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into long bones, short bones, flat bones, and irregular to the body’s bone tissue, bone organoids hold a promising
bones, which are distributed in different anatomical regions application prospect in the research of skeletal diseases.
of the body and fulfill distinct functions. For example, Xie et al. constructed engineered bone healing tissue
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the short bones distributed in the hands and feet have an organoids using BMSCs and hydrogel microspheres and
irreplaceable role in the body’s ability to perform complex used them to repair bone defects in rabbits, enabling rapid
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and fine movements. 57 bone regeneration within 4 weeks. Park et al. established
trabecular bone organoids by co-culturing bone lining cells
2.3.2. Construction of bone organoids and bone marrow mononuclear cells on demineralized
Compared with other organoids of the musculoskeletal bone matrix scaffolds, thus enabling investigation of the
system, bone organoid fabrication has been well investigated, process of local bone remodeling. Extending their utility
and the construction strategies are relatively mature. The beyond restorative therapies, bone organoids serve as
most common cell sources for bone organoid construction versatile platforms for constructing pathomimetic disease
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59
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are MSCs, iPSCs, as well as human periosteum-derived models. Frenz-Wiessner et al. generated human bone
cells and embryonic stem cells. iPSCs, which are somatic marrow organoids using commercially available iPSCs and
cells genetically reprogrammed to have the characteristics leveraged them for genetic disease modeling. Iordachescu
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of embryonic stem cells, have been extensively applied in et al. engineered trabecular bone organoids by co-culturing
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organoid construction. iPSCs, used as the source for mouse human osteoblasts and osteoclast precursors as well as
organoids by O’Connor et al., through the time-dependent bovine femoral trabecular fragments derived from New
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sequential exposure of growth factors, successfully realized Zealand cattle, and then, the organoids were subsequently
the construction of osteochondral organoid. Cardier et al. exposed to microgravity to simulate the process of bone
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Successfully generate osteogenic organoids using allogeneic loss, providing a reliable model for osteoporosis research.
MSCs with collagen microbeads and PRP clots as ECM Furthermore, bone organoids have been utilized to model
and scaffolds. These organoids were subsequently used for pathological conditions of diseases including bone tumors,
the treatment of congenital pseudoarthrosis of the tibia. osteomyelitis, and bone deformities (Figure 4). 67
Beyond that, Fuller et al. established cost-effective bone 2.4. Cartilage organoids
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organoid models by inoculating the mouse preosteoblast
cell lines into hydrogel extracellular matrices, which can 2.4.1. Physiological structure of cartilage
reduce the use of animal models. Matrix materials, as Cartilage is a highly specialized, avascular, and aneural
the integral components of bone organoid construction, connective tissue that provides support, protection,
have also undergone significant advancements. Matrigels, shock absorption, and friction reduction in the human
natural biochemical hydrogels, and synthetic biochemical body. It is primarily located in synovial joints, the spine,
hydrogels have been increasingly employed and refined ribs, trachea, and other regions. Cartilage consists
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for the fabrication of bone organoids to increase the mainly of chondrocytes and ECM, with the latter
construction efficiency and to meet specific purposes determining the distinct properties of different cartilage
(Table 4). 63 types. Chondrocytes are responsible for synthesizing
and secreting ECM components, including collagen and
2.3.3. Applications of bone organoids proteoglycans, and also secrete cytokines to regulate tissue
Bone disease is a relatively common non-fatal disease, repair and the cartilage microenvironment. Within the
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including fractures, osteoarthritis, osteoporosis, and bone ECM components, collagen fibrils primarily provide tensile
tumors, which can impair the motor function of patients, strength and structural stability, whereas proteoglycans
cause economic burden, and seriously affect their quality of confer compressive resistance. Based on compositional
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life. As an in vitro cell culture model that is highly similar variations in the ECM, cartilage is classified into three
Table 4. Construction of bone organoids
Cell source Inducing factor Matrix material References
hBMSC/rBMSC TGF-β3, ascorbic acid, dexamethasone GelMA 58
BMSC N/A CM, PRP 61
MC3T3-E1 and RAW 264.7 cell lines BMP, β-glycerol phosphate, RANK-L, M-CSF Matrigel 62
Bone marrow mononuclear cells VD3, PGE2 DBP 63
Osteoblasts and osteoclasts β-glycerol phosphate, ascorbic acid, RANK-L, M-CSF Human blood clot-like fibrin domes 66
Abbreviations: BMP: Bone morphogenetic protein; CM: Collagen microbeads; DBP: Demineralized bone paper; GelMA: Gelatin methacrylate;
hBMSC: Human bone marrow mesenchymal stem cells; M-CSF: Macrophage colony-stimulating factor; PGE2: Prostaglandin E2; PRP: Platelet-rich
plasma; RANK-L: Receptor activator of nuclear factor-kappa B ligand; rBMSC: Rabbit bone marrow mesenchymal stem cells; VD3: Vitamin D3.

Volume 1 Issue 3 (2025) 7 doi: 10.36922/OR025320025