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Table 2. Cell sources in tendon organoid engineering
Cell type Key characteristics Advantages Limitations References
TSPCs Reside in ECM rich in BGN and FMOD. • Superior proliferative/ • Aged TSPCs show 36,78–80
• Multipotent (differentiates into migratory ability vs. reduced self-renewal,
tenocytes, osteocytes, chondrocytes, tenocytes. clonogenicity, and
adipocytes). • High stability and low produce fragile
• High self-renewal proliferation/ immunogenicity in vitro. organoids with poor
migration ability. • Form functional ECM. organization.
MSCs • Multipotent; self-renew and • Enhance tendon remodeling. • Variability in tenogenic 37,81–88
differentiate into tissue-specific cells. • hUCMSCs and ADSCs are differentiation
• Secrete bioactive molecules (cytokines, compatible with biomaterials efficiency depending
exosomes). for organoid construction. on source and culture
• Immunomodulatory and anti- conditions.
inflammatory properties.
iPSCs • Differentiated into iPSC-MSCs, then • Addresses donor scarcity. • Complex differentiation 89
tenocyte-like cells. • Enables personalized protocols.
• Mechanosensitive differentiation on therapies. • Risk of incomplete
aligned ultrafine fibers. • Express tenogenic markers tenogenic commitment.
(e.g., SCX, COL1).
Amniotic-Derived • Include AECs and AMSCs. • High tenogenic potential • Limited long-term 67,90–97
Cells • Low immunogenicity and anti- (expresses SCX, TNMD). stability data in
inflammatory properties. • Minimal ethical concerns. organoid systems.
• Dual functionality
(tenogenesis and
immunomodulation).
Abbreviations: ADSCs: Adipose-derived stem cells; AECs: amniotic epithelial cells; AMSCs: amniotic mesenchymal stromal cells; BGN: Biglycan;
COL1: Type 1 collagen; ECM: extracellular matrix; FMOD: Fibromodulin; hUCMSCs: Human umbilical cord mesenchymal stem cells; iPSCs: Induced
Pluripotent Stem Cells; MSCs: Mesenchymal Stem Cells; SCX: Scleraxis; TNMD: Tenomodulin; TSPCs: Tendon Stem/Progenitor Cells.

intercellular interactions. Platelet-derived growth factor necessity of combinatorial signal modulation. Future
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(PDGF) promotes tenocyte proliferation and migration 46,107 research will further explore the synergistic mechanisms
and stimulates angiogenesis without increasing fibrosis. of these biochemical elements, providing more
46
Beyond growth factors, cytokines represent another key comprehensive theoretical support for the construction
regulator in tendon organoid development by mediating of tendon organoids. Another critical limitation lies in the
intercellular communication and immune responses. lack of temporal control over biochemical cues. Current
Incorporating specific regulatory cytokines into 3D organoid systems often apply static biochemical factors,
scaffolds has emerged as a promising strategy for organoid failing to recapitulate this dynamic sequence. Emerging
cultivation. For example, hydrogels capable of sustained strategies, such as microfluidic gradient generators, offer
release of the corticosteroid triamcinolone acetonide have potential solutions but have yet to be systematically
been used to modulate chemokines, reduce inflammation, applied to tendon organoids. Such approaches will bridge
and recruit TSPCs. Together, these biochemical cues are the gap between reductionist single-factor studies and
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essential for the functional maintenance and injury repair the complexity of native microenvironments, ultimately
of tendon organoids. enabling the construction of mature, functional tendon
By strategically selecting and combining different organoids.
biochemical factors, it is possible to control cell signaling 4.3. Physical factors
pathways and precisely regulate cell fate and behavior,
thereby constructing tendon organoids with specific The self-assembly of stem cells into organoids requires
structures and functions. The combined use of multiple additional stimuli and the establishment of specific
biochemical factors is a widely recognized approach. cellular niches to exhibit biological properties similar to
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However, current studies predominantly focus on single those of actual organs. Physical factors play a crucial role
signaling pathways, although native tendon development in simulating the dynamic environment within native
and repair rely on spatiotemporally coordinated crosstalk tissues. 110,111 These factors primarily include the selection
between multiple pathways. For instance, synergistic and physical properties of scaffold materials, as well
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activation of TGF-β3 and mechanical loading has as the application of biomechanical stimuli. Together,
been shown to enhance tenogenic differentiation more they provide essential support for the development and
effectively than TGF-β3 alone, underscoring the functional maintenance of tendon organoids.
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Volume 1 Issue 3 (2025) 8 doi: 10.36922/OR025170016