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a more targeted approach, focusing on specialized areas significantly enhance cartilage regeneration. In addition,
within bone/cartilage organoid research. This emphasis intelligent hydrogel systems, which respond to stimuli such
on niche areas might lead to fewer publications but higher as ultraviolet, reactive oxygen species, temperature, and
impact per study, as these focused research efforts tend to enzymes, are capable of releasing drugs and growth factors
address specific challenges in the field, making them more over extended periods. These findings open important
influential. directions for further design and application in bone
organoid construction. 55
4.2. Research keyword analysis
(iii). Red Cluster: Genetics and molecule
Across the cluster analysis of 210 high-frequency keywords,
each appearing more than three times, we identified Three-dimensional cell models, which spatially organize
four major clusters that highlight the primary research multiple cell types, such as organoids, are favored for
directions and key topics of interest within this field. gaining comprehensive insights into tissue pathophysiology
and constructing accurate in vitro tissue and disease
(i). Green Cluster: Stem cell biology and differentiation models. Compared to traditional tumor cell lines and
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Recent advancements in stem cell research have animal models, tumor organoids preserve the phenotypic
significantly improved our understanding of critical and genetic characteristics of the original tumors, enabling
aspects of organogenesis, particularly through the their expansion and long-term culture in vitro. Recent
utilization of the self-organizing properties of both adult research highlights the use of next-generation sequencing
stem cells and pluripotent stem cells. Several studies have and organoid models to investigate bone cancers, such
48
57
utilized human pluripotent stem cell-derived mesoderm as osteosarcoma in 3D culture systems. Key molecular
to induce chondrocyte differentiation, which then self- pathways, such as runt-related transcription factor 2,
assembles into cartilaginous organoids. These organoids which promotes osteoblast differentiation, and SRY-box
have demonstrated efficacy in repairing critical-sized bone transcription factor 9, which drives chondrogenesis, have
defects in mice. 49,50 This finding underscores the pivotal been shown to play crucial roles in joint regeneration and
role of stem cells in the development of bone/cartilage bone tumor development in these 3D skeletal organoids. 58,59
organoids. The ability to direct stem cells toward both In addition to their role in studying bone tumors,
chondrogenic and osteogenic lineages highlights their organoids have been used in bone marrow disease models.
versatility and potential in regenerative medicine. However, For example, the in vitro simulation of human myeloma
further research is needed to improve the maturation and bone disease was successfully achieved by co-culturing
functionality of these organoids and to better replicate the osteoblasts, osteoclasts, and multiple myeloma cells within
60
complex interactions at the osteochondral interface. 3D bone organoids. Furthermore, molecules such as
forkhead box 1, forkhead box O3, and the combination of
41
(ii). Blue Cluster: Tissue engineering BQ-123-CHI and R-954-HA (BR5) have been utilized in
61
Three-dimensional printing, as a powerful tool in disease models of cartilage organoids.
tissue engineering, offers advanced technology that (iv). Yellow Cluster: Tissue repair and regeneration
enables precise control over biophysical properties such as
organoid size, cell density, and structural organization. This Recent studies have highlighted the promising role of
characteristic allows the creation of tissue-like structures cartilage organoids in bone and cartilage regeneration,
that closely mimic natural tissues by facilitating 3D cell with successful integration and interaction of organoids
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cultures within complex biomimetic architectures. 51,52 with native cartilage in human tibial plateau explants
Hydrogels, with tunable physical and chemical properties, and tissue repair in non-primate models using allogeneic
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serve as the primary material in 3D bioprinting and induced pluripotent stem cell-derived cartilage organoids.
tissue engineering, providing scaffolds that support cell The combination of 3D bioprinting and microsphere-based
53
growth and mimic the native tissue environment. Shen culture systems has also enabled the engineering of bone
64
et al. developed an innovative RGD-SF-DNA hydrogel callus tissue organoids, promoting rapid bone regeneration.
54
microsphere (RSD-MS) using a microfluidic system. These advancements emphasize the potential of organoids
By integrating photopolymerization with self-assembly, in personalized medicine and regenerative therapies,
they created RSD-MSs for the construction of cartilage though challenges such as understanding cell interactions
organoids. In vitro studies demonstrated that RSD-MSs and ensuring vascularization remain. Overcoming these
significantly promoted the proliferation, adhesion, obstacles is a key to fully realizing the therapeutic potential
and chondrogenic differentiation of bone marrow of bone/cartilage organoids for tissue repair and clinical
mesenchymal stem cells. Furthermore, in vivo studies have applications.
shown that seeding bone marrow mesenchymal stem cells There are also significant interconnections among the
onto RSD-MSs to create cartilage organoid pre-cursors different keywords. Studies have highlighted the essential

Volume 1 Issue 3 (2025) 11 doi: 10.36922/or.8295