Natural and Hybrid Bioadhesive Polymeric Platforms for Bone Regeneration: A PRISMA-Guided Systematic Review of Design Strategies and Translational Challenges.

Bone adhesives have long been pursued in orthopedic and regenerative medicine, but their clinical translation remains limited, particularly in wet and mechanically demanding environments. This PRISMA-guided systematic review analyzes bioadhesive biomaterials and adhesive regenerative platforms for bone regeneration, focusing on material composition, adhesion mechanisms, fabrication strategies, biological performance, and translational limitations. Current evidence shows a clear shift from passive adhesive systems toward multifunctional regenerative platforms that combine wet adhesion with osteogenic, angiogenic, immunomodulatory, antimicrobial, and controlled-release functions. Hybrid polymer networks, catechol-mediated chemistry, Schiff-base reactions, dynamic crosslinking, and nanocomposite or ion-releasing strategies emerge as dominant design approaches. However, adhesion testing remains highly heterogeneous, with lap shear, tensile, peel, and related assays performed under variable dry, wet, or pseudo-physiological conditions, limiting cross-study comparison and benchmarking against clinical standards. In vivo evidence is mainly concentrated in small-animal, non-load-bearing defect models, whereas large-animal validation, load-relevant testing, long-term safety data, and disease-specific models remain scarce. Overall, the main translational bottleneck appears to lie not only in adhesive chemistry, but also in the absence of standardized, bone-specific, and mechanically relevant interfacial performance metrics. This review provides an integrated perspective linking adhesion mechanics, biological function, and translational readiness to guide the future development of bioadhesive biomaterials for bone regeneration.