{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:53:24Z","timestamp":1790646804236,"version":"4.1.0"},"reference-count":108,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The prevalence of osteoporosis, a skeletal disorder characterized by reduced bone mass, microarchitectural deterioration, and increased fracture risk, poses a substantial global healthcare burden. Although animal models and two-dimensional cell cultures have been used to advance bone research, they do not completely replicate the multicellular interactions, extracellular matrix organization, and biomechanical environment of human bone, limiting their translational relevance. This review provides a critical synthesis of recent advances in bone organoid technology, emphasizing biological complexity, technical innovation, and relevance to osteoporosis modeling. Beyond summarizing progress, we distinguish validated capabilities from aspirational claims and identify the methodological gaps that must be addressed before bone organoids can reliably support drug screening, regenerative medicine, and precision approaches. Advances in stem cell biology, tissue engineering, and three-dimensional culture systems have enabled the use of self-organizing, multicellular organoids that reproduce key physiological and pathological features of bone. These systems model estrogen-deficiency-induced bone loss, glucocorticoid-associated osteoporosis, aging-related degeneration, and genetic susceptibility. By integrating osteogenic and endothelial components within biomimetic matrices, bone organoids can support mechanistic studies and pharmacological testing. However, their incomplete vascularization, limited mechanical fidelity, instability, and lack of standardized benchmarks restrict their translational readiness. Overcoming these barriers requires technological refinement, quantitative metrics, and regulatory alignment.<\/jats:p>","DOI":"10.3390\/ijms27073118","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:11:59Z","timestamp":1774872719000},"page":"3118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Bone Organoids as Advanced Models for Osteoporosis: Development, Application, and Future Prospects"],"prefix":"10.3390","volume":"27","author":[{"given":"Chao","family":"Liu","sequence":"first","affiliation":[{"name":"The First Clinical College of Shenyang Campus, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Clinical College of Shenyang Campus, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1369-1480","authenticated-orcid":false,"given":"Rui","family":"Yu","sequence":"additional","affiliation":[{"name":"The First Clinical College of Shenyang Campus, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1007\/s00198-006-0172-4","article-title":"An estimate of the worldwide prevalence and disability associated with osteoporotic fractures","volume":"17","author":"Johnell","year":"2006","journal-title":"Osteoporos. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S131","DOI":"10.2215\/CJN.04151206","article-title":"Normal bone anatomy and physiology","volume":"3","author":"Clarke","year":"2008","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13036-023-00395-z","article-title":"Microfluidic device for enhancement and analysis of osteoblast differentiation in three-dimensional cell cultures","volume":"17","author":"Killinger","year":"2023","journal-title":"J. Biol. Eng."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.stem.2019.05.005","article-title":"Engineering stem cell self-organization to build better organoids","volume":"24","author":"Brassard","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"eabd6495","DOI":"10.1126\/sciadv.abd6495","article-title":"Trabecular bone organoid model for studying the regulation of localized bone remodeling","volume":"7","author":"Park","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41526-021-00146-8","article-title":"Trabecular bone organoids: A micron-scale \u2018humanised\u2019 prototype designed to study the effects of microgravity and degeneration","volume":"7","author":"Iordachescu","year":"2021","journal-title":"npj Microgravity"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1038\/s41592-024-02172-2","article-title":"Generation of complex bone marrow organoids from human induced pluripotent stem cells","volume":"21","author":"Fairley","year":"2024","journal-title":"Nat. Methods"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Undale, A.H., Westendorf, J.J., Yaszemski, M.J., and Khosla, S. (2009). Mesenchymal stem cells for bone repair and metabolic bone diseases. Mayo Clinic Proceedings, Elsevier.","DOI":"10.4065\/84.10.893"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"119536","DOI":"10.1016\/j.biomaterials.2019.119536","article-title":"Progress in 3D bioprinting technology for tissue\/organ regenerative engineering","volume":"226","author":"Matai","year":"2020","journal-title":"Biomaterials"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/s41413-024-00376-y","article-title":"Engineering bone\/cartilage organoids: Strategy, progress, and application","volume":"12","author":"Bai","year":"2024","journal-title":"Bone Res."},{"key":"ref_11","unstructured":"Cengiz, A. (2017). Bone Tissue Engineering with Mesenchymal Stem Cell Seeded Scaffold Assisted Perfusion Bioreactors: Fen Bilimleri Enstit\u00fcs\u00fc. [Ph.D. Thesis, Hacettepe University]."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6941","DOI":"10.1016\/j.biomaterials.2005.04.059","article-title":"Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells","volume":"26","author":"Jaquiery","year":"2005","journal-title":"Biomaterials"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10457","DOI":"10.1038\/s41598-018-28699-x","article-title":"Osteogenic differentiation of human mesenchymal stem cells in a 3D woven scaffold","volume":"8","author":"Persson","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8680","DOI":"10.1073\/pnas.1301190110","article-title":"Engineering bone tissue substitutes from human induced pluripotent stem cells","volume":"110","author":"Kahler","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1126\/science.aaw7567","article-title":"Organoids by design","volume":"364","author":"Takebe","year":"2019","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nasello, G., Alam\u00e1n-D\u00edez, P., Schiavi, J., P\u00e9rez, M.\u00c1., McNamara, L., and Garc\u00eda-Aznar, J.M. (2020). Primary human osteoblasts cultured in a 3D microenvironment create a unique representative model of their differentiation into osteocytes. Front. Bioeng. Biotechnol., 8.","DOI":"10.3389\/fbioe.2020.00336"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/nbt.2958","article-title":"3D bioprinting of tissues and organs","volume":"32","author":"Murphy","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Barabaschi, G.D., Manoharan, V., Li, Q., and Bertassoni, L.E. (2015). Engineering pre-vascularized scaffolds for bone regeneration. Engineering Mineralized and Load Bearing Tissues, Springer.","DOI":"10.1007\/978-3-319-22345-2_5"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.biomaterials.2017.10.046","article-title":"Stem cell-based bone regeneration in diseased microenvironments: Challenges and solutions","volume":"196","author":"Sui","year":"2019","journal-title":"Biomaterials"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.actbio.2021.03.003","article-title":"3D bioprinting of prevascularised implants for the repair of critically-sized bone defects","volume":"126","author":"Nulty","year":"2021","journal-title":"Acta Biomater."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16064","DOI":"10.1021\/acsnano.5c03106","article-title":"Synthetically Engineered Bacterial Extracellular Vesicles and IL-4-Encapsulated Hydrogels Sequentially Promote Osteoporotic Fracture Repair","volume":"19","author":"Zhou","year":"2025","journal-title":"ACS Nano"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2501254","DOI":"10.1002\/adma.202501254","article-title":"Dynamic GelMA\/DNA Dual-Network Hydrogels Promote Woven Bone Organoid Formation and Enhance Bone Regeneration","volume":"37","author":"Zhu","year":"2025","journal-title":"Adv. Mater."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"C743","DOI":"10.1152\/ajpcell.00738.2024","article-title":"Estrogen deficiency alters vascularization and mineralization dynamics: Insight from a novel 3-D humanized and vascularized bone organoid model","volume":"328","author":"Bukhari","year":"2025","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gao, Q., Teissier, V., Zhu, W., Makarcyzk, M.J., Shinohara, I., Murayama, M., Susuki, Y., Chow, S.K., Bunnell, B.A., and Wu, J. (2024). Personalized bone organoid using iPSC-derived cells for clinically relevant applications. Res. Sq., preprint.","DOI":"10.21203\/rs.3.rs-5349885\/v1"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4463","DOI":"10.1021\/acsbiomaterials.4c00574","article-title":"Hydroxyapatite nanoparticles promote the development of bone microtissues for accelerated bone regeneration by activating the FAK\/Akt pathway","volume":"10","author":"Li","year":"2024","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Shao, H., Nian, Z., Jing, Z., Zhang, T., Zhu, J., Li, X., Gong, Y., and He, Y. (2022). Additive manufacturing of hydroxyapatite bioceramic scaffolds with projection based 3D printing. Chin. J. Mech. Eng. Addit. Manuf. Front., 1.","DOI":"10.1016\/j.cjmeam.2022.100021"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"035018","DOI":"10.1088\/1758-5090\/ac73b9","article-title":"Long-term mechanical loading is required for the formation of 3D bioprinted functional osteocyte bone organoids","volume":"14","author":"Zhang","year":"2022","journal-title":"Biofabrication"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"22197","DOI":"10.1039\/C7RA02767B","article-title":"PHBV\/bioglass composite scaffolds with co-cultures of endothelial cells and bone marrow stromal cells improve vascularization and osteogenesis for bone tissue engineering","volume":"7","author":"Wu","year":"2017","journal-title":"RSC Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2006796","DOI":"10.1002\/adfm.202006796","article-title":"Bone-on-a-chip: Microfluidic technologies and microphysiologic models of bone tissue","volume":"31","author":"Mansoorifar","year":"2021","journal-title":"Adv. Funct. Mater."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Langhans, S.A. (2018). Three-dimensional in vitro cell culture models in drug discovery and drug repositioning. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00006"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2302088","DOI":"10.1002\/adhm.202302088","article-title":"Bone organoids: Recent advances and future challenges","volume":"13","author":"Zhao","year":"2024","journal-title":"Adv. Healthc. Mater."},{"key":"ref_32","first-page":"421746","article-title":"Biology of bone tissue: Structure, function, and factors that influence bone cells","volume":"2015","author":"Sasso","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1177\/0022034510377791","article-title":"Aging and bone","volume":"89","author":"Boskey","year":"2010","journal-title":"J. Dent. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nm.3074","article-title":"WNT signaling in bone homeostasis and disease: From human mutations to treatments","volume":"19","author":"Baron","year":"2013","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.abb.2008.03.018","article-title":"Functions of RANKL\/RANK\/OPG in bone modeling and remodeling","volume":"473","author":"Boyce","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.tibtech.2024.01.004","article-title":"Mini-bones: Miniaturized bone in vitro models","volume":"42","author":"Fois","year":"2024","journal-title":"Trends Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/jbmr.320","article-title":"The amazing osteocyte","volume":"26","author":"Bonewald","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1302\/2046-3758.91.BJR-2019-0043.R2","article-title":"Mechanotransduction in osteogenesis","volume":"9","author":"Stewart","year":"2020","journal-title":"Bone Jt. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"100","DOI":"10.22203\/eCM.v015a08","article-title":"Osteogenesis and angiogenesis: The potential for engineering bone","volume":"15","author":"Kanczler","year":"2008","journal-title":"Eur. Cell. Mater."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5046953","DOI":"10.1155\/2017\/5046953","article-title":"Structure and functions of blood vessels and vascular niches in bone","volume":"2017","author":"Ramasamy","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41556-019-0439-6","article-title":"Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization","volume":"22","author":"Baccin","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.stem.2020.04.017","article-title":"A human skeletal muscle atlas identifies the trajectories of stem and progenitor cells across development and from human pluripotent stem cells","volume":"27","author":"Xi","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1093\/jbmr\/zjae069","article-title":"Skeletal stem and progenitor cells in bone development and repair","volume":"39","author":"Trompet","year":"2024","journal-title":"J. Bone Miner. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/j.cell.2012.05.012","article-title":"Wnt\/\u03b2-catenin signaling and disease","volume":"149","author":"Clevers","year":"2012","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"272","DOI":"10.7150\/ijbs.2929","article-title":"TGF-\u03b2 and BMP signaling in osteoblast differentiation and bone formation","volume":"8","author":"Chen","year":"2012","journal-title":"Int. J. Biol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1007\/s11914-013-0145-4","article-title":"Notch signaling and bone remodeling","volume":"11","author":"Regan","year":"2013","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e1437","DOI":"10.1002\/advs.202501437","article-title":"Microsphere Strategy to Generate Conformal Bone Organoid Units with Osteoimmunomodulation and Sustainable Oxygen Supply for Bone Regeneration","volume":"12","author":"Deng","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e2501376","DOI":"10.1002\/adhm.202501376","article-title":"3D Bioprinting of Prevascularized Bone Organoids for Rapid In Situ Cranial Bone Reconstruction","volume":"14","author":"Duan","year":"2025","journal-title":"Adv. Healthc. Mater."},{"key":"ref_49","first-page":"e70510","article-title":"Ketone body 3-hydroxybutyrate mitigates apoptosis and enhances osteogenesis in bone organoid construction via the cAMP\/PKA\/CREB signaling pathway","volume":"39","author":"Jiang","year":"2025","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Fuller, J., Lefferts, K.S., Shah, P., and Cottrell, J.A. (2024). Methodology and Characterization of a 3D Bone Organoid Model Derived from Murine Cells. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084225"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e35329","DOI":"10.1002\/jbm.b.35329","article-title":"A bioartificial and vasculomorphic bone matrix-based organoid mimicking microanatomy of flat and short bones","volume":"112","author":"Toni","year":"2024","journal-title":"J. Biomed. Mater. Res. Part B Appl. Biomater."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1315243","DOI":"10.1155\/2017\/1315243","article-title":"Bone microenvironment, stem cells, and bone tissue regeneration","volume":"2017","author":"Lu","year":"2017","journal-title":"Stem Cells Int."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1177\/0192623313512428","article-title":"Osteoporosis\u2014Bone remodeling and animal models","volume":"42","author":"Bonucci","year":"2014","journal-title":"Toxicol. Pathol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1172\/JCI27071","article-title":"Pathogenesis of osteoporosis: Concepts, conflicts, and prospects","volume":"115","author":"Raisz","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.tem.2012.03.008","article-title":"Estrogen and the skeleton","volume":"23","author":"Sundeep","year":"2012","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Cheng, C.-H., Chen, L.-R., and Chen, K.-H. (2022). Osteoporosis due to hormone imbalance: An overview of the effects of estrogen deficiency and glucocorticoid overuse on bone turnover. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031376"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"536","DOI":"10.3803\/EnM.2021.1021","article-title":"Update on glucocorticoid induced osteoporosis","volume":"36","author":"Cho","year":"2021","journal-title":"Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1007\/s10787-025-01749-3","article-title":"Molecular mechanisms and treatment strategies for estrogen deficiency-related and glucocorticoid-induced osteoporosis: A comprehensive review","volume":"33","author":"Mohanty","year":"2025","journal-title":"Inflammopharmacology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"100054","DOI":"10.1016\/j.jposna.2024.100054","article-title":"Bone health: Quality vs. quantity","volume":"7","author":"Docaj","year":"2024","journal-title":"J. Pediatr. Orthop. Soc. N. Am."},{"key":"ref_60","first-page":"e10488","article-title":"Bone aging, cellular senescence, and osteoporosis","volume":"5","author":"Pignolo","year":"2021","journal-title":"J. Bone Miner. Res. Plus"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s11914-023-00783-w","article-title":"Multiple mechanisms explain genetic effects at the CPED1-WNT16 bone mineral density locus","volume":"21","author":"Addish","year":"2023","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Yang, G.K., Chen, H., Cheng, K.L., Tang, M.F., Wang, Y., Hung, L.A., Cheng, C.J., Mak, K.K., and Lee, Y.W. (2024). Potential Interaction between WNT16 and Vitamin D on Bone Qualities in Adolescent Idiopathic Scoliosis Patients and Healthy Controls. Biomedicines, 12.","DOI":"10.3390\/biomedicines12010250"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"101775","DOI":"10.1016\/j.berh.2022.101775","article-title":"Risk assessment tools for osteoporosis and fractures in 2022","volume":"36","author":"Carey","year":"2022","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.jmst.2022.07.008","article-title":"Hydrogels for bone organoid construction: From a materiobiological perspective","volume":"136","author":"Wu","year":"2023","journal-title":"J. Mater. Sci. Technol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Aboul-Soud, M.A., Alzahrani, A.J., and Mahmoud, A. (2021). Induced pluripotent stem cells (iPSCs)\u2014Roles in regenerative therapies, disease modelling and drug screening. Cells, 10.","DOI":"10.3390\/cells10092319"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Kong, Y., Yang, Y., Hou, Y., Wang, Y., Li, W., and Song, Y. (2024). Advance in the application of organoids in bone diseases. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1459891"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Wu, Y., Fuh, J., and Ozbolat, I.T. (2022). 3D Bioprinting in Tissue and Organ Regeneration, Academic Press.","DOI":"10.1016\/B978-0-12-824291-9.00006-3"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/s44222-023-00063-3","article-title":"Human disease models in drug development","volume":"1","author":"Loewa","year":"2023","journal-title":"Nat. Rev. Bioeng."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Badr-Eldin, S.M., Aldawsari, H.M., Kotta, S., Deb, P.K., and Venugopala, K.N. (2022). Three-dimensional in vitro cell culture models for efficient drug discovery: Progress so far and future prospects. Pharmaceuticals, 15.","DOI":"10.3390\/ph15080926"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"707","DOI":"10.20945\/2359-3997000000566","article-title":"Anabolic therapy for osteoporosis: Update on efficacy and safety","volume":"66","author":"Bandeira","year":"2022","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1001\/jama.2021.0233","article-title":"Anabolic therapy for osteoporosis","volume":"326","author":"Ensrud","year":"2021","journal-title":"JAMA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2207875","DOI":"10.1002\/adma.202207875","article-title":"Vesicular antibodies: Shedding light on antibody therapeutics with cell membrane nanotechnology","volume":"35","author":"Zhao","year":"2023","journal-title":"Adv. Mater."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"43492","DOI":"10.1021\/acsami.3c08550","article-title":"Engineering highly vascularized bone tissues by 3D bioprinting of granular prevascularized spheroids","volume":"15","author":"Fang","year":"2023","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.stem.2022.04.003","article-title":"Engineering multiscale structural orders for high-fidelity embryoids and organoids","volume":"29","author":"Shao","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1093\/stmcls\/sxad072","article-title":"Application of organoids in regenerative medicine","volume":"41","author":"Wu","year":"2023","journal-title":"Stem Cells"},{"key":"ref_76","first-page":"327","article-title":"Fabrication of physical and chemical crosslinked hydrogels for bone tissue engineering","volume":"12","author":"Xue","year":"2022","journal-title":"Bioact. Mater."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.actbio.2021.04.020","article-title":"Engineering hydrogels for personalized disease modeling and regenerative medicine","volume":"132","author":"Tayler","year":"2021","journal-title":"Acta Biomater."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Stacy, N.I., and Harvey, J.W. (2022). Structure of the Bone Marrow. Schalm\u2019s Veterinary Hematology, John Wiley & Sons.","DOI":"10.1002\/9781119500537.ch3"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3390\/organoids2030010","article-title":"Organoid models and next-generation sequencing for bone marrow and related disorders","volume":"2","author":"Rausch","year":"2023","journal-title":"Organoids"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ceb.2021.06.004","article-title":"Advanced models of human skeletal muscle differentiation, development and disease: Three-dimensional cultures, organoids and beyond","volume":"73","author":"Jalal","year":"2021","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1186\/s12951-023-02115-7","article-title":"Novel scaffold platforms for simultaneous induction osteogenesis and angiogenesis in bone tissue engineering: A cutting-edge approach","volume":"21","author":"Saberi","year":"2023","journal-title":"J. Nanobiotechnol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1152\/japplphysiol.00595.2020","article-title":"Mechanisms of bone blood flow regulation in humans","volume":"130","author":"Draghici","year":"2021","journal-title":"J. Appl. Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"121041","DOI":"10.1016\/j.biomaterials.2021.121041","article-title":"Spatiotemporal blood vessel specification at the osteogenesis and angiogenesis interface of biomimetic nanofiber-enabled bone tissue engineering","volume":"276","author":"Zhai","year":"2021","journal-title":"Biomaterials"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Liu, Z., Wang, Q., Zhang, J., Qi, S., Duan, Y., and Li, C. (2023). The mechanotransduction signaling pathways in the regulation of osteogenesis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241814326"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/s41392-023-01501-9","article-title":"Cellular mechanotransduction in health and diseases: From molecular mechanism to therapeutic targets","volume":"8","author":"Di","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"100741","DOI":"10.1016\/j.mtbio.2023.100741","article-title":"Microenvironment-targeted strategy steers advanced bone regeneration","volume":"22","author":"Hao","year":"2023","journal-title":"Mater. Today Bio"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41578-021-00279-y","article-title":"Engineering organoids","volume":"6","author":"Hofer","year":"2021","journal-title":"Nat. Rev. Mater."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12929-024-01035-4","article-title":"Exploiting urine-derived induced pluripotent stem cells for advancing precision medicine in cell therapy, disease modeling, and drug testing","volume":"31","author":"Yin","year":"2024","journal-title":"J. Biomed. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Mollaki, V. (2021). Ethical challenges in organoid use. BioTech, 10.","DOI":"10.3390\/biotech10030012"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"8127","DOI":"10.1007\/s00018-021-03983-8","article-title":"Pharmaceutical therapeutics for articular regeneration and restoration: State-of-the-art technology for screening small molecular drugs","volume":"78","author":"Chen","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_91","first-page":"15","article-title":"The horizon of bone organoid: A perspective on construction and application","volume":"18","author":"Chen","year":"2022","journal-title":"Bioact. Mater."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Gr\u00e4ssel, S., and Muschter, D. (2017). Peripheral nerve fibers and their neurotransmitters in osteoarthritis pathology. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18050931"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1002\/jbmr.4404","article-title":"A functional three-dimensional microphysiological human model of myeloma bone disease","volume":"36","author":"Visconti","year":"2021","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1242\/dev.150201","article-title":"The hope and the hype of organoid research","volume":"144","author":"Huch","year":"2017","journal-title":"Development"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.biomaterials.2008.10.022","article-title":"Biodegradable poly(\u03b5-caprolactone) nanowires for bone tissue engineering applications","volume":"30","author":"Porter","year":"2009","journal-title":"Biomaterials"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Duan, Q., Shao, H., Luo, N., Wang, F., Cheng, L., Ying, J., and Zhao, D. (2025). 3D-printed artificial bone scaffolds: The design of materials, the incorporation of bioactive substances, and the integration of vascularized tissue flaps. Front. Bioeng. Biotechnol., 13.","DOI":"10.3389\/fbioe.2025.1614727"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nrendo.2012.36","article-title":"Arterial calcification and bone physiology: Role of the bone\u2013vascular axis","volume":"8","author":"Thompson","year":"2012","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.cell.2016.05.082","article-title":"Modeling development and disease with organoids","volume":"165","author":"Clevers","year":"2016","journal-title":"Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1016\/j.stemcr.2022.11.019","article-title":"Lessons learnt, and still to learn, in first in human stem cell trials","volume":"18","author":"Barker","year":"2023","journal-title":"Stem Cell Rep."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Kumar, N., Saraber, P., Ding, Z., and Kusumbe, A.P. (2021). Diversity of vascular niches in bones and joints during homeostasis, ageing, and diseases. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.798211"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1002\/stem.3368","article-title":"Vascularization of human brain organoids","volume":"39","author":"Matsui","year":"2021","journal-title":"Stem Cells"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e76707","DOI":"10.7554\/eLife.76707","article-title":"Generation of vascularized brain organoids to study neurovascular interactions","volume":"11","author":"Sun","year":"2022","journal-title":"elife"},{"key":"ref_103","first-page":"440","article-title":"Mimicking the native bone regenerative microenvironment for in situ repair of large physiological and pathological bone defects","volume":"3","author":"Wang","year":"2022","journal-title":"Eng. Regen."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"100276","DOI":"10.1016\/j.medntd.2023.100276","article-title":"Organoid intelligence: Integration of organoid technology and artificial intelligence in the new era of in vitro models","volume":"21","author":"Shi","year":"2024","journal-title":"Med. Nov. Technol. Devices"},{"key":"ref_105","first-page":"372","article-title":"Revolutionising oral organoids with artificial intelligence","volume":"5","author":"Yang","year":"2024","journal-title":"Biomater. Transl."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.1093\/eurheartj\/ehae619","article-title":"Cardiovascular care with digital twin technology in the era of generative artificial intelligence","volume":"45","author":"Thangaraj","year":"2024","journal-title":"Eur. Heart J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"115237","DOI":"10.1016\/j.addr.2024.115237","article-title":"Advanced 3D imaging and organoid bioprinting for biomedical research and therapeutic applications","volume":"208","author":"Maharjan","year":"2024","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.eng.2024.09.009","article-title":"New orientation of interdisciplinarity in medicine: Engineering medicine","volume":"45","author":"Wu","year":"2025","journal-title":"Engineering"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3118\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:14:05Z","timestamp":1774872845000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":108,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27073118"],"URL":"https:\/\/doi.org\/10.3390\/ijms27073118","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]}}}