Tendon organoids: Advances in bioengineering strategies and translational applications

As critical connective tissues transmitting from muscles to bones, tendons play a central role in movement and postural stability. However, their low cellularity, limited metabolic activity, and propensity for degeneration render them vulnerable to acute and chronic injuries. Traditional therapeutic approaches, such as autografts and allografts, are constrained by donor scarcity, immune rejection, and suboptimal functional recovery, driving the emergence of tissue engineering and organoid technologies as innovative solutions. Tendon organoids, which recapitulate the native tendon’s three-dimensional (3D) structure, cellular complexity, and biomechanical niche, offer a physiologically relevant in vitro model for advancing our understanding of tendon development and pathology. This comprehensive review systematically examines recent advances in tendon organoid research, highlighting four key determinants in the construction of tendon organoids: (i) Selection and optimization of cell sources, particularly tendon stem/progenitor cells; (ii) regulation of biochemical cues through spatiotemporal coordination and signaling pathway modulation; (iii) design of biomimetic 3D microenvironments, including physical scaffolds and mechanical stimulation; and (iv) integration of engineering strategies, such as single-cell omics, gene editing, 3D bioprinting, and artificial intelligence (AI) for system optimization. Notably, tendon organoids demonstrate multidimensional potential in translational applications, including regenerative medicine, disease modeling, drug screening, and biomechanical research. To overcome current technical bottlenecks, future investigations should prioritize AI-driven organoid design, standardized manufacturing protocols, and solutions for clinical translation challenges. By bridging fundamental research and clinical therapeutics, this review outlines a theoretical framework and technical roadmap for the refined construction and application of tendon organoids, highlighting their transformative potential in regenerative medicine and precision healthcare.