Controversies Surrounding Critical-Size Defects: Influence of Age and Biological Characteristics

Critical-size defects (CSDs) in craniofacial reconstruction refer to osseous gaps that fail to heal spontaneously, increasing the risk of neurological impairment and craniofacial dysmorphology. Despite decades of investigation, controversy still exists surrounding the definition of CSDs, with criteria varying across species, experimental models, and patient populations. This review integrates past and contemporary perspectives, while examining how age, dura mater biology, and stem cell dynamics influence regenerative potential. For instance, pediatric patients demonstrate increased healing capacity due to their metabolically active dura and enriched stem cell niches, while aging patients face diminished osteogenesis due to chronic age-related inflammation (inflammaging) and stem cell senescence. Meanwhile, experimental models highlight that defect size, embryonic bone origin, and proximity to cranial sutures affect healing, thus highlighting the need for standardized, age-specific definitions of CSDs. Advances in biomaterials, like bioceramic composites and dura-integrative hydrogels, show promise in advancing osteogenesis and vascularization across age groups. Additionally, dura-targeted regenerative strategies that leverage dural signaling represent a novel and promising solution to cranial repair. However, the transition from translational to clinical practice remains limited due to the lack of standardization in the literature and scarce long-term clinical data. In this review, CSD re-classification is proposed through an age-stratified framework that integrates biological, structural, and clinical variables. Standardizing models will help isolate determinants of calvarial healing and refine treatment strategies.