Advanced alginate engineering strategies toward next-generation precision orthopedics

The rising clinical demand for treating musculoskeletal defects necessitates viable alternatives to traditional bone grafting. Alginate, a naturally derived polysaccharide, has become a leading bioink for 3D bioprinting owing to its abundance, rapid ionic crosslinking, and scalable manufacturing. Yet, intrinsic drawbacks-poor cell adhesivity, unpredictable degradation kinetics, and overall low bioactivity-continue to impede clinical translation. Advances in chemical modification and mechanical reinforcement have begun to reprogram alginate into dynamic extracellular matrix mimics with enhanced osteogenic guidance. These structural modifications are further complemented by sophisticated fabrication techniques such as ion-exchange-mediated stiffness gradients, multi-material extrusion, and 4D printing. Concurrently, the design of next-generation bioinks is transitioning from passive scaffolding to active immunomodulation to drive endogenous regeneration. Yet, clinical translation remains constrained by critical challenges, notably ensuring long-term in vivo stability, matching scaffold degradation kinetics with de novo tissue formation, and navigating the complex manufacturing and regulatory requirements for combination products. By evaluating advanced alginate engineering strategies, with a specific focus on patient-specific, immunomodulatory, and dynamically adaptive grafts, as well as its emerging applications in organoid culture, this review serves as a valuable reference to guide the future development and clinical translation of next-generation alginate-based biomaterials.