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the complete and complex spatial composition, making it becoming increasingly feasible. For example, Grass et al.
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difficult to accurately emulate the functional characteristics generated neuromuscular organoids containing spinal
of the adult organs. The development of musculoskeletal motor neurons through a defined induction protocol.
system organoids began relatively late, and the inherent Current organoid models often lack organ-specific cell
complexity of musculoskeletal tissues—with their multiple types, which may play critical roles in disease pathogenesis
functions such as support, protection, and hematopoiesis— and treatment—such as macrophages and other immune
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makes the creation of organoids capable of faithfully cells. Consequently, recapitulating the crosstalk between
replicating these physiological structures particularly the immune and musculoskeletal systems represents a
challenging. The rotator cuff is a representative component pressing challenge that must be addressed to advance the
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of the musculoskeletal system, characterized by a gradient application of rotator cuff organoids in regenerative repair.
transition zone from bone to calcified fibrocartilage, Development of the musculoskeletal system organoids
fibrocartilage, tendon, and muscle. This region exhibits is still at an early stage, and poor reproducibility represents
gradual changes in cell types and ECM composition, a prominent issue. Poor reproducibility of organoids,
presenting a major challenge for developing rotator cuff stemming from variability in cell types, matrix materials,
organoids that accurately reconstruct this multi-tissue cytokines, culture protocols, and other factors, affects
architecture. Several recent studies have predicted that this the comparability of results and the difficulty of clinical
challenge can be surmounted through the design of scaffold translation. The generation of organoids relies heavily
materials by means of 3D printing and microfluidics. In on the robust self-organization capacity of cells, a
addition, microfluidic organ chips have been reported as process that is inherently difficult to control, leading to
a technology that enables multitissue crosstalk, and the considerable batch-to-batch heterogeneity and insufficient
concept of musculoskeletal system organoid chips has also standardization. Furthermore, the absence of generally
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been proposed, 121,122 showing significant advantages in recognized international criteria specifying the essential
solving the problem of complex organoid construction. attributes of qualified organoids constitutes another

Inadequate vascularization constitutes a critical barrier major impediment to standardization. Standardization
compromising the release of the application potential of of originating cells, optimization of culture systems and
rotator cuff organoid techniques. Poor healing of rotator microfluidic organ-on-a-chip, and adoption of strict
cuff injuries is usually associated with poor local blood quality control standards are essential for achieving
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supply. Therefore, the application of organoids for rotator standardized construction of organoids. It is hoped that
cuff repair requires the construction of rotator cuff in the future, challenges related to organoid reproducibility
organoids with a functional vascular network to support will be resolved, barriers to clinical translation will be
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the survival of large volumes of tissues and to improve overcome, and the full application potential of organoid
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repair outcomes. This is actually a common problem technology will be realized. For instance, Lawlor et al.
for most organoids. To overcome this challenge, some demonstrated that extrusion-based 3D cellular bioprinting
researchers have adopted co-culture with endothelial technology enhances organoid reproducibility and enables
cells, pericytes, MSCs, etc., to achieve vascularization of high-throughput production. Separately, Brandenberg
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the organoids. In addition, Garreta et al. reported a et al. achieved standardized organoid generation through
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method for vascularization of renal organoids, through microcavity array platforms, significantly reducing batch-
to-batch heterogeneity and facilitating applications in drug
which they utilized renal dECM hydrogels and assembled discovery pipelines.
hPSC-derived endothelial organoids with renal organoids
to produce organoid models possessing vascular-like Furthermore, the high maintenance costs of organoid
structures. The vascularization problem inherent to rotator culture, along with inherent dimensional constraints and
cuff organoids can also be solved by the construction and scalability challenges, hinder their broader applications in
assembly of vascular organoids. Mechanical stimulation, the biomedical field. 131
electrical stimulation, shear stress, and other methods that
may improve the vascularization of musculoskeletal system 5. Conclusion
organoids have also been explored. Beyond the vascular Research on musculoskeletal system organoids remains in
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system, factors released by the nervous system play crucial its early stage, yet it has already demonstrated considerable
roles in bone metabolism and regeneration processes. potential, with applications emerging in regenerative
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However, most of the current organoid models lack robust medicine, drug screening, and disease modeling.
neural innervation, limiting their ability to recapitulate Despite existing limitations, the potential of organoids is
complex physiological microenvironments. With advancing expected to be further unlocked through technological
technologies such as 3D bioprinting, creating sophisticated advancements and the establishment of standardized
organoid systems with functional neural integration is cultivation protocols, thereby accelerating their transition

Volume 1 Issue 3 (2025) 13 doi: 10.36922/OR025320025