Mechanobiological compartmentalization in scaffold-guided bone regeneration for large segmental long-bone defects

Scaffold-guided bone regeneration (SGBR) is an emerging strategy for reconstructing large segmental bone defects, but the biological basis and conditions of its clinical performance remain incompletely defined. In this narrative review, we consolidate a mechanobiological framework that conceptualizes SGBR as the spatiotemporal compartmentalization of the bone-healing cascade, whereby temporary architectures may organize a large defect into multiple, communicating, graft-loaded mechano-transport compartments. Within this nested scaffold-graft-host-fixation system, these compartments are defined by their local mechanical environment, transport properties, and evolving biological composition, which together influence hematoma organization, immune and vascular responses, graft incorporation, osteogenesis, and remodeling. We synthesize fracture and nonunion biology, the diamond concept, interfragmentary-motion theory, scaffold architecture studies, preclinical defect models, and heterogeneous early clinical evidence. Because current clinical evidence consists mainly of case reports and small heterogeneous case series, we interpret these data as feasibility signals. By integrating established mechanisms spatially and temporally, the framework proposes the evolving graft-loaded repair compartment as the mesoscale functional unit of SGBR and yields testable biomaterials design propositions. It proposes that durable regeneration depends on both stage-appropriate local compartment competence and progressive continuity between compartments; accordingly, pore architecture, graft distribution, graft-loaded permeability, surface bioactivity, degradation, wet-state mechanics, and fixation coupling should be evaluated as interacting variables under clinically relevant conditions. Finally, we map these variables to healing stages and technological readiness, identify evidence gaps, and define validation requirements for the implanted patient-specific scaffold-graft construct.