Macromolecule-based hydrogels for meniscus regeneration: Natural, synthetic and hybrid systems.

Abstract

Meniscal injuries have limited intrinsic healing capacity because of the tissue's regional vascular gradient, anisotropic load-bearing architecture, and long-term exposure to compressive, shear and sliding forces. Hydrogel engineering offers an important strategy for meniscal regeneration by providing tissue-like hydrated networks, tunable mechanical properties, bioactive delivery capacity and minimally invasive implantation. Centered on the "structure-property-function" relationship, this Review systematically summarizes recent advances in biomacromolecule-based hydrogels for meniscal repair, comparing natural, synthetic and hybrid hydrogel systems. We focus on lubrication, wet adhesion, degradation control, pore architecture and fatigue-resistant design, and further discuss hydrogel-mediated delivery strategies for growth factors, stem cells and extracellular vesicles. We also analyse the major barriers to clinical translation, including mechanical mismatch, insufficient long-term integration, scarce clinical-trial evidence, scalable manufacturing, sterilization and quality control, and regulatory classification. Finally, we highlight emerging directions such as zonally precise hydrogels, stimuli-responsive matrices, 4D bioprinting, digital-twin modelling and AI-assisted formulation design. We further propose a clinically oriented design framework that links tear morphology and the continuum of vascular zones to specific hydrogel roles, thereby providing practical guidance for developing lesion-specific meniscal-regeneration hydrogels that combine load-bearing performance, biological instructiveness and potential for clinical translation.