Biomass-Derived Hydrogels for Load-Bearing Connective Tissue Repair: Integrative Reinforcement, Bio-Functional Design, and Emerging Pathways Toward Clinical Translation.

Restoring load-bearing connective tissues (bone, cartilage, tendon, and ligament) remains a central challenge in regenerative medicine. While autografts and synthetic grafts provide temporary solutions, they are hampered by donor-site morbidity, immune complications, and poor long-term stability. Hydrogels, with their extracellular matrix-like architecture and biocompatibility, have emerged as versatile scaffolds for regeneration. Yet their intrinsic mechanical fragility has limited clinical use in mechanically demanding environments. Recently, both intrinsic and biomimetic reinforcement strategies have advanced hydrogel mechanics, while composition-structure designs incorporating bio-functional components and tailored architectures have expanded their therapeutic scope. However, the complexity of native tissues renders single-strategy solutions insufficient to simultaneously achieve robust mechanics, functional bioactivity, and physiological adaptability. This review uniquely consolidates mechanical reinforcement and bio-functional design strategies for biomass-derived hydrogels, emphasizing integrative concepts that couple macroscopic architecture, dynamic bonding, interfacial engineering, and multiphase doping. By framing hydrogel development through a cross-strategy and systems perspective, this article addresses a critical gap in the field and highlights a rational pathway toward next-generation scaffolds. Looking forward, stimuli-responsive hydrogels with adaptability, gradient, and multiphasic architectures, and AI-guided optimization are set to redefine design. Integrating materials science, biomechanics, and computational intelligence will yield patient-specific, translatable hydrogels with strong mechanics and regenerative efficacy.