and conducted in 6 clinical centres in Bergen, Norway, APHP Créteil and CHU Nantes in France, UA Madrid and UIC Barcelona in Spain and the University Hospital of Southern Denmark. The clinical centres were all open in February 2020, ready to recruit patients. However, the restrictions of the COVID-19 pandemic have dramatically delayed the inclusion of patients and obliged the suspension of the clinical trial for a period of 10 months.
Despite the COVID-19 restrictions, the clinical centres could transport bone marrow to the manufacturing centres where they could produce and ship, with an accompanied person, the ATMPs within Europe. Autologous MSCs were expanded in culture with human platelet lysate. After 2 weeks of culture, autologous MSCs were harvested, quality controlled and transported to the clinical centres where they were associated with a synthetic bone substitute to be grafted in edentulous areas.
Overall 60 patients have been included, 17 coming from UiB-HUH (Bergen, Norway), 8 in UCM (Madrid, Spain), 8 in CHU-NANTES, France, 8 in UIC (Barcelona, Spain), 12 in AP-HP (Paris, France) and 6 in SDU (Denmark). From this population, 42 patients were randomised to the test group and 17 to the test group according to a ratio test:control of 2:1. Mean age for patients was similar with 55.9 years and 62.1 years in the control and in the test group, respectively (p>0.05). 38 patients (27 in the test group and 11 in the control group) went the bone augmentation surgery. Adverse effects were reported in 3/38 patients, but none was related to the cell therapy procedure.
After 5 months of bone augmentation and healing, new bone formation was assessed clinically, radiographically and by histology of bone biopsies. All measurements were done by one specialist in oral radiology at UiB in Bergen.
After surgery, there were statistically significant differences between groups in terms of post-surgery total length of reconstructed areas with 22 mm and 18 mm for test and control group respectively (p=0.019 Mann-Whitney test). Both test and control regenerative surgical interventions have provided a significant increase in bone width over time at the level of the defect (p<0.05). The histology of biopsies demonstrated vertical newly formed bone in all the augmented areas. 21 out of the 60 included patients have undergone the final visits of implant placement, 5 months after bone augmentation procedure (10 in the control group and 11 in the test group). All patients had sufficient bone for dental implant installation. Some of these patients have successfully received prosthetic dentures restoring function and aesthetic prosthetic rehabilitation.
Cell manufacturing partners (EFS, UULM) have continued to improve and to standardise the manufacturing process. They have tested automated bioreactors in order to decrease production costs.
In addition to perform the clinical trial, the partners have collaborated with the SME Mimetis Biomaterials to produce personalised biomaterial scaffolds by 3D printing from medical images. These 3D scaffolds together with human stem cells have been tested in rodents. Bone regeneration with anatomy fitting 3D scaffolds and stem cells was also demonstrated in a large animal model of mandibular bone augmentation.
The European project MAXIBONE has therefore demonstrated the safety and efficacy of cultured autologous MSCs and biomaterials as an alternative to bone grafting. MAXIBONE has addressed limitations and advancements in cell-based therapies by optimising current methodologies and standard operating procedures in all stages of treatment from bone marrow harvest to MSCs culture, loading onto biomaterials and clinical applications.
