Stem cell therapy for craniofacial bone regeneration: a randomized, controlled feasibility trial

Abstract

Stem cell therapy offers potential in the regeneration of craniofacial bone defects; however, it has not been studied clinically. Tissue repair cells (TRCs) isolated from bone marrow represent a mixed stem and progenitor population enriched in CD90- and CD14-positive cells. In this phase I/II, randomized, controlled feasibility trial, we investigated TRC cell therapy to reconstruct localized craniofacial bone defects. Twenty-four patients requiring localized reconstruction of jawbone defects participated in this longitudinal trial. For regenerative therapy, patients were randomized to receive either guided bone regeneration (GBR) or TRC transplantation. At 6 or 12 weeks following treatment, clinical and radiographic assessments of bone repair were performed. Bone biopsies were harvested and underwent quantitative micro-computed tomographic (μCT) and bone histomorphometric analyses. Oral implants were installed, subsequently restored, and functionally loaded with tooth restorations. Reconstructed sites were assessed for 1 year following therapy. No study-related, serious adverse events were reported. Following therapy, clinical, radiographic, tomographic, and histological measures demonstrated that TRC therapy accelerated alveolar bone regeneration compared to GBR therapy. Additionally, TRC treatment significantly reduced the need for secondary bone grafting at the time of oral implant placement with a five fold decrease in implant bony dehiscence exposure (residual bone defects) as compared to GBR-treated sites(p < 0.01). Transplantation of TRCs for treatment of alveolar bone defects appears safe and accelerates bone regeneration, enabling jawbone reconstruction with oral implants. The results from this trial support expanded studies of TRC therapy in the treatment of craniofacial deformities (ClinicalTrials.gov number CT00755911).

Trial registration: ClinicalTrials.gov NCT00755911.

Figures

Figure 1

Trial profile and consort diagram. (A) Trial timeline. (B) Consort diagram of patient distribution. μCT, micro-computed tomography; BVF, bone volume fraction; BMD, bone mineral density.

Figure 2

Tissue repair cells (TRCs) promote regeneration of alveolar bone defects. (A) Digital radiographic images of linear bone height density measures for guided bone regeneration (GBR) and TRC groups at the time of tooth extraction (baseline) and 6 weeks after treatment. (B) Standardized digital radiography (SDR) was used to assess linear changes in radiographic bone height from baseline to 6- and 12-week time points. In the baseline images (A), the (orange) lines show the full extent (height) of the original defect, created following extraction of the tooth. In the 6-week images, the (green) lines show the extent (height) to which there was radiographic bone fill. These heights were calculated and the linear length of the bone fill was determined by calculating the percentage of the original defect which was filled with radiographic evidence of bone. (C) Clinical photographs of the defect site created immediately following removal of the tooth, at reentry into the site 6 weeks following treatment, and 12 months following treatment after full restoration of the site with an oral implant supported crown. (D) In some patients, residual bony defects were noted at the time of reentry into the defect sites, and in other patients, remaining bone deficiencies were identified during implant placement. There was significantly greater implant exposure in those patients receiving GBR versus those patients receiving TRCs (p < 0.04). (E) Micro-computed tomographic and histomorphometric analyses. Micro-CT and histological evaluation (H&E staining) of bone formation in a representative specimen from a GBR-treated site and a TRC treated site 6 weeks following treatment (original magnification: 2×). Both sections show varying degrees of mature cortical bone with high vascularity, as indicated by the abundance of blood vessels. Bone volume fraction (BVF), bone mineral density (BMD), and histomorphometric measures were quantified and compared between TRC and GBR treated sites at 6 and 12 weeks.

Figure 3

In vitro TRC characteristics and clinical regeneration outcomes. The in vitro osteogenic potential [alkaline phosphatase (AP)-fold induction, top] and extracellular matrix mineralization (von Kossa staining, bottom) of each TRC population was correlated with its clinical capacity to form bone in vivo [as measured by BMD (mg/cc) and BVF]. Statistically significant differences (p < 0.05) were noted between BMD and osteogenic differentiation, while nonsignificant differences were found between mineralization and BMD/BVF.