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Mesenchymal Stem Cell Therapy for Osteoradionecrosis of the Mandible: a Systematic Review of Preclinical and Human Studies

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Abstract

Background

Osteoradionecrosis (ORN) of the mandible is a severe complication of radiotherapy for head and neck cancer and is arduously difficult to manage. Current treatment options carry risks with some patients remaining incurable. Mesenchymal stromal/stem cell (MSC) therapy has shown promising results supporting osteogenesis and regeneration of radiotherapy-damaged tissues. The aim of this study was to systematically review the literature on the safety and efficacy of MSCs in treating ORN.

Methods

A systematic search was performed on MEDLINE, Embase, Cochranes Library online databases, and clinicaltrials.gov to identify preclinical and clinical studies examining the effect of MSCs on osseous healing of ORN. The preclinical studies were assessed according to the SYRCLEs guidelines and risk of bias tool.

Results

Six studies (n = 142) from 5 countries were eligible for analysis. Of these four were preclinical studies and two clinical case studies. Preclinical studies found MSC treatment to be safe, demonstrating bone restorative effects and improved soft tissue regeneration. In the clinical cases, healing of bone and soft tissue was reported with no serious adverse events.

Conclusion

The evidence from the included studies suggests that MSCs may have beneficial regenerative effects on the healing of ORN. None of the studies reported adverse events with the use of MSCs. More carefully controlled studies with well-identified cells are however needed to demonstrate the efficacy of MSCs in a clinical setting.

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Acknowledgements

Thank you to librarian Jette Meelby at the health scientific library at Nordsjællands Hospital Hillerød, for help with preparation and development of the search string.

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Authors and Affiliations

  1. Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Anders Kierkegaard Gundestrup, Charlotte Duch Lynggaard, Kathrine Kronberg Jakobsen, Christian Grønhøj & Christian von Buchwald

  2. Department of Oral and Maxillofacial Surgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Lone Forner

  3. Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland

    Terhi J. Heino

  4. Department of Immunology, Cell Therapy Facility, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Anne Fischer-Nielsen

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  1. Anders Kierkegaard Gundestrup
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Contributions

AG, CDL, CG and CvB conceived the study design. AG, CL and LF were responsible for search preparation, literature search, article screening and selection. The initial draft of the manuscript was written by AG and CDL, and all authors critically revised the work. The final manuscript was read and approved by all authors.

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Correspondence to Christian von Buchwald.

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Appendix

Appendix

Advanced search strategy

The final search was conducted on the 25th of March 2020. The complete search strings can be found below. The MEDLINE search revealed 89 results, including MeSH terms. The EMBASE search revealed 128 studies including all paper types. These results were imported into Covidence.org 2020 review software for screening. The screening process flowchart can be seen in Fig. 1.

Cochrane Library was searched with fewer central keywords in order to identify reviews of interest. The keywords for condition were:

“osteoradionecrosis” OR “ORN” OR “Osteoradionecrosis of the jaw” OR “ORNJ” OR “ONJ”.

This search revealed five Cochrane reviews. None of these reviews investigated the use of mesenchymal stem/stromal cells as a possible treatment for osteoradionecrosis, and thus the included studies of the reviews were not included in our analysis. ClinicalTrials.gov was searched for all trials including the condition “osteoradionecrosis”. 14 results were found. Only one trial seemed to fit our inclusion criteria, and none of the exclusion criteria. However, in that study no results have been published, and the author did not respond to our inquiry.

Table 3 MEDLINE Search
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Table 4 Embase Search
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Gundestrup, A.K., Lynggaard, C.D., Forner, L. et al. Mesenchymal Stem Cell Therapy for Osteoradionecrosis of the Mandible: a Systematic Review of Preclinical and Human Studies. Stem Cell Rev and Rep 16, 1208–1221 (2020). https://doi.org/10.1007/s12015-020-10034-5

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