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for constructing tumor organoids can be categorized as models’ predictive validity for human drug responses
tissue-derived or cell-derived. For tissue-derived organoids, is insufficient (with a preclinical translation failure rate
patient tumor tissues undergo initial processing, mechanical exceeding 90%), and even drugs passing animal testing
dissociation, and enzymatic digestion, yielding tissue must undergo four costly and protracted clinical trial
fragments that serve as tissue-derived organoid seeds. phases. 204,205 Clinical research trials consist of four phases:
For example, Nie et al. constructed OS organoids using Phase I: Establishment of tolerability and safety in healthy
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20 biopsy tissues and 12 surgical specimens from OS volunteers; Phase II: Evaluation of therapeutic effect and
patients, with success rates exceeding 90%. Notably, these adverse reactions in patients; Phase III: Establish the
tissue-derived OS organoids formed within 2 weeks and effectiveness and safety of the drug compared with placebo
demonstrated sustained proliferation for several months or current standard treatment; and Phase IV: Determination
while maintaining phenotypic stability. Further, Suzuki of benefits and risks after authorization. It may take between
et al. developed tumor-derived organoids from human 10 and 15 years to bring a new drug to clinical use. 206
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malignant giant-cell tumors (GCTB) tissues and genetically MSK organoids offer significant advantages in drug
confirmed that the developed organoid lines represented screening as an alternative to animal experiments. They
malignantly transformed GCTB. Cell-derived organoids closely mimic human tissue structure and function,
are developed from single cell types or established cell lines. providing more accurate insights into drug mechanisms
Common cell sources include stem cells, tumor cell lines, or and efficacy while reducing errors caused by interspecies
specialized cells. Forsythe et al. developed patient-specific differences in animal models. In adition, organoid
sarcoma organoids using patient-derived tumor cells, and experiments are characterized by shorter durations and
these organoids provide a vital platform for personalized lower costs, enabling high-throughput screening and
oncology and rare tumor research. Compared to animal enhancing research efficiency. They also circumvent ethical
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models for tumors with unclear pathological mechanisms or concerns associated with animal testing, providing a more
rare tumors, tumor organoid cultivation offers a standardized efficient platform to enhance predictive accuracy of drug
and controllable environment, thus ensuring reproducibility development and shortening drug development cycles.
and robustness in subsequent therapeutic testing. For example, Occhetta et al. encapsulated cartilage
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The construction of animal models for genetic diseases cells in PEG hydrogel and subjected to high compressive
represents a significant challenge in MSK disease modeling. loads to simulate the pathological process of OA, with
While the rapid advancement of gene-editing technologies various anti-inflammatory and anti-catabolic drugs added
has substantially reduced modeling complexity, persisting for testing. O’Connor et al. developed osteochondral
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issues include off-target effects, low knockout efficiency, organoids with a cartilage core and a calcified outer ring
uncertainty in integration sites, and animal ethics by inducing iPSC microclusters with TGF-β and BMP-2
restrictions. MSK organoid models not only circumvent to simulate endochondral ossification. This model can
ethical issues associated with animal experimentation but be used to screen potential OA-modifying drugs, as OA
also offer advantages, including scalable production and affects not only cartilage but also subchondral bone. As for
high construction rates. These genetically diseased organoid high-throughput drug screening, Wei et al. developed
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models exhibit high-fidelity recapitulation of pathological a human cartilage organoid-based system for high-
phenotypes, complete retention of disease-associated throughput drug screening. From a library of over 2,000
mutational profiles, and robust capabilities for multi-gene FDA-approved drugs, they identified the α2-adrenergic
editing. For example, Gao et al. successfully constructed receptor inhibitor phentolamine as a compound capable
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NMOs from patient-derived iPSCs as an in vitro disease of simultaneously promoting chondrogenesis and
model for ALS. These NMOs recapitulate disease-relevant suppressing hypertrophy. Meanwhile, the drug was further
pathological features, including impaired skeletal muscle demonstrated to promote hyaline cartilage regeneration in
contraction, NMJ degeneration, and aberrant protein mice and minipigs. In the evaluation of pharmacodynamic
aggregation. In another study, the 3D skeletal muscle model efficacy, researchers utilized osteochondral organoids to
constructed from DMD patient-derived iPSCs accurately simulate the pathological processes of OA by inducing
recapitulates the pathological features of DMD. This inflammatory responses through the addition of pro-
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model integrates fully human, iPSC-derived, complex, inflammatory cytokines, such as IL-1β. They tested
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multilineage muscle constructs containing key isogenic the therapeutic effects of the adenosine A2A receptor
cellular constituents of skeletal muscle. agonist 2-(4-[2-Carboxyethyl]phenethylamino)-5’-N-
ethylcarboxamidoadenosine on OA. The drug significantly
4.4. Organoids for the drug screening
upregulated the expression of forkhead box O (FOXO) 1
Although animal models remain the primary method for and FOXO3 in the cell nucleus, proteins that are typically
drug screening, they exhibit significant limitations. Animal suppressed or abnormally expressed in OA.

Volume 1 Issue 3 (2025) 15 doi: 10.36922/OR025280024