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For example, in bone organoid construction, osteogenic task. To overcome the bottlenecks encountered in the
differentiation and mineralization of MSCs can be precisely construction of MSK organoids using assembloids, a
regulated by adjusting the concentration of delivered BMPs. synergistic approach combining co-culture and bioprinting
Organoid-on-a-chip also provides a unique platform can be adopted. Co-culture is not merely a simple mixture
for in-depth analysis of metabolic characteristics and of cells. It involves spatio-temporal programming of
drug response in MSK organoids. Its inherent microscale multi-lineage stem cells at the molecular and cellular level,
nature facilitates the integration of real-time pH, combined with multi-modal bioprinting to synchronously
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oxygen concentration, and metabolite sensors. This construct mechanical adaptation, vascularization, and
enables monitoring of the organoid microenvironment neural innervation at the macro scale. This approach can
and secreted components, providing direct data for systematically recreate the complex physiological process
assessing energy metabolism or cellular differentiation where neural signals drive muscle contraction, which, in
processes. For example, Scheinpflug et al. developed turn, coordinates skeletal movement, thereby overcoming
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a microphysiological system capable of studying human the functional limitations of current organoid consortia.
skeletal biology under simultaneous control of oxygen This provides a new paradigm for modeling MSK diseases,
tension and mechanical loading. Moreover, Tong et al. drug testing, and regenerative repair.
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developed an MSK OoC to investigate the mechanisms It is encouraging to note that there have been
of muscle-bone communication under IH. They revealed encouraging pioneering explorations on the path of
that muscle mitochondrial protein SIRT3 modulates bone multi-tissue integration to build composite organoids
metabolism through regulating the myokine CXCL5. This to support MSK organoids. Pirosa et al. innovatively
study reports a novel microphysiological model for muscle- utilized PCL/HA/GelMA composite scaffolds as the
bone axis research. The powerful interconnectivity of structural foundation, loaded with hMSCs and HUVECs.
OoC also makes it an ideal framework for building multi- A vascularized osteochondral organoid was successfully
OoC systems. Functional crosstalk between the MSK constructed with the dual-chamber microphysiological
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organoids and other key organoids through microfluidic system bioreactor. The key breakthrough of this model
channels can establish highly biomimetic circulation. Jin is that it integrates blood vessels, bone, and cartilage,
et al. used a high-throughput microfluidic array platform which are physiologically closely related and functionally
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to integrate other types of organoids with 3D micro-hepatic interdependent tissue units, to achieve functional crosstalk.
tissue to establish a multi-organ model that simulates drug Histological and gene expression analyses demonstrate
absorption and metabolism (Figure 6A-D). This closed- that hMSCs exhibited clear osteogenic and chondrogenic
loop design not only realistically reproduces the dynamic differentiation features in different spatial regions of
material exchange and signaling between organs but the scaffold, suggesting that spatial regulation of the
also constructs a complex in vitro microenvironment for microenvironment induced heterogeneous differentiation
the study of systemic physiopathology and prediction of of cell fates. More importantly, the capillary-like network
pharmacokinetics. This greatly improves the physiological formed by the self-assembly of HUVECs not only
relevance and accuracy of drug safety evaluation and provided channels for nutrient and oxygen delivery but
efficacy prediction. also its secreted paracrine factors were also demonstrated
to significantly promote osteogenic and chondrogenic
6.2. Assembloids differentiation of hMSCs, which vividly recapitulated the

The construction of MSK organoids is a complex project central regulatory role of the vasculature in vivo on skeletal
involving the assembly of multiple cell and tissue types. development and homeostasis. This demonstrates that it is
To break through the bottleneck of current single-tissue- feasible to functionally integrate multiple heterogeneous
confined organoids for biomimetics and to move towards tissues in vitro and achieve promotive interactions between
the system-level simulation that realistically reproduces them. This is a promising and fundamental step toward the
the overall physiological functions of the MSK system, construction of more complex assembloids.
the core strategy lies in the adoption of the “Assembloids”
technology. From molecular signaling, intercellular 6.3. Artificial intelligence (AI)
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communication to inter-tissue fusion, assembloids can AI is profoundly changing the current research method,
rebuild the intrinsic multi-level interactions network and through data-driven intelligent optimization,
of the MSK system and ultimately realize the system- analysis, and control, it can significantly improve the
level physiological response of neural command to efficiency of organoid research in MSK systems. In the
muscle contraction, driving the skeletal structure to optimization of organoid construction and culture, AI
produce coordinated movement. However, realizing can break through the traditional empirical trial-and-
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this revolutionary breakthrough is by no means an easy error method. Through machine learning algorithms,

Volume 1 Issue 3 (2025) 23 doi: 10.36922/OR025280024