## 4 Discussion
### Animal Models  
Different animal models have been used to investigate mandibular BTE, including rats, rabbits, mini-pigs, domestic swine, dogs, sheep, and primates. Rats are cost-effective, easy to handle, and may be genetically engineered to construct different pathological states. However, rats have a higher metabolic rate and osteogenic potential compared with humans. Furthermore, the bone mineral density of rat cortical bone differs greatly from that of humans, and the operating space of rats is limited by their small size [149]. Rabbits are the most commonly used laboratory animals, as they are easy to acquire, house, and handle, with a short developmental cycle, reaching skeletal maturity at 6 months of age [150]. Rabbits exhibit faster cortical bone remodeling and bone turnover compared with rodents or primates. Due to their faster bone remodeling and large amounts of adipose tissue in the medullary spaces of the mandible, it is difficult to extrapolate in vivo results to human trials [151]. Dog models are widely used in maxillofacial research due to similarities with humans regarding the similar bone mineral density of the mandible and periodontal tissue and comparable intracortical remodeling, similar levels of collagen, and insulin-like growth factor-1 in cortical and cancellous bone. However, the rate of trabecular bone turnover in dogs is highly variable and higher compared to humans [152; 153]. Pig bone models are used due to similarities in terms of bone mineral density and bone mineral concentration and the similar bone remodeling processes. Furthermore, mature swine have a similar bone structure to humans, with a well-developed Haversian system and a similar bone regeneration rate [154]. Swine are large animals, which are difficult to handle and maintain under experimental conditions [155]. The sheep model for bone regeneration was used due to its similar bone turnover and bone modeling rates to those of humans [156]. Sheep bones are sufficiently large to compare multiple surgical procedures simultaneously. However, the bones of sheep have a different microstructure and undergo seasonal periods of bone loss [157]. Non-human primates and humans share significant genetic homology, have comparable osteonal remodeling in skeletally mature individuals, and develop similar bone diseases and age-associated bone loss. Primates are generally used in bone biomechanics and loading studies when other large animal models do not adequately represent human bone. The use of non-human primates is expensive and is associated with some cultural and ethical questions [135]. The primary rationale for nHPs is the opportunity to match the genetic background and, therefore, the biological responsiveness of the model, as closely as possible to that of humans. Nonetheless, it has been assumed that the non-human primate model will provide the most predictive model for immunological and biological response due to its genetic background, particularly in the setting of delivery of BMPs, although the variation in response between primates limits these investigations [5; 158]. The follow-up duration and the critical defect size varied widely and depended strongly on the animal used. Furthermore, the critical defect size was not uniform, even within a single animal model. Establishing uniform critical-sized defects is particularly difficult with small animals. Thus, it is difficult to fuse the results of the studies into unique conclusions to extrapolate to clinical conditions. Future studies on mandibular bone regeneration should maintain standardized animal models, possibly with larger animals (sheep, swine, and dogs), with standardized defects and follow-up periods.