Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial

Cecilie Gjerde, Kamal Mustafa, Sølve Hellem, Markus Rojewski, Harald Gjengedal, Mohammed Ahmed Yassin, Xin Feng, Siren Skaale, Trond Berge, Annika Rosen, Xie-Qi Shi, Aymen B Ahmed, Bjørn Tore Gjertsen, Hubert Schrezenmeier, Pierre Layrolle, Cecilie Gjerde, Kamal Mustafa, Sølve Hellem, Markus Rojewski, Harald Gjengedal, Mohammed Ahmed Yassin, Xin Feng, Siren Skaale, Trond Berge, Annika Rosen, Xie-Qi Shi, Aymen B Ahmed, Bjørn Tore Gjertsen, Hubert Schrezenmeier, Pierre Layrolle

Abstract

Background: Autologous grafting, despite some disadvantages, is still considered the gold standard for reconstruction of maxillofacial bone defects. The aim of this study was to evaluate bone regeneration using bone marrow-derived mesenchymal stromal cells (MSCs) in a clinical trial, a less invasive approach than autologous bone grafting. This comprehensive clinical trial included subjects with severe mandibular ridge resorption.

Methods: The study included 11 subjects aged 52-79 years with severe mandibular ridge resorption. Bone marrow cells were aspirated from the posterior iliac crest and plastic adherent cells were expanded in culture medium containing human platelet lysate. The MSCs and biphasic calcium phosphate granules as scaffolds were inserted subperiosteally onto the resorbed alveolar ridge. After 4-6 months of healing, new bone formation was assessed clinically and radiographically, as were safety and feasibility. Bone at the implant site was biopsied for micro-computed topography and histological analyses and dental implants were placed in the newly regenerated bone. Functional outcomes and patient satisfaction were assessed after 12 months.

Results: The bone marrow cells, expanded in vitro and inserted into the defect together with biphasic calcium phosphate granules, induced significant new bone formation. The regenerated bone volume was adequate for dental implant installation. Healing was uneventful, without adverse events. The patients were satisfied with the esthetic and functional outcomes. No side effects were observed.

Conclusions: The results of this comprehensive clinical trial in human subjects confirm that MSCs can successfully induce significant formation of new bone, with no untoward sequelae. Hence, this novel augmentation procedure warrants further investigation and may form the basis of a valid treatment protocol, challenging the current gold standard.

Trial registration: EudraCT, 2012-003139-50. Registered on 21 August 2013. ClinicalTrials.gov, NCT 02751125 . Registered on 26 April 2016.

Trial registration: ClinicalTrials.gov NCT02751125.

Keywords: Alveolar ridge augmentation; Biphasic calcium phosphate; Bone regeneration; Bone tissue engineering; Dental implants; Mesenchymal stem cells.

Conflict of interest statement

This study conforms with the Declaration of Helsinki, and was approved by the Norwegian ethical committee (2013/1284/REK Vest, University of Bergen) and by the Norwegian Medicines Agency (13/12062-15; EudraCT 2012-003139-50). The clinical trial followed the European guidelines for advanced therapeutic medicinal products (https://ichgcp.net/clinical-trials-registry/NCT02751125).

All patients consented to participate in the clinical trial and to publish the data.

All authors consented to publication of this manuscript.

The authors declare that they have no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Cell attachment assay. A Syringes containing BCP granules (a) and MSCs (b). B Mixture of BCP and MSCs. C, D Cell attachment to biomaterial determined using DAPI staining after arrival at operating theater
Fig. 2
Fig. 2
Clinical procedure. a Narrow alveolar ridge before augmentation (arrow). b Mixture of BCP and MSCs placed on alveolar ridge. c Membrane placed over transplanted graft. d Soft tissue healing after 5 months. e New alveolar ridge after 5 months of healing. f Core biopsy taken and dental implant installed on newly formed bone. g Eight months post augmentation and 2 months after implant installation. h Implant-supported crown in occlusion
Fig. 3
Fig. 3
Cast of alveolar ridge. Before (a) and after (b) augmentation illustrating amount of bone reconstructed. Arrows indicate the width of the alveolar ridge
Fig. 4
Fig. 4
CBCT measurements. Overlapping of bone outline contours of superimposed models at T0 (before grafting, green) (a) and T1 (6 months after grafting, red) (b), achieved and viewed in axial (c), sagittal (d), and coronal (e) images of ridge before and after reconstruction
Fig. 5
Fig. 5
μ-CT and histological analyses. A μ-CT images of biopsies from Patients 1–10. B Histology of core biopsies from patients. Note abundant lamellar bone with entrapped osteocytes in extracellular matrix at high magnification around remaining BCP particles (*). a, c Hematoxylin and eosin staining, b, d Masson trichrome staining. Magnification ×1.25 and ×10
Fig. 6
Fig. 6
Ostell measurements. Implant installation (T0), at loading (T1), and at 18 months follow-up (T2). Data presented as mean ± SD showing increased implant stability after loading

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