In our mouse model, implant osseointegration is evident by day 14 (Fig. 3). The similarities between this mouse model and

large animal models of osseointegration allowed us to explore the molecular and cellular characteristics that affect implant osseointegration. Abundant new bone forms around maxillary implants (Fig. 3) but the source(s) of the osteoblasts are not currently known. Because there is no obvious marrow space in the murine maxillae, we speculated that the new bone arises from the nasal and oral periostea of the maxilla (Fig. 5A). Implant bed preparation injures the periosteum, and the typical response to such an injury is cell proliferation in the fibrous layer [14]. In a mechanically neutral environment, CDK inhibitor drugs these proliferating skeletal progenitor cells differentiate into osteoblasts and give rise to new bone [23]. Consequently, all efforts should be made to preserve the periosteum at the site of implant placement because in this tissue resides the skeletal stem cells that generate the new bone [22]. A finding from these analyses that has direct clinical relevance was the extensive cell death observed in the alveolar bone in response to the implant surgery, and the cell death in the crest of the cortical bone in response to the

raised flap (Fig. 4 and Fig. 5). In both cases, only the mineralized matrix MK2206 of the dead bone is retained and it provides some mechanical support for the implant. The dead bone must eventually be resorbed by osteoclasts, and replaced by new bone (e.g., see [43]). This process of cortical bone remodeling does not take place immediately

(Fig. 2) but rather, appears to be part of the normal bone turnover process. In humans, this bone turnover is measured in years [44]; in mice, this bone turnover is measured in months. Lepirudin In this window of time, between TRAP-mediated bone resorption and ALP+ ve new bone formation, the implant may lose some of its stability [45]. The same cycle of bone resorption and bone formation likely occurs in humans, and a key consideration for the timing of prosthetic loading will undoubtedly be this phase of peri-implant bone turnover. Canine models of oral implant osseointegration have been extensively employed in the past, and have a significant advantage because human size implants can be directly tested in a dog model. There are a number of serious limitations, however, including the cost associated with a large study in canines and the complete lack of genetic, molecular and cellular tools for analyses. Once the small size of the mouse is overcome, there are a number of advantages to this model of oral implant osseointegration. Our long-term objective is to be able to predict implant success versus failure by careful analysis of the steps leading up to new bone formation around implants.