Stem Cell Therapy for Bone Regeneration in Maxillofacial and Orthopaedic Surgery

The clinical trial is an interventional study designed as a phase II using advanced therapy medicinal product (ATMP) aiming to evaluate of the efficacy, safety, and tolerability of the clinical single local application of autologous bone marrow mesenchymal stem cells (MSC) combined with biphasic calcium phosphate (BCP) granules as bone replacement graft in patients with jaw atrophy, before dental implant placement. Adult patients, of both genders aged 18 years or above were, therefore, recruited based on the criterion of having vertical and lateral loss of alveolar bone volume (width less than 4 mm), where the placement of a dental implant could not provide adequate primary stability. Our preliminary data from 20 patients included in study showed that MSC combined with biomaterials induce the formation of new bone. Interestingly, the outcome measures as healing and bone volume monitored and evaluated by cone beam CT (CBCT), µCT and histology clearly demonstrated formation of the new bone with good quality and quantity enabling us to install dental implants. The present study is the first to address systemic immune profiling in humans, after transplantation of MSC and biomaterial (BCP) construct for bone regeneration. We employed liquid biopsy to study safety and immune efficacy of autologous bone marrow MSC therapy. Blood samples from the patients enrolled in the study were collected and used after informed consent to evaluate the response/course of cell therapy by characterizing the grafted MSC in terms of safety, immunomodulation, and role in new bone formation. For this purpose, Mass cytometry is used as a high throughput method of immune phenotyping at single cell level. The preliminary data indicates a role of circulating MSC and immune tolerance during MSC-driven bone regeneration. A report has been published in a PhD thesis which was defended recently at the University of Bergen in Norway (Neha Rana 2023). A manuscript is under construction.

The potential and value of cell-based therapies was explored in the early 90th when therapeutically relevant cells as MSC were applied for the regeneration of skeletal tissue. By using MSC, good results have been reported for bone repair in limited number of clinical case reports. However, production of MSC for clinical applications requires adhering to Good Manufacturing Practices (GMP) to ensure the product safety and efficacy. This is a complex and often expensive process that starts from the qualification of the starting material, the definition of the culture process and of the quality controls to be applied in the final product. The project is aimed at development of an innovative system for cell production testing growth factors and including directly the biomaterial in a compact novel bioreactor system. We propose to culture MSC in close automated bioreactor systems without or with the synthetic biomaterials in order to produce a 3D bone graft substitute with a minimal costs and maximum safety. This will lead to evolution of cell production and reduction of the costs. Further, Phase I/II clinical trials will be performed aiming to assess the safety and effectiveness of bone marrow derived autologous MSCs delivered with an alloplastic scaffold and covered with a resorbable barrier membrane, for restoring bone. This new interventional therapy will be compared retrospectively if the use of MSC and biomaterial as bone grafting engineered construct is equally good or better than the gold standard of bone augmentation, i.e. the autologous bone graft. The project will allow merging the new innovative diagnostic concept, liquid biopsy, with a cutting edge technology, mass cytometry which will be employed to monitor the cells both during the preclinical as well as the clinical trials. The data generated will enable us to characterize cellular systems and disentangle rare cells in heterogeneous tissues such as blood in ways that previously have not been possible.