Alveolar bone tissue engineering in critical-size defects of experimental animal models: a systematic review and meta-analysis

Regeneration of large, 'critical-size' bone defects remains a clinical challenge. Bone tissue engineering (BTE) is emerging as a promising alternative to autogenous, allogeneic and biomaterial-based bone grafting. The objective of this systematic review was to answer the focused question: in animal models, do cell-based BTE strategies enhance regeneration in alveolar bone critical-size defects (CSDs), compared with grafting with only biomaterial scaffolds or autogenous bone? Following PRISMA guidelines, electronic databases were searched for controlled animal studies reporting maxillary or mandibular CSD and implantation of mesenchymal stem cells (MSCs) or osteoblasts (OBs) seeded on biomaterial scaffolds. A random effects meta-analysis was performed for the outcome histomorphometric new bone formation (%NBF). Thirty-six studies were included that reported on large- (monkeys, dogs, sheep, minipigs) and small-animal (rabbits, rats) models. On average, studies presented with an unclear-to-high risk of bias and short observation times. In most studies, MSCs or OBs were used in combination with alloplastic mineral-phase scaffolds. In five studies, cells were modified by ex vivo gene transfer of bone morphogenetic proteins (BMPs). The meta-analysis indicated statistically significant benefits in favour of: (1) cell-loaded vs. cell-free scaffolds [weighted mean difference (WMD) 15.59-49.15% and 8.60-13.85% NBF in large- and small-animal models, respectively]; and (2) BMP-gene-modified vs. unmodified cells (WMD 10.06-20.83% NBF in small-animal models). Results of cell-loaded scaffolds vs. autogenous bone were inconclusive. Overall, heterogeneity in the meta-analysis was high (I2 > 90%). In summary, alveolar bone regeneration is enhanced by addition of osteogenic cells to biomaterial scaffolds. The direction and estimates of treatment effect are useful to predict therapeutic efficacy and guide future clinical trials of BTE.