## 4 Discussion  
Each bone defect has a unique shape and size, making it difficult to achieve a perfect fit with grafts or implants. In large animals, the determination of CSBDs is multifactorial, involving considerations such as species, age, anatomical location, and defect geometry. While no universally accepted definition exists, segmental bone defects exceeding 1-2 cm are frequently regarded as critical in clinical and preclinical research [7; 8; 9]. Specifically for the mandible, the current literature predominantly describes defects larger than 2-3 cm as critical, as they do not heal independently [36; 37]. CSBDs represent a fundamental challenge in mandibular bone tissue engineering, as they surpass the bone's natural regenerative capacity and require scaffold-based intervention [8; 37]. However, variability in how CSBDs are defined across preclinical studies complicates direct comparisons and slows clinical translation [37]. This systematic review defined CSBDs as segmental mandibular defects greater than 2 cm in length. This pragmatic threshold was chosen to strike a balance between scientific rigor and the need to include a representative number of relevant large animal studies. While more differentiated criteria based on species, defect volume, or periosteal status would have offered finer resolution, such stratification would have excessively narrowed the available literature and impeded meaningful synthesis. A 2 cm cutoff ensures that all included studies examined defects unlikely to heal spontaneously under standard conditions, providing a robust foundation for evaluating scaffold performance across different designs and biomaterials [8; 9; 37]. A significant inconsistency was observed in the reporting of the characteristics of the experimental animals in the included studies. Information such as age, sex, and weight of the animals was described in a heterogeneous manner or, in some cases, omitted entirely. This lack of standardization limits the ability to directly compare results across studies and  
Figure 5: Assessment of the risk of bias [25]. The tool evaluates ten domains related to methodological rigor and internal validity, including sequence generation, baseline characteristics, allocation concealment, random housing, blinding of caregivers and investigators, random outcome assessment, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other potential biases. Each domain was judged as “low risk,” “high risk,” or “unclear risk” based on the information reported in the articles. The figure summarizes the distribution of risk levels across all studies. may substantially impact the interpretation of findings, particularly in the context of bone regeneration, which is highly dependent on the animal's age and physiological condition. Furthermore, notable differences were observed in how scaffold porosity and pore size were measured and reported. While some studies utilized Micro-CT, others provided only theoretical values based on design specifications. In several cases, measurement methods were unspecified or unclear. Pore size reporting also varied considerably, with some studies presenting average values, others reporting ranges, and some omitting this data entirely (Table 3). This lack of consistency hinders the direct comparison of scaffold performance and complicates the identification of optimal architectural parameters for bone regeneration. Across the included studies, defects exceeding 2 cm consistently exhibited impaired spontaneous healing, validating the critical nature of the defects and the necessity for engineered scaffolds. Moreover, scaffold properties--such as a porosity greater than 50% and pore sizes between 300 and 700 \(\upmu\)m--proved essential for promoting vascularization, bone formation, and mechanical strength within these large, non-healing defects.