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Assisted Tissue Emergence” has been proposed, utilizing With ongoing advancements in stem cell technology,
3D bioprinting to control geometric shapes and cell biomaterials, and bioengineering, tendon organoids
density, thereby facilitating the generation of centimeter- are expected to achieve significant breakthroughs
scale tissues with self-organizing characteristics. The in structural complexity, functional integrity, and
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continuous evolution of tissue engineering techniques compatibility with human physiology. The development
provides critical technological and theoretical support for strategies in tendon organoid engineering are presented
the development of functional centimeter-scale tendon in Table 1.
organoids.
4. Construction of tendon organoids
3.2.3. From single-tissue to multi-tissue collaborative Although research on the construction of tendon organoids
construction
is still in its early stages, numerous studies have identified key
Tendons do not exist in isolation within the body but components essential for their development. These include
interact closely with surrounding tissues, such as muscles, the selection of appropriate cell sources, the provision of
bones, nerves, and blood vessels. Constructing fully a suitable physical environment and biochemical factors,
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functional tendon organoids requires the collaborative and the integration of engineering strategies to facilitate
integration of multiple tissue types. Although the successful organoid formation.
creation of a fully functional tendon organoid has not
yet been achieved, trends in multi-tissue collaborative 4.1. Cell selection
construction have emerged in the study of other As mentioned earlier, the collagen composition, directional
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organoids. For example, researchers have utilized human growth, and prevention of fibrosis are critical dynamic
pluripotent stem cells and co-development strategies to processes in the construction of tendon organoids.
successfully generate self-organizing organoid models The use of appropriate cell types can better control the
containing neural, muscular, and skeletal tissues. This functional realization of tendon organoids. In tendon
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multi-tissue collaborative approach offers new insights for tissue engineering, stem cells such as TSPCs, mesenchymal
the future development of tendon organoids, potentially stem cells (MSCs), and induced pluripotent stem cells
enabling the integration of tendons with other relevant (iPSCs) are utilized for their stemness to self-renew and
tissues to better replicate the physiological environment differentiate into the cellular composition and collagen
of the human body. structure of native tendons. Most adult stem cells exhibit

Table 1. Developmental strategies in tendon organoid engineering
Development Key strategies or models Representative Advantages Limitations References
stage materials/technologies
Transitional • Cell sheet technology; • Decellularized • Closer mimicry of • Still lacks full 68–71
2D culture use of decellularized tendon slices. the in vivo tendon 3D spatial and
tendon slices for cell • Co-culture inserts. environment than mechanical
sheet formation. monolayer. properties.
Early 3D • Scaffold-based 3D • Collagen hydrogels, • Supports ECM • Limited scalability. 72,73
culture culture. PLGA, Matrigel. formation, tenogenic • Variable mechanical
• Hydrogel embedding of differentiation. properties.
stem cells.
Advanced 3D • Bioreactors; mechanical • Stretchable • Improved structural • Still millimeter- 66,74
culture stimulation. hydrogels. organization. scale.
• Self-organizing • Dynamic bioreactors. • Enhanced tenogenic • Limited
hydrogel constructs. phenotype. vascularization.
Macro-level • BATE. • 3D bioprinting • Scalable to centimeter • Functional 74
• Large-scale, platforms. range. maturation and
geometrically defined • Customized bioinks. • Enables tissue long-term stability
constructs. integration studies. are still under study.
Multi-tissue • Co-development with • Pluripotent stem • Potential for complex • No successful, fully 75,76
organoids human pluripotent cells. tissue integration. functional tendon
stem cells. • Multi-lineage • Better mimics model yet.
• Integration with neural, differentiation physiological conditions; • High complexity.
muscular, and skeletal protocols. supports collaborative • Technical challenges
components. tissue development. in tissue integration.
2D: Two-dimensional; 3D: Three-dimensional; BATE: Bioprinting-assisted tissue emergence; ECM: extracellular matrix;
PLGA: Poly(lactic-co-glycolic acid).

Volume 1 Issue 3 (2025) 6 doi: 10.36922/OR025170016