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Complementing earlier models, Ma et al. engineered organ chip systems, researchers co-cultured multiple
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an organotypic immunocompetent BMOC to address the cells and studied many biological processes related to
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critical translational gap in chimeric antigen receptor T-cell tumor bone metastasis, such as invasion, intravasation,
(CAR-T) therapy development (Figure 6B). Conventional extravasation, 91-94 and angiogenesis. 92,94,95 These studies
preclinical platforms—limited by poor physiological provide deeper insights into the mechanism of tumor
relevance to human immunity—fail to predict clinical bone metastasis and important information that can help
outcomes such as resistance or relapse. By recapitulating develop new treatment methods. For example, BMOC
the stromal-immune niche dynamics of leukemia bone platforms uniquely address the clinical imperative of
marrow, this chip enabled unprecedented real-time breast cancer bone metastasis research—where about
monitoring of CAR-T cell functions: from extravasation 70% of metastatic cases involve skeletal colonization—by
and target recognition to immune synapse formation and providing human-relevant models to decipher tumor-
tumor killing. Beyond observation, the platform modeled stromal crosstalk during metastatic progression. 91,94 Unlike
diverse clinical responses (remission, resistance, and traditional models hampered by sampling limitations,
relapse) and identified key failure drivers through a novel these systems enable longitudinal observation of metastatic
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matrix-based analytical index. This index quantitatively cascades. Exemplifying this, Hao et al. engineered a self-
demarcated functional heterogeneity across CAR designs mineralizing bone-on-a-chip that spontaneously develops
and donor sources, transforming the chip into a predictive 85-µm-thick osteoid tissue mimicking human bone matrix
“(pre-)clinical-trial-on-chip.” Crucially, this approach without exogenous differentiation agents (Figure 6D).
provides a physiologically relevant framework for When co-cultured with DTCs, the platform revealed
optimizing personalized CAR-T products—a capability rapid cancer invasion into mineralized matrices, capturing
unattainable with animal models or static co-cultures. unique colonization hallmarks previously only observable
in vivo. Critically, this humanized model overcomes
The BMOCs demonstrate transformative potential in
modeling human-specific bone marrow pathophysiology species barriers that undermine animal studies, while its
miniaturized design enables high-throughput screening of
by overcoming conventional culture limitations for metastasis-inhibiting therapeutics.
studying myelotoxic injury and genetic disorders. This
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vascularized platform uniquely captures dynamic injury- The BMOC platforms uniquely overcome traditional
recovery cycles—unlike static 3D cultures or animal modeling limitations by enabling precise recapitulation of
models—faithfully recapitulating key aspects of marrow the bone perivascular niche’s hemodynamic regulation—a
dysfunction, including clinically relevant myeloerythroid critical determinant of tumor dormancy induction
toxicity following chemotherapeutic/radiation exposure, previously unmodelable in static systems. This capability is
endogenous recovery after drug-induced myelosuppression, exemplified through the strategic integration of endothelial
and crucially, disease-specific hematopoietic defects cells and MSCs to reconstruct physiologically relevant
through patient-derived cells. For example, when modeling microvascular networks, faithfully mirroring human
Shwachman–Diamond syndrome (SDS), the chip revealed BMME. 92,94 Building on this foundation, Marturano-Kruik
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a previously unreported neutrophil maturation defect et al. demonstrated a human triculture model integrating
through co-culture of SDS patient cluster of differentiation endothelial cells, BMSCs, and breast cancer cells within
34-positive (CD34 ) cells with stromal components 3D bone matrices. By precisely controlling interstitial
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(Figure 6C), thereby validating its human pathophysiology- flow velocities and oxygen gradients, they established
mirroring capability while enabling the discovery of disease self-sustaining capillary networks without angiogenic
mechanisms inaccessible to animal studies. As a human- supplementation—mimicking slow-flow conditions
specific alternative, BMOCs bridge critical gaps in toxicity that maintain nutrient/signaling exchange in native
testing and rare disease research, accelerating therapeutic perivascular niches. Crucially, cancer cells exposed to these
development while circumventing translational and ethical physiological flows adopted a slow-cycling phenotype,
constraints of traditional approaches. directly linking hemodynamic parameters to dormancy-
priming microenvironments. This vascularized platform
4.2. Metastatic niche recapitulation: From tumor thus provides unprecedented access to spatiotemporal
colonization to dormancy regulation of tumor colonization and quiescence transitions.
With the development of microfluidic technology and Ji et al. pioneered a multi-niche integrated BMOC
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bioengineering, the microfluidic organ chip system platform by converging 3D bioprinting and microfluidics,
has become an important platform for studying tumor enabling comprehensive recapitulation of metastatic
metastasis. Although the bone organ-on-a-chip platform progression from pre-metastatic niche (PMN) establishment
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was introduced late in bone metastasis research, its to dormancy escape—a continuum previously unmodeled
contributions to this field are similar. Using microfluidic in single-niche systems. This platform synchronously
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Volume 1 Issue 3 (2025) 15 doi: 10.36922/OR025200017