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interleukin-1β (IL-1β), and matrix metalloproteinases primarily in oncology research. However, its application
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(MMPs). Mechanical stress—such as cyclic stretching, to tendon diseases remains limited due to the absence
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overloading, or shear force—is applied using bioreactors of tendon-specific cellular and drug response datasets.
to mimic repetitive strain and mechanical overuse, which Establishing specialized databases to capture interactions
contribute to tendon injuries. 170 between therapeutic agents and tendon-specific cells could
significantly improve targeted drug development. 180
Aging, a major factor in tendon degeneration, can be
modeled using senescent cells or oxidative stress inducers, Drug discovery using tendon organoids begins with
such as hydrogen peroxide, allowing researchers to examine constructing models that replicate the native properties
age-related changes in tenocyte function, including of tendons. Researchers culture organoids with aligned
reduced matrix production and increased susceptibility to collagen fibers and apply mechanical stimuli to simulate
damage. Similarly, genetic predispositions are investigated physiological forces. Pathological conditions are recreated
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by introducing specific mutations or using patient-derived by introducing inflammatory cytokines, including IL-1β
cells with known genetic risk factors, providing insights and TNF-α, or proteolytic enzymes like matrix MMP-13,
into the genetic and epigenetic influences on tendon enabling controlled testing of drug candidates. 181
maintenance and degeneration. 178 Current drug candidates for tendon repair include
Tendon organoids facilitate the study of critical small-molecule inhibitors of MMPs to reduce collagen
processes, such as inflammation, collagen disorganization, degradation and growth factors, such as connective tissue
and impaired matrix remodeling. Furthermore, they growth factor, to enhance ECM production and accelerate
serve as a testing platform for novel therapeutic strategies, healing. In addition, biologics that regulate inflammation—
including inhibitors of catabolic enzymes, matrix-repair such as IL-10 mimetics or inhibitors of proinflammatory
agents, and anti-inflammatory treatments. By bridging the cytokines—offer potential solutions for controlling
gap between basic research and clinical applications, tendon inflammation without impairing tendon regeneration. 182
organoids represent a valuable tool for understanding Tendon organoids also hold promise for personalized
disease progression and developing targeted therapies for medicine. Patient-derived TSPCs or tenocytes can be used
tendon disorders. to generate customized organoids, allowing researchers
to assess drug responses based on individual genetic
5.3. Drug testing and epigenetic factors. For example, organoids derived

Tendon organoids are valuable tools for evaluating the from patients predisposed to tendinopathy or chronic
safety and efficacy of drugs targeting tendon injuries and inflammation can identify the most effective treatments
degenerative diseases. Current clinical treatments for tendon for specific conditions. This personalized approach moves
pathologies include non-steroidal anti-inflammatory drugs beyond the one-size-fits-all model, optimizing therapeutic
(NSAIDs), such as ibuprofen and naproxen, corticosteroid outcomes. 183
injections, and platelet-rich plasma (PRP) therapy. Tendon organoids streamline drug discovery by
While NSAIDs and corticosteroids alleviate pain and providing a human-relevant, reproducible, and cost-
inflammation, they do not repair structural tendon damage effective model. They reduce reliance on animal studies,
and may even hinder healing with prolonged use. PRP which often fail to fully replicate human tendon biology, and
therapy, which delivers growth factors, such as PDGF and enable high-throughput screening of therapeutic candidates.
TGF-β, to promote tendon repair, has shown inconsistent By simulating the tendon microenvironment, organoids
outcomes. These variations may stem from differences facilitate rigorous preclinical evaluation of new therapies for
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in disease stages or subtype heterogeneity, suggesting that safety and efficacy before progression to clinical trials.
classification-based screening using tendon organoids
could improve treatment evaluation. 5.4. Biomechanics and mechanobiology studies
The limitations of existing therapies underscore the Tendon organoids serve as a powerful model for
need for next-generation drugs targeting key molecular investigating the interaction between cells and mechanical
pathways involved in tendon repair. Potential approaches forces, a fundamental aspect of tendon biology. By applying
include enhancing collagen synthesis, preventing matrix cyclic stretching or other mechanical stimuli, researchers
degradation, and modulating inflammation with greater can replicate the mechanical loading conditions that
specificity. The Connectivity Map (CMap) database, a large- tendons experience in vivo. This enables the study of how
scale computational drug discovery tool, compares disease- mechanical forces regulate matrix organization, collagen
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associated gene expression profiles with drug-induced fiber alignment, and tenocyte differentiation.
expression patterns to identify therapeutic candidates. Mechanical loading plays a crucial role in maintaining
While CMap has successfully facilitated drug repurposing, the structure and function of tendons. When subjected

Volume 1 Issue 3 (2025) 15 doi: 10.36922/OR025170016