A WNT protein therapeutic accelerates consolidation of a bone graft substitute in a pre-clinical sinus augmentation model.

AIM: Autologous bone grafts consolidate faster than bone graft substitutes (BGSs) but resorb over time, which compromises implant support. We hypothesized that differences in consolidation rates affected the mechanical properties of grafts and implant stability, and tested whether a pro-osteogenic protein, liposomal WNT3A (L-WNT3A), could accelerate graft consolidation. MATERIALS AND METHODS: A transgenic mouse model of sinus augmentation with immunohistochemistry, enzymatic assays, and histology were used to quantitatively evaluate the osteogenic properties of autografts and BGSs. Composite and finite element modelling compared changes in the mechanical properties of grafts during healing until consolidation, and secondary implant stability following remodelling activities. BGSs were combined with L-WNT3A and tested for its osteogenic potential. RESULTS: Compared with autografts, BGSs were bioinert and lacked osteoprogenitor cells. While in autografted sinuses, new bone arose evenly from all living autograft particles, new bone around BGSs solely initiated at the sinus floor, from the internal maxillary periosteum. WNT treatment of BGSs resulted in significantly higher expression levels of pro-osteogenic proteins (Osterix, Collagen I, alkaline phosphatase) and lower levels of bone-resorbing activity (tartrate-resistant acid phosphatase activity); together, these features culminated in faster new bone formation, comparable to that of an autograft. CONCLUSIONS: WNT-treated BGSs supported faster consolidation, and because BGSs typically resist resorption, their use may be superior to autografts for sinus augmentation.

Interspecies comparison of alveolar bone biology: Tooth extraction socket healing in mini pigs and mice.

BACKGROUND: in an effort to identify and validate which animal models are best suited for dental implant research, we used multiscale analyses to examine tooth extraction wound healing in a well-accepted model, the Yucatan mini pig and a more controversial model, the laboratory mouse. METHODS: first molar extractions were performed in adult, skeletally mature mini pigs and mice. Alveolar bone repair was evaluated at early, intermediate and late timepoints using quantitative micro-computed tomographic (µCT) imaging, histology, molecular, and cellular assays. Vital dye labeling was employed to quantify mineral apposition rates (MAR) in both species. RESULTS: Despite a 3000-fold difference in weight, the relative proportions of the mini pig and murine maxillae and are equivalent. Quantitative µCT demonstrated that within the posterior alveolar bone, the volume of mineralized bone was lower in mini pig than in the mice; during healing, however, the bone volume fraction was equivalent. The histologic appearance of healing sites was also comparable, and alkaline phosphatase (ALP) and tartrate resistant acid phosphatase (TRAP) staining showed a similar temporal and spatial distribution of bone remodeling. Vital dye labeling indicated equivalent MAR between the species. The absolute duration of the healing period differed: in mice, complete healing was accomplished in ∼21 days. In mini pigs, the same process took four times longer. CONCLUSIONS: Extraction socket healing is histologically equivalent between mini pigs and mice, supporting the hypothesis that the underlying mechanisms of alveolar bone healing are conserved among species.

An osteopenic/osteoporotic phenotype delays alveolar bone repair.

Aging is associated with a function decline in tissue homeostasis and tissue repair. Aging is also associated with an increased incidence in osteopenia and osteoporosis, but whether these low bone mass diseases are a risk factor for delayed bone healing still remains controversial. Addressing this question is of direct clinical relevance for dental patients, since most implants are performed in older patients who are at risk of developing low bone mass conditions. The objective of this study was to assess how an osteopenic/osteoporotic phenotype affected the rate of new alveolar bone formation. Using an ovariectomized (OVX) rat model, the rates of tooth extraction socket and osteotomy healing were compared with age-matched controls. Imaging, along with molecular, cellular, and histologic analyses, demonstrated that OVX produced an overt osteoporotic phenotype in long bones, but only a subtle phenotype in alveolar bone. Nonetheless, the OVX group demonstrated significantly slower alveolar bone healing in both the extraction socket, and in the osteotomy produced in a healed extraction site. Most notably, osteotomy site preparation created a dramatically wider zone of dying and dead osteocytes in the OVX group, which was coupled with more extensive bone remodeling and a delay in the differentiation of osteoblasts. Collectively, these analyses demonstrate that the emergence of an osteoporotic phenotype delays new alveolar bone formation.