Autologous stem cells as a promising therapeutic approach for augmentation of alveolar bone
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The current gold standard for reconstructive bone surgery is based on autologous bone grafts. However, the risk of complications at both the donor and recipient sites is considerable. There is therefore a need to explore alternative methods of bone regeneration which will restore a defect to full functionality and meet esthetic demands. Nowhere is this a greater challenge than in reconstruction of defects in the orofacial region. Preliminary data, from limited in vitro and in vivo studies, indicate that bone marrow-derived MSC have potential application in bone tissue regeneration. However, interpretation of these studies is complicated by lack of conformity with respect to cell type (expanded or native), culture medium, source of growth factors, expansion time, cell dose and other variables. Moreover, biopsies are required to confirm the osteogenic capacity of the implanted cells and this has not been done routinely. In most studies to date, follow-up has been limited to radiographs, which do not allow differentiation between bone tissue formed by the implanted cells and by the native cells from the border of the osseous defect. The question also remains as to whether the presence of any new bone should qualify as clinical success, or whether a successful outcome requires evidence of new bone formation at the center of the regenerated area. With respect to culture and expansion of MSC for bone tissue engineering, a further issue has arisen, namely the exclusion of animal-derived products from culture medium, requiring a human-derived source of growth factors to replace FBS. The work presented in this thesis was undertaken in order to develop and validate each step in a standardized protocol for expanding autologous MSC in vitro in a GMP-compliant facility (Study II). The expanded MSC produced by this protocol were then applied in a phase I/II clinical trial of restoration of the mandibular alveolar ridge in 11 patients. The surgery was carried out by one experienced oral surgeon (Study III). The same surgeon also undertook the post-operative follow-up, with standardized patient evaluations at each appointment. Bone regeneration was confirmed in all 11 patients, as evidenced by radiographs and biopsies taken at installation of all 21 dental implants. All the implants osseo-integrated. All patients considered the outcomes to be satisfactory, with minimum pain and no morbidity. In a retrospective study of 59 patients who had undergone advanced alveolar ridge reconstruction in accordance with the current gold standard procedure, using autologous bone grafts (Study I), patient satisfaction and OHRQoL among participants was favorable. Despite their overall satisfaction with the outcome, these patients reported significant pain and morbidity. Furthermore, procedures based on autologous grafts from the iliac crest require substantial resources including hospitalization and sick leave. The following conclusions are drawn from this series of studies. Firstly, a standard protocol has been established for GMP expansion of autologous human MSC, using PL as a source of growth factors instead of FBS. Secondly, fresh autologous MSC can be manufactured, expanded and applied in bone regeneration, despite considerable geographic distance between the cell production facility and the clinical center. Thirdly, this protocol was successfully applied for alveolar ridge bone regeneration in 11 patients, with clinical outcomes comparable to those achieved using grafted autologous bone, recovered surgically from a second site. Although patient satisfaction with the new protocol was no different from the standard approach, those treated according to the new protocol reported low pain and morbidity. The results of the comprehensive trial confirm that bone marrow mesenchymal stem cells can successfully promote bone regeneration, with no unexpected adverse events and minimal pain. Hence, this novel augmentation procedure warrants further investigation. It has the potential to form the basis of a new therapeutic approach which may challenge the current gold standard.
Has partsPaper I: Gjerde C, Shanbhag S, Neppelberg E, Mustafa K, Gjengedal H. Patient experience following iliac crest-derived alveolar bone grafting and implant placement. Int J Implant Dentistry 2020; 6:4. The article is available in the main thesis. The article is also available at: https://doi.org/10.1186/s40729-019-0200-8
Paper II: Rojewski M, Lofti R, Gjerde C, Mustafa K, Veronesi E, Ahmed A, Wiesneth M, et al. Translational of a standardized manufacturing protocol for mesenchymal stromal cells: A systematic comparison of validation and manufacturing data. Cytotherapy 2019; 21:468-482. The article is available in the main thesis. The article is also available at: https://doi.org/10.1016/j.jcyt.2019.03.001
Paper III: Gjerde C, Mustafa K, Hellem S, Rojewski M, Gjengedal H, Yassin M, Feng X, et al. Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial. Stem Cell Res Ther 2018; Aug 9;9(1):213 DOI: 10.1186/s13287-018- 0951-9. The article is available in the main thesis. The article is also available at: https://doi.org/10.1186/s13287-018-0951-9