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Table 2. Comparative analysis of models for constructing the human bone marrow microenvironment
Model feature Traditional 2D 3D models Animal models BMOCs
(e.g., Transwell) (e.g., organoids) (in vivo)
Spatial complexity Low (planar) Medium (3D structure) High (native High (multi-compartment)
architecture)
Cell–cell/ECM interactions Limited Good Native Controllable & tunable
Dynamic microenvironment Minimal (static) Limited (often static) Native High (precise perfusion control)
Multi-niche integration Difficult Challenging Native High (multi-niche designed)
Human relevance Medium (human cells) Medium (human cells) Low (species High (human cells, tunable)
difference)
Throughput and scalability High Medium Low Medium–high (depends on design)
Real-time monitoring/imaging Easy Challenging Difficult Relatively easy
Abbreviations: BMOC: Bone marrow on a chip; ECM: Extracellular matrix.

through multicellular integration, 3D culture systems, and adhesion/migration assays demonstrated this
modular architectures, and dynamic microenvironment system’s capacity to visualize hematopoietic cell dynamics
simulation. Current BMOC platforms successfully model across fibroblast microenvironments, revealing complex
key niches—including hematopoietic, perivascular, and intercellular interactions. Concurrently, Marturano-Kruik
endosteal niches—enabling physiologically relevant et al. developed a perfused vascularized niche model
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recapitulation of in vivo conditions. These advances provide to study breast cancer colonization and drug resistance
visualizable platforms for investigating bone marrow in bone. This platform assessed stable vascular network
physiology and pathological mechanisms. establishment (through flow rate, shear stress, and oxygen
Hematopoietic stem and progenitor cells (HSPCs), as the gradient modulation), MSC-supported vasculogenesis,
source of all blood cell lineages, require specialized niches and cancer cell proliferation/drug resistance phenotypes,
for long-term maintenance in microfluidic environments. providing a functional tool to investigate neoplastic
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Sieber et al. developed a HAP-coated zirconia scaffold- dynamics in perivascular niches.
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based 3D co-culture model integrating MSCs and umbilical Furthermore, BMOCs effectively model the endosteal
cord blood-derived HSPCs (Figure 5A). This microfluidic niche—a critical microenvironment adjacent to trabecular
multi-organ chip system sustained stable HSPC culture bone composed of mineralized tissue and stromal cells that
for 28 days while preserving intrinsic biological properties regulates HSCs’ survival, proliferation, and differentiation
and multilineage differentiation potential, demonstrating while balancing hematopoiesis and bone metabolism.
significant promise for regenerative medicine applications. Souquet et al. engineered a compartmentalized
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Modular chip advancements further accelerated progress. biomimetic marrow chip with discrete vascular and
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Sharipol et al. created a modularly assembled murine endosteal niches. Utilizing maskless photolithography for
BMOC using commercial microfluidic platforms, geometric optimization, this platform evaluated HSPC
integrating vascular channels, semi-porous membranes, interactions with niche-specific cells, demonstrating
and marrow compartments with key cellular components that the osteoblast-organized endosteal niche precisely
to maintain long-term functional HSCs (Figure 5B). regulates HSPC quiescence and differentiation decisions—
Complementarily, Aleman et al. incorporated 3D overcoming traditional limitations in visualizing opaque
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architecture, cell–cell/matrix interactions, and perfusion bone matrices.
dynamics to investigate niche interactions with normal and Remarkably, innovations in organ-on-chip technology
malignant hematopoietic cells. now enable multi-niche integration within unified BMOC
The BMME constitutes a sophisticated assembly of platforms. To delineate relationships among parallel human
functionally specialized regions. Perfusion-based 3D BMME niches (endothelial, perivascular, and central
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co-culture techniques enable comprehensive reconstruction marrows), Nelson et al. created a 96-well high-throughput
of niche characteristics, particularly for perivascular microfluidic system integrating endosteal, central marrow,
microenvironments and endosteal compartments. Kotha and perivascular niches (Figure 5C and D). Through
et al. engineered a human perivascular niche platform osteogenic differentiation of MSCs forming a bone-like
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with tunable multicellular composition to analyze 3D endosteal layer, and endothelial cell/MSC seeding in
cellular interactions guiding hematopoietic cell trafficking. fibrin-collagen hydrogels generating central marrow and
Evaluations encompassing confocal imaging of marrow 3D microvascular networks, this model demonstrated
fibroblasts/endothelial cells, gene expression profiling, significant expression of niche-specific cytokines (e.g., stem

Volume 1 Issue 3 (2025) 12 doi: 10.36922/OR025200017