The application of tissue engineering in cartilage regeneration: technological advances and future challenges

Cartilage tissue, owing to its avascular, aneural, and alymphatic nature, possesses a highly limited capacity for self-repair. Damage caused by trauma, degenerative diseases, or congenital malformations seldom heals spontaneously, constituting a long-standing clinical challenge in orthopedic and plastic surgery. Tissue engineering offers a promising strategy for cartilage regeneration by combining seed cells, biomaterial scaffolds, and bioactive molecules to construct substitutes that recapitulate the structure and function of native cartilage. The evolution of biomaterials and scaffold design is traced from natural and synthetic polymers to decellularized extracellular matrix (dECM), nanocomposite scaffolds, and stimuli-responsive hydrogel systems. Advances in biomanufacturing are examined in parallel, with particular attention to the role of 3D/4D bioprinting in fabricating architecturally complex tissue constructs, as well as the contributions of electrospinning and cell sheet engineering. Moving beyond materials and fabrication, the ongoing transition from cell-based regeneration toward cell-free approaches, particularly exosome-mediated endogenous repair and organoid-based micro-tissue construction, is discussed, alongside biomimetic design strategies such as gradient scaffolds, physically responsive scaffolds, and vascular-immune microenvironment regulation. Critical barriers to clinical translation are also identified, including manufacturing costs, process standardization, long-term efficacy and safety validation, patient stratification, and regulatory pathways. The review concludes by outlining future directions such as multi-technology convergence, endogenous regeneration strategies, and the development of off-the-shelf products, with the aim of providing a systematic reference for research and clinical translation in this rapidly evolving field.