Immunoregenerative Microenvironment Modulation in Tendon-Ligament Regeneration: Evolution of Chitosan-Based Composite...

Tendon and ligament injuries remain challenging to treat because healing may result in fibrosis, incomplete tendon-bone integration, impaired biomechanical properties, and reinjury. This review critically synthesizes preclinical evidence on chitosan-based composite biomaterials for tendon-ligament regeneration, focusing on their evolution from structural scaffolds toward multifunctional immunoregenerative platforms. Evidence across immune regulation, inflammatory signaling, angiogenesis, progenitor-cell activity, extracellular matrix remodeling, fibrocartilage formation, enthesis regeneration, tendon-bone healing, and biomechanical recovery was evaluated, while distinguishing direct chitosan-related evidence from contextual evidence derived from broader biomaterial systems. Chitosan-based platforms may support multiple regenerative domains through structural guidance, bioadhesion, localized delivery of bioactive components, and formulation-dependent immunomodulatory activity. However, heterogeneity in chitosan physicochemical properties, composite formulations, experimental models, and outcome measures limits direct comparison and prevents definitive attribution of multicomponent effects to chitosan alone. We propose the Immunoregenerative Cascade Theory and Immunoregenerative Tendon-Ligament Unit as complementary, hypothesis-generating frameworks for organizing temporal and spatial-functional interactions during regeneration. These frameworks are not validated causal or predictive models. Future research should prioritize standardized biomaterial characterization, longitudinal molecular-histological-biomechanical assessment, emerging multi-omics approaches, clinically relevant large-animal validation, and mechanism-guided biomaterial design to establish whether immunoregulatory effects translate into durable structural and functional tendon-ligament regeneration with long-term reproducible clinically meaningful recovery outcomes.