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REVIEW ARTICLE

Convergence of 3D bioprinting, bone organoids, and organ-on-chip systems for orthopedic disease modeling and regenerative applications

Weida Li1,2,3† ,  Yi Wang1,2,3† ,  Yue Cui1,2,3† ,  Xingbiao Ma1,2,3 ,  Qiuyu Zhu1,2,3 ,  Hongyu Chen1,2 ,  Fangda Gan4 ,  Qiang Wu1,2 ,  Zuyan Lu1,2* ,  Ye Sun1,2,3* ,  Yongqiang Hao1,2*
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1 Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2 Clinical and Translational Research Center for 3D Printing Technology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
3 Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
4 Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Mcgill University, Montreal, Québec, Canada
†These authors contributed equally to this work.
IJB, 026230236 https://doi.org/10.36922/IJB026230236
Received: 4 June 2026 | Revised: 25 June 2026 | Accepted: 26 June 2026 | Published online: 26 June 2026
(This article belongs to the Special Issue 3D Printing in Clinical Application)
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Bone disorders remain difficult to model because native bone is a mineralized, vascularized, mechanosensitive, and multicellular organ whose remodeling depends on tightly coordinated matrix, transport, biochemical, and mechanical cues. This review examines how three-dimensional (3D) bioprinting-enabled bone organoids and organ-on-chip systems can be integrated to construct more physiologically relevant platforms for orthopedic research. Unlike previous reviews that discuss bone organoids, 3D bioprinting, or bone-on-chip systems as separate technologies, this review addresses the conceptual and translational gap between biological self-organization, programmable biofabrication, and dynamic microphysiological regulation in orthopedic modeling. We synthesize current advances in bone microenvironment modeling, focusing on organoid-based biomimicry, programmable scaffold fabrication, perfusable and mechanically active chip systems, and disease-oriented applications. The analysis shows that 3D bioprinting transforms bone microenvironment reconstruction from empirical scaffold fabrication into a controllable strategy, enabling the systematic engineering of matrix composition, pore architecture, mineralization, vascular-like channels, multicellular organization, and biochemical patterning. Organ-on-chip platforms further enhance these constructs by introducing dynamic perfusion, mechanical stimulation, compartmentalized crosstalk, and disease-relevant microenvironmental regulation. Together, these technologies support emerging applications in bone defect repair, osteoporosis and metabolic bone disease modeling, osteoarthritis and osteochondral interface reconstruction, and bone tumor or metastasis research. Despite persistent limitations in tissue maturation, vascular hierarchy, immune and hematopoietic integration, long-term stability, and standardization, the convergence of organoids, 3D bioprinting, and microphysiological systems provides a versatile foundation for mechanistic studies, drug evaluation, personalized therapeutic testing, and future regenerative strategies in orthopedics.

Graphical abstract
Keywords
3D bioprinting
Bone organoids
Organ-on-a-chip
Bone microenvironment
Orthopedic disease modeling
Funding
This work was supported by the China National Natural Science Funds (Grant Numbers: 82472423, 82172446, 82202660, and 82402819).
Conflict of interest
Yongqiang Hao is an Editorial Board Member of this journal, but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. The authors declare no conflict of interest.
References
  1. Hoong CWS, Saul D, Khosla S, Sfeir JG. Advances in the management of osteoporosis. BMJ. 2025;390:e081250. doi: 10.1136/bmj-2024-081250
  2. Kim JS, Borges S, Clauw DJ, et al. FDA/Arthritis Foundation osteoarthritis drug development workshop recap: Assessment of long-term benefit. Semin Arthritis Rheum. 2022;56:152070. doi: 10.1016/j.semarthrit.2022.152070
  3. Huang EE, Zhang N, Shen H, et al. Novel Techniques and Future Perspective for Investigating Critical-Size Bone Defects. Bioengineering (Basel). 2022;9(4):171. doi: 10.3390/bioengineering9040171
  4. DiGirolamo DJ, Clemens TL, Kousteni S. The skeleton as an endocrine organ. Nat Rev Rheumatol. 2012;8(11):674-683. doi: 10.1038/nrrheum.2012.157
  5. Schlesinger PH, Blair HC, Beer Stolz D, et al. Cellular and extracellular matrix of bone, with principles of synthesis and dependency of mineral deposition on cell membrane transport. Am J Physiol Cell Physiol. 2020;318(1):C111-C124. doi: 10.1152/ajpcell.00120.2019
  6. Wang L, You X, Zhang L, Zhang C, Zou W. Mechanical regulation of bone remodeling. Bone Res. 2022;10(1):16. doi: 10.1038/s41413-022-00190-4
  7. Yuste I, Luciano FC, González-Burgos E, Lalatsa A, Serrano DR. Mimicking bone microenvironment: 2D and 3D in vitro models of human osteoblasts. Pharmacol Res. 2021;169:105626. doi: 10.1016/j.phrs.2021.105626
  8. Verdugo-Avello F, Wychowaniec JK, Villacis-Aguirre CA, D'Este M, Toledo JR. Bone microphysiological models for biomedical research. Lab Chip. 2025;25(5):806-836. doi: 10.1039/d4lc00762j
  9. Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014;345(6194):1247125. doi: 10.1126/science.1247125
  10. Tang XY, Wu S, Wang D, et al. Human organoids in basic research and clinical applications. Signal Transduct Target Ther. 2022;7(1):168. doi: 10.1038/s41392-022-01024-9
  11. Bai L, Zhou D, Li G, Liu J, Chen X, Su J. Engineering bone/cartilage organoids: strategy, progress, and application. Bone Res. 2024;12(1):66. doi: 10.1038/s41413-024-00376-y
  12. Zhu M, Fan Z, Chen M, Xu K, Jiang Y, Su J. Biomineralization empowers bone organoids. Biomaterials. 2026;326:123703. doi: 10.1016/j.biomaterials.2025.123703
  13. Huang D, Li Z, Li G, et al. Biomimetic structural design in 3D-printed scaffolds for bone tissue engineering. Mater Today Bio. 2025;32:101664. doi: 10.1016/j.mtbio.2025.101664
  14. Huang MS, Christakopoulos F, Roth JG, Heilshorn SC. Organoid bioprinting: from cells to functional tissues. Nat Rev Bioeng. 2025;3(2):126-142. doi: 10.1038/s44222-024-00268-0
  15. Ajalik RE, Alenchery RG, Cognetti JS, et al. Human Organ-on-a-Chip Microphysiological Systems to Model Musculoskeletal Pathologies and Accelerate Therapeutic Discovery. Front Bioeng Biotechnol. 2022;10:846230. doi: 10.3389/fbioe.2022.846230
  16. Zhong C, Tang Z, Yu X, et al. Advances in the Construction and Application of Bone-on-a-Chip Based on Microfluidic Technologies. J Biomed Mater Res B Appl Biomater. 2024;112(12):e35502. doi: 10.1002/jbm.b.35502
  17. Chauhdari T, Zaidi SA, Su J, Ding Y. Organoids meet microfluidics: recent advancements, challenges, and future of organoids-on-chip. In Vitro Model. 2025;4(1):71-88. doi: 10.1007/s44164-025-00086-7
  18. Papamichail L, Koch LS, Veerman D, Broersen K, van der Meer AD. Organoids-on-a-chip: microfluidic technology enables culture of organoids with enhanced tissue function and potential for disease modeling. Front Bioeng Biotechnol. 2025;13:1515340. doi: 10.3389/fbioe.2025.1515340
  19. Lou X, Zhou Q, Dong Z, Bai L, Su J, Yue H. Innovative strategies for bone organoid: Synergistic application and exploration of advanced technologies. J Orthop Translat. 2025;54:180-198. doi: 10.1016/j.jot.2025.07.010
  20. Zhao Y, Landau S, Okhovatian S, et al. Integrating organoids and organ-on-a-chip devices. Nat Rev Bioeng. 2024;2(7):588-608. doi: 10.1038/s44222-024-00207-z
  21. Gao D, Li R, Pan J, et al. 3D bioprinting bone/cartilage organoids: construction, applications, and challenges. J Orthop Translat. 2025;55:75-93. doi: 10.1016/j.jot.2025.08.008
  22. Hu Y, Zhang H, Wang S, et al. Bone/cartilage organoid on-chip: Construction strategy and application. Bioact Mater. 2023;25:29-41. doi: 10.1016/j.bioactmat.2023.01.016
  23. Duan J, Fang Y, Tian Y, Wang Z, Yang B, Xiong Z. 3D Bioprinting of Prevascularized Bone Organoids for Rapid In Situ Cranial Bone Reconstruction. Adv Healthc Mater. 2025;14(16):e2501376. doi: 10.1002/adhm.202501376
  24. Ressler A, Žužić A, Ivanišević I, Kamboj N, Ivanković H. Ionic substituted hydroxyapatite for bone regeneration applications: A review. Open Ceramics. 2021;6:100122. doi: 10.1016/j.oceram.2021.100122
  25. Li X, Kordsmeier J, Xiong J. New Advances in Osteocyte Mechanotransduction. Curr Osteoporos Rep. 2021;19(1):101-106. doi: 10.1007/s11914-020-00650-y
  26. Qin L, Liu W, Cao H, Xiao G. Molecular mechanosensors in osteocytes. Bone Res. 2020;8:23. doi: 10.1038/s41413-020-0099-y
  27. Barnes GL, Kostenuik PJ, Gerstenfeld LC, Einhorn TA. Growth factor regulation of fracture repair. J Bone Miner Res. 1999;14(11):1805-1815. doi: 10.1359/jbmr.1999.14.11.1805
  28. Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11(6):411-425. doi: 10.1038/nrc3055
  29. Owen-Woods C, Kusumbe A. Fundamentals of bone vasculature: Specialization, interactions and functions. Semin Cell Dev Biol. 2022;123:36-47. doi: 10.1016/j.semcdb.2021.06.025
  30. Glaser DE, Curtis MB, Sariano PA, et al. Organ-on-a-chip model of vascularized human bone marrow niches. Biomaterials. 2022;280:121245. doi: 10.1016/j.biomaterials.2021.121245
  31. Maggiotto F, Bova L, Micheli S, et al. 3D bioprinting for the production of a perfusable vascularized model of a cancer niche. Front Bioeng Biotechnol. 2025;13:1484738. doi: 10.3389/fbioe.2025.1484738
  32. Harris N, Miller C, Zou M. A Versatile Platform for Designing and Fabricating Multi-Material Perfusable 3D Microvasculatures. Micromachines (Basel). 2025;16(6):691. doi: 10.3390/mi16060691
  33. Pan B, Shao L, Jiang J, et al. 3D printing sacrificial templates for manufacturing hydrogel constructs with channel networks. Mater Des. 2022;222:111012. doi: 10.1016/j.matdes.2022.111012
  34. Su R, Wang F, McAlpine MC. 3D printed microfluidics: advances in strategies, integration, and applications. Lab Chip. 2023;23(5):1279-1299. doi: 10.1039/d2lc01177h
  35. Scheinpflug J, Höfer CT, Schmerbeck SS, et al. A microphysiological system for studying human bone biology under simultaneous control of oxygen tension and mechanical loading. Lab Chip. 2023;23(15):3405-3423. doi: 10.1039/d3lc00154g
  36. Wu X, Shi W, Liu X, Gu Z. Recent advances in 3D-printing-based organ-on-a-chip. EngMedicine. 2024;1(1):100003. doi: 10.1016/j.engmed.2024.100003
  37. Zhang YS, Haghiashtiani G, Hübscher T, et al. 3D extrusion bioprinting. Nat Rev Methods Primers. 2021;1(1):75. doi: 10.1038/s43586-021-00073-8
  38. Lv N, Zhou Z, Hou M, et al. Research progress of vascularization strategies of tissue-engineered bone. Front Bioeng Biotechnol. 2024;11:1291969. doi: 10.3389/fbioe.2023.1291969
  39. Chen Y, Guo B, Ma G, Cao H. Sensory nerve regulation of bone homeostasis: Emerging therapeutic opportunities for bone-related diseases. Ageing Res Rev. 2024;99:102372. doi: 10.1016/j.arr.2024.102372
  40. Lee SS, Du X, Kim I, Ferguson SJ. Scaffolds for bone-tissue engineering. Matter. 2022;5(9):2722-2759. doi: 10.1016/j.matt.2022.06.003
  41. Tang X, Xu H, Liu X, Yang Y, Li Z. Advances in 3D-Printed scaffolds for bone defect repair: material strategies and synergistic functional performance. Front Bioeng Biotechnol. 2025;13:1707406. doi: 10.3389/fbioe.2025.1707406
  42. Zenobi E, Merco M, Mochi F, et al. Tailoring the Microarchitectures of 3D Printed Bone-like Scaffolds for Tissue Engineering Applications. Bioengineering (Basel). 2023;10(5):567. doi: 10.3390/bioengineering10050567
  43. Zhao Y, Liu D, Ren L, Wang X, Ma D. Recent Progress of 3D Printing Bioceramic Scaffolds for Bone Regeneration. Tissue Eng Part B Rev. 2025:19373341251372914. doi: 10.1177/19373341251372914
  44. Wang J, Wu Y, Li G, et al. Engineering Large-Scale Self-Mineralizing Bone Organoids with Bone Matrix-Inspired Hydroxyapatite Hybrid Bioinks. Adv Mater. 2024;36(30):e2309875. doi: 10.1002/adma.202309875
  45. Qin D, Wang N, You XG, Zhang AD, Chen XG, Liu Y. Collagen-based biocomposites inspired by bone hierarchical structures for advanced bone regeneration: ongoing research and perspectives. Biomater Sci. 2022;10(2):318-353. doi: 10.1039/d1bm01294k
  46. Ralston SH. Bone structure and metabolism. Medicine. 2021;49(9):567-571. doi: 10.1016/j.mpmed.2021.06.009
  47. Zhang Y, Zhao Y, Sun Z, et al. Bone-on-a-chip recapitulates dynamic bone remodeling. Acta Biomater. 2025;208:280-292. doi: 10.1016/j.actbio.2025.10.039
  48. Yu L, Wei M. Biomineralization of Collagen-Based Materials for Hard Tissue Repair. Int J Mol Sci. 2021;22(2):944. doi: 10.3390/ijms22020944
  49. Ramirez-Fernandez O, Zuñiga-Aguilar E. Design and Development of a Bone-on-a-Chip System to Generate Microphysiologic Models. In: Microphysiological Systems for Disease Modeling. Cham, Switzerland: Springer Nature Switzerland; 2025:101-105. doi: 10.1007/978-3-031-82123-3_10
  50. de Souza JR, Rahimnejad M, Soares IPM, et al. 3D Printing β-TCP-laden GelMA/Alginate Interpenetrating-Polymer-Network Biomaterial Inks for Bone Tissue Engineering. Bioprinting. 2025;49:e00413. doi: 10.1016/j.bprint.2025.e00413
  51. Tolmacheva N, Bhattacharyya A, Noh I. Calcium Phosphate Biomaterials for 3D Bioprinting in Bone Tissue Engineering. Biomimetics (Basel). 2024;9(2):95. doi: 10.3390/biomimetics9020095
  52. Chen X, Sun Z, Peng X, et al. Graphene Oxide/Black Phosphorus Functionalized Collagen Scaffolds with Enhanced Near-Infrared Controlled In Situ Biomineralization for Promoting Infectious Bone Defect Repair through PI3K/Akt Pathway. ACS Appl Mater Interfaces. 2024;16(38):50369-50388. doi: 10.1021/acsami.4c10284
  53. Yu SY, Wu T, Xu KH, et al. 3D bioprinted biomimetic MOF-functionalized hydrogel scaffolds for bone regeneration: Synergistic osteogenesis and osteoimmunomodulation. Mater Today Bio. 2025;32:101740. doi: 10.1016/j.mtbio.2025.101740
  54. Liu Y, Wan Y, Li C, et al. Gradient scaffolds in bone-soft tissue interface engineering: Structural characteristics, fabrication techniques, and emerging trends. J Orthop Translat. 2025;50:333-353. doi: 10.1016/j.jot.2024.10.015
  55. Ye F, Yang H, Hong C, Wu X, Dai H. Design and characterization of 3D printed gradient scaffolds with spatial distribution of pore sizes. Ceram Int. 2025;51(9):12185-12196. doi: 10.1016/j.ceramint.2025.01.070
  56. Picado-Tejero D, Mendoza-Cerezo L, Rodríguez-Rego JM, Carrasco-Amador JP, Marcos-Romero AC. Recent Advances in 3D Bioprinting of Porous Scaffolds for Tissue Engineering: A Narrative and Critical Review. J Funct Biomater. 2025;16(9):328. doi: 10.3390/jfb16090328
  57. Petite H, Viateau V, Bensaïd W, et al. Tissue-engineered bone regeneration. Nat Biotechnol. 2000;18(9):959-963. doi: 10.1038/79449
  58. Banerjee D, Singh YP, Datta P, et al. Strategies for 3D bioprinting of spheroids: A comprehensive review. Biomaterials. 2022;291:121881. doi: 10.1016/j.biomaterials.2022.121881
  59. Liu H, Liu J, Sun C, Wang Y, Sun Y, Shi X. Design and Fabrication of Biomimetic Gradient Bone Tissue Engineering Scaffolds: Evolution from Single-Gradient to Multi-Gradient. Gels. 2026;12(2):131. doi: 10.3390/gels12020131
  60. Maharjan S, Ma C, Singh B, et al. Advanced 3D imaging and organoid bioprinting for biomedical research and therapeutic applications. Adv Drug Deliv Rev. 2024;208:115237. doi: 10.1016/j.addr.2024.115237
  61. Wang C, Yue H, Liu J, Zhao Q, He Z, Li K, et al. Advanced reconfigurable scaffolds fabricated by 4D printing for treating critical-size bone defects of irregular shapes. Biofabrication. 2020;12(4):045025. doi: 10.1088/1758-5090/abab5b
  62. Bhandari A, Ghosh RN, Namboothiri PK, Peter M. A review of stimuli-responsive materials in 4D bioprinting for biomedical applications. Mater Adv. 2026;7(1):17-39. doi: 10.1039/D5MA00679A
  63. Sorokina LV, Shahbazian-Yassar R, Shokuhfar T. Collagen biomineralization: pathways, mechanisms, and thermodynamics. Emergent Mater. 2021;4(5):1205-1224. doi: 10.1007/s42247-021-00226-1
  64. Adams GJ, Cook RB, Hutchinson JR, Zioupos P. Microarchitecture and morphology of bone tissue over a wide range of BV/TV assessed by micro-computed tomography and three different threshold backgrounds. Med Eng Phys. 2022;106:103828. doi: 10.1016/j.medengphy.2022.103828
  65. Huang CY, Lin WL. High-throughput quantification of osteogenesis in WJ-MSCs using Alizarin Red S, von Kossa, and Picro-Sirius red. Future Sci OA. 2025;11(1):2567169. doi: 10.1080/20565623.2025.2567169
  66. Zhu Y, Yu X, Liu H, et al. Strategies of functionalized GelMA-based bioinks for bone regeneration: Recent advances and future perspectives. Bioact Mater. 2024;38:346-373. doi: 10.1016/j.bioactmat.2024.04.032
  67. Jo HJ, Kang MS, Kim JM, Raja IS, Jang HJ, Park KM, Han DW. Bioactive Ions-Loaded Bioinks Primed for 3D Printing of Artificial Tissues. Biomed Mater Devices. 2024;2(2):811-833. doi: 10.1007/s44174-023-00151-3
  68. de Silva L, Bernal PN, Rosenberg A, Malda J, Levato R, Gawlitta D. Biofabricating the vascular tree in engineered bone tissue. Acta Biomater. 2023;156:250-268. doi: 10.1016/j.actbio.2022.08.051
  69. Petrillo S, Genova T, Chinigò G, et al. Endothelial Cells Promote Osteogenesis by Establishing a Functional and Metabolic Coupling With Human Mesenchymal Stem Cells. Front Physiol. 2021;12:813547. doi: 10.3389/fphys.2021.813547
  70. de Barros NR, Harb SV, da Silva Horinouchi CD, et al. Advances in 3D Bioprinting and Microfluidics for Organ-on-a-Chip Platforms. Polymers (Basel). 2025;17(22):3078. doi: 10.3390/polym17223078
  71. Cao UMN, Zhang Y, Chen J, Sayson D, Pillai S, Tran SD. Microfluidic Organ-on-A-chip: A Guide to Biomaterial Choice and Fabrication. Int J Mol Sci. 2023;24(4):3232. doi: 10.3390/ijms24043232
  72. Tsiklin IL, Shabunin AV, Kolsanov AV, Volova LT. In Vivo Bone Tissue Engineering Strategies: Advances and Prospects. Polymers (Basel). 2022;14(15):3222. doi: 10.3390/polym14153222
  73. Wrublewsky S, Schultz J, Ammo T, et al. Biofabrication of prevascularized spheroids for bone tissue engineering by fusion of microvascular fragments with osteoblasts. Front Bioeng Biotechnol. 2024;12:1436519. doi: 10.3389/fbioe.2024.1436519
  74. Dornhof J, Zieger V, Kieninger J, et al. Bioprinting-based automated deposition of single cancer cell spheroids into oxygen sensor microelectrode wells. Lab Chip. 2022;22(22):4369-4381. doi: 10.1039/d2lc00705c
  75. Meyer KV, Winkler S, Lienig P, Dräger G, Bahnemann J. 3D-Printed Microfluidic Perfusion System for Parallel Monitoring of Hydrogel-Embedded Cell Cultures. Cells. 2023;12(14):1816. doi: 10.3390/cells12141816
  76. Liu H, Chen H, Han Q, et al. Recent advancement in vascularized tissue-engineered bone based on materials design and modification. Mater Today Bio. 2023;23:100858. doi: 10.1016/j.mtbio.2023.100858
  77. Zhou C, Li Z, Xu J, Yu D, Xuan L, Wang X. Multilayered microfluidic platform for three-dimensional vascularized organ-on-a-chip applications. Bio-Des Manuf. 2025;8(6):930-947. doi: 10.1631/bdm.2500091
  78. Hsu HH, Ko PL, Peng CC, Cheng YJ, Wu HM, Tung YC. Studying sprouting angiogenesis under combination of oxygen gradients and co-culture of fibroblasts using microfluidic cell culture model. Mater Today Bio. 2023;21:100703. doi: 10.1016/j.mtbio.2023.100703
  79. Huang CBX, Tu TY. Recent advances in vascularized tumor-on-a-chip. Front Oncol. 2023;13:1150332. doi: 10.3389/fonc.2023.1150332
  80. Crippa M, Talò G, Lamouline A, et al. A microfluidic model of human vascularized breast cancer metastasis to bone for the study of neutrophil-cancer cell interactions. Mater Today Bio. 2022;17:100460. doi: 10.1016/j.mtbio.2022.100460
  81. Barbato MG, Pereira RC, Mollica H, Palange A, Ferreira M, Decuzzi P. A permeable on-chip microvasculature for assessing the transport of macromolecules and polymeric nanoconstructs. J Colloid Interface Sci. 2021;594:409-423. doi: 10.1016/j.jcis.2021.03.053
  82. Lee S, Kim YG, Jung HI, Lim JS, Nam KC, Choi HS, Kwak BS. Bone-on-a-chip simulating bone metastasis in osteoporosis. Biofabrication. 2024;16(4):045025. doi: 10.1088/1758-5090/ad6cf9
  83. Choi JUA, Kijas AW, Lauko J, Rowan AE. The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States. Front Cell Dev Biol. 2021;9:770143. doi: 10.3389/fcell.2021.770143
  84. Zhang Y, Yu T, Ding J, Li Z. Bone-on-a-chip platforms and integrated biosensors: Towards advanced in vitro bone models with real-time biosensing. Biosens Bioelectron. 2023;219:114798. doi: 10.1016/j.bios.2022.114798
  85. Cho S, Lee S, Ahn SI. Design and engineering of organ-on-a-chip. Biomed Eng Lett. 2023;13(2):97-109. doi: 10.1007/s13534-022-00258-4
  86. Vis MAM, Zhao F, Bodelier ESR, et al. Osteogenesis and osteoclastogenesis on a chip: Engineering a self-assembling 3D coculture. Bone. 2023;173:116812. doi: 10.1016/j.bone.2023.116812
  87. Sang W, Ural A. Influence of Osteocyte Lacunar-Canalicular Morphology and Network Architecture on Osteocyte Mechanosensitivity. Curr Osteoporos Rep. 2023;21(4):401-413. doi: 10.1007/s11914-023-00792-9
  88. Moriishi T, Komori T. Osteocytes: Their Lacunocanalicular Structure and Mechanoresponses. Int J Mol Sci. 2022;23(8):4373. doi: 10.3390/ijms23084373
  89. Banh L, Cheung KK, Chan MWY, Young EWK, Viswanathan S. Advances in organ-on-a-chip systems for modelling joint tissue and osteoarthritic diseases. Osteoarthritis Cartilage. 2022;30(8):1050-1061. doi: 10.1016/j.joca.2022.03.012
  90. Lin X, Chen J, Feng X, Wang H, Li R, Liu H, Liu H, Sun C. In situ deformation measurement of 3D printed scaffold and mechano-regulation in tissue engineering. Opt Lasers Eng. 2023;169:107719. doi: 10.1016/j.optlaseng.2023.107719
  91. Peitso V, Sarmadian Z, Henriques J, Lauwers E, Paggi CA, Mobasheri A. Development of a Microphysiological Cartilage-on-Chip Platform for Dynamic Biomechanical Stimulation of Three-Dimensional Encapsulated Chondrocytes in Agarose Hydrogels. Curr Protoc. 2024;4(12):e70079. doi: 10.1002/cpz1.70079
  92. Rindt WD, Krug M, Yamada S, et al. A 3D bioreactor model to study osteocyte differentiation and mechanobiology under perfusion and compressive mechanical loading. Acta Biomater. 2024;184:210-225. doi: 10.1016/j.actbio.2024.06.041
  93. Nonaka T, Murata D, Yoshizato H, et al. Bio-3D printing of scaffold-free ADSC-derived cartilage constructs comparable to natural cartilage in vitro. J Orthop Surg Res. 2025;20(1):182. doi: 10.1186/s13018-025-05604-7
  94. Busch C, Nyamondo K, Wheadon H. Complexities of modeling the bone marrow microenvironment to facilitate hematopoietic research. Exp Hematol. 2024;135:104233. doi: 10.1016/j.exphem.2024.104233
  95. Andreev D, Kachler K, Schett G, Bozec A. Rheumatoid arthritis and osteoimmunology: The adverse impact of a deregulated immune system on bone metabolism. Bone. 2022;162:116468. doi: 10.1016/j.bone.2022.116468
  96. Paggi CA, Teixeira LM, Le Gac S, Karperien M. Joint-on-chip platforms: entering a new era of in vitro models for arthritis. Nat Rev Rheumatol. 2022;18(4):217-231. doi: 10.1038/s41584-021-00736-697.
  97. Martinelli C, Chakraborty S, Buccioli G, et al. Engineering macrophage responses through 3D scaffold microarchitecture. Mater Today Bio. 2025;35:102328. doi: 10.1016/j.mtbio.2025.102328
  98. Olijnik AA, Rodriguez-Romera A, Wong ZC, et al. Generating human bone marrow organoids for disease modeling and drug discovery. Nat Protoc. 2024;19(7):2117-2146. doi: 10.1038/s41596-024-00971-7
  99. Bourgine PE. Human bone marrow organoids: emerging progress but persisting challenges. Trends Biotechnol. 2026;44(1):11-21. doi: 10.1016/j.tibtech.2025.05.028
  100. Morgan M, Nazemian V, Harrington K, Ivanusic JJ. Mini review: The role of sensory innervation to subchondral bone in osteoarthritis pain. Front Endocrinol (Lausanne). 2022;13:1047943. doi: 10.3389/fendo.2022.1047943
  101. Bukhari MMM, Khabooshani M, Naqvi SM, McNamara LM. Estrogen deficiency alters vascularization and mineralization dynamics: insight from a novel 3-D humanized and vascularized bone organoid model. Am J Physiol Cell Physiol. 2025;328(3):C743-C756. doi: 10.1152/ajpcell.00738.2024
  102. Sriram G, Makkar H. Microfluidic organ-on-chip systems for periodontal research: advances and future directions. Front Bioeng Biotechnol. 2024;12:1490453. doi: 10.3389/fbioe.2024.1490453
  103. Hu Q, Acharya A, Shum HC, Leung WK, Pelekos G. Gum-on-a-Chip Exploring Host-Microbe Interactions: Periodontal Disease Modeling and Drug Discovery. J Tissue Eng. 2025;16:20417314251314356. doi: 10.1177/20417314251314356
  104. Chen C, Hui J, Tian T, et al. Biomimetic bone-vessel interface-on-a-chip for simulating periodontal physiological and pathological microenvironment. Regen Biomater. 2025;12:rbaf111. doi: 10.1093/rb/rbaf111
  105. Komatsu N, Takayanagi H. Mechanisms of joint destruction in rheumatoid arthritis - immune cell-fibroblast-bone interactions. Nat Rev Rheumatol. 2022;18(7):415-429. doi: 10.1038/s41584-022-00793-5
  106. Collet Q, Velard F, Laurent F, Josse J. Intracellular Staphylococcus aureus in osteoblasts and osteocytes and its impact on bone homeostasis during osteomyelitis. Bone. 2025;198:117536. doi: 10.1016/j.bone.2025.117536
  107. Van Os L, Engelhardt B, Guenat OT. Integration of immune cells in organs-on-chips: a tutorial. Front Bioeng Biotechnol. 2023;11:1191104. doi: 10.3389/fbioe.2023.1191104
  108. Piergiovanni M, Leite SB, Corvi R, Whelan M. Standardisation needs for organ on chip devices. Lab Chip. 2021;21(15):2857-2868. doi: 10.1039/d1lc00241d
  109. Wang Y, Gao Y, Pan Y, et al. Emerging trends in organ-on-a-chip systems for drug screening. Acta Pharm Sin B. 2023;13(6):2483-2509. doi: 10.1016/j.apsb.2023.02.006
  110. Takegahara N, Kim H, Choi Y. RANKL biology. Bone. 2022;159:116353. doi: 10.1016/j.bone.2022.116353
  111. Li B, Wang P, Jiao J, Wei H, Xu W, Zhou P. Roles of the RANKL-RANK Axis in Immunity-Implications for Pathogenesis and Treatment of Bone Metastasis. Front Immunol. 2022;13:824117. doi: 10.3389/fimmu.2022.824117
  112. Gharacheh H, Guvendiren M. Three-dimensional bioprinting vascularized bone tissue. MRS Bull. 2023;48(6):668-675. doi: 10.1557/s43577-023-00547-y
  113. Dalisson B, Charbonnier B, Aoude A, et al. Skeletal regeneration for segmental bone loss: Vascularised grafts, analogues and surrogates. Acta Biomater. 2021;136:37-55. doi: 10.1016/j.actbio.2021.09.053
  114. Haeusner S, Jauković A, Kupczyk E, Herrmann M. Review: cellularity in bone marrow autografts for bone and fracture healing. Am J Physiol Cell Physiol. 2023;324(2):C517-C531. doi: 10.1152/ajpcell.00482.2022
  115. Quek J, Vizetto-Duarte C, Teoh SH, Choo Y. Towards Stem Cell Therapy for Critical-Sized Segmental Bone Defects: Current Trends and Challenges on the Path to Clinical Translation. J Funct Biomater. 2024;15(6):145. doi: 10.3390/jfb15060145
  116. Zhang X, Jiang W, Wu X, et al. Divide-and-conquer strategy with engineered ossification center organoids for rapid bone healing through developmental cell recruitment. Nat Commun. 2025;16(1):6200. doi: 10.1038/s41467-025-61619-y
  117. Rahimnejad M, Nasrollahi Boroujeni N, Jahangiri S, et al. Prevascularized Micro-/Nano-Sized Spheroid/Bead Aggregates for Vascular Tissue Engineering. Nanomicro Lett. 2021;13(1):182. doi: 10.1007/s40820-021-00697-1
  118. Chen S, Chen X, Geng Z, Su J. The horizon of bone organoid: A perspective on construction and application. Bioact Mater. 2022;18:15-25. doi: 10.1016/j.bioactmat.2022.01.048
  119. Shen Y, Benlabiod C, Watson E, et al. comBO: A combined human bone and lympho-myeloid bone marrow organoid for preclinical modeling of hematopoietic disorders. Cell Stem Cell. 2026;33(3):421-437.e7. doi: 10.1016/j.stem.2026.01.010
  120. Mirkhalaf M, Men Y, Wang R, No Y, Zreiqat H. Personalized 3D printed bone scaffolds: A review. Acta Biomater. 2023;156:110-124. doi: 10.1016/j.actbio.2022.04.014
  121. Morrison AI, Sjoerds MJ, Vonk LA, Gibbs S, Koning JJ. In vitro immunity: an overview of immunocompetent organ-on-chip models. Front Immunol. 2024;15:1373186. doi: 10.3389/fimmu.2024.1373186
  122. Arutyunyan I, Elchaninov A, Sukhikh G, Fatkhudinov T. Cryopreservation of Tissue-Engineered Scaffold-Based Constructs: from Concept to Reality. Stem Cell Rev Rep. 2022;18(4):1234-1252. doi: 10.1007/s12015-021-10299-4
  123. Nulty J, Freeman FE, Browe DC, et al. 3D bioprinting of prevascularised implants for the repair of critically-sized bone defects. Acta Biomater. 2021;126:154-169. doi: 10.1016/j.actbio.2021.03.003
  124. Ahire JJ, Kumar V, Rohilla A. Understanding Osteoporosis: Human Bone Density, Genetic Mechanisms, Gut Microbiota, and Future Prospects. Probiotics Antimicrob Proteins. 2024;16(3):875-883. doi: 10.1007/s12602-023-10185-0
  125. Koh NYY, Miszkiewicz JJ, Fac ML, Wee NKY, Sims NA. Preclinical Rodent Models for Human Bone Disease, Including a Focus on Cortical Bone. Endocr Rev. 2024;45(4):493-520. doi: 10.1210/endrev/bnae004
  126. Kong Y, Yang Y, Hou Y, Wang Y, Li W, Song Y. Advance in the application of organoids in bone diseases. Front Cell Dev Biol. 2024;12:1459891. doi: 10.3389/fcell.2024.1459891
  127. Lipreri MV, Di Pompo G, Boanini E, et al. Bone on-a-chip: a 3D dendritic network in a screening platform for osteocyte-targeted drugs. Biofabrication. 2023;15(4):045019. doi: 10.1088/1758-5090/acee23
  128. Wang H, Zhu W, Xu C, Su W, Li Z. Engineering organoids-on-chips for drug testing and evaluation. Metabolism. 2025;162:156065. doi: 10.1016/j.metabol.2024.156065
  129. McDonald MM, Kim AS, Mulholland BS, Rauner M. New Insights Into Osteoclast Biology. JBMR Plus. 2021;5(9):e10539. doi: 10.1002/jbm4.10539
  130. Sharipol A, Lesch ML, Soto CA, Frisch BJ. Bone Marrow Microenvironment-On-Chip for Culture of Functional Hematopoietic Stem Cells. Front Bioeng Biotechnol. 2022;10:855777. doi: 10.3389/fbioe.2022.855777
  131. Shi V, Morgan EF. Estrogen and estrogen receptors mediate the mechanobiology of bone disease and repair. Bone. 2024;188:117220. doi: 10.1016/j.bone.2024.117220
  132. Shroff T, Aina K, Maass C, et al. Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics. Open Biol. 2022;12(3):210333. doi: 10.1098/rsob.210333
  133. Schini M, Vilaca T, Gossiel F, Salam S, Eastell R. Bone Turnover Markers: Basic Biology to Clinical Applications. Endocr Rev. 2023;44(3):417-473. doi: 10.1210/endrev/bnac031
  134. Zhou L, Huang J, Li C, et al. Organoids and organs-on-chips: Recent advances, applications in drug development, and regulatory challenges. Med. 2025;6(4):100667. doi: 10.1016/j.medj.2025.100667
  135. Li X, Zhang Z, Tian T, Chen C, Xu X, He Y, Zang Y, Mao H, Hui J, Liu H. High-throughput microfluidic generation of self-assembled, uniform 3D vascularized and mineralized bone organoids without matrix biomaterials. Talanta Open. 2025;12:100531. doi: 10.1016/j.talo.2025.100531
  136. Paek K, Kim S, Tak S, Kim MK, Park J, Chung S, et al. A high-throughput biomimetic bone-on-a-chip platform with artificial intelligence-assisted image analysis for osteoporosis drug testing. Bioeng Transl Med. 2023;8(1):e10313. doi: 10.1002/btm2.10313
  137. Lampart FL, Iber D, Doumpas N. Organoids in high-throughput and high-content screenings. Front Chem Eng. 2023;5:1120348. doi: 10.3389/fceng.2023.1120348
  138. Bozal SB, Sjogren G, Costa AP, et al. Development of an automated 3D high content cell screening platform for organoid phenotyping. SLAS Discov. 2024;29(7):100182. doi: 10.1016/j.slasd.2024.100182
  139. Liu C, Zhang X, Yu R. Bone Organoids as Advanced Models for Osteoporosis: Development, Application, and Future Prospects. Int J Mol Sci. 2026;27(7):3118. doi: 10.3390/ijms27073118
  140. Xie Z, Liu M, Wang S, et al. Advances and Challenges in Constructing Bone Organoids Using Cells Derived from Human Pluripotent Stem Cells: A Review. Stem Cell Rev Rep. 2026;22:371-402. doi: 10.1007/s12015-025-11017-0
  141. Hu Y, Chen X, Wang S, Jing Y, Su J. Subchondral bone microenvironment in osteoarthritis and pain. Bone Res. 2021;9(1):20. doi: 10.1038/s41413-021-00147-z
  142. Johnson PA, Ackerman JE, Kurowska-Stolarska M, Coles M, Buckley CD, Dakin SG. Three-dimensional, in-vitro approaches for modelling soft-tissue joint diseases. Lancet Rheumatol. 2023;5(9):e553-e563. doi: 10.1016/s2665-9913(23)00190-x
  143. Nordberg RC, Wen DH, Wang D, Hu JC, Athanasiou KA. Challenges and recent advances in engineering the osteochondral interface. Curr Opin Biomed Eng. 2024;31:100546. doi: 10.1016/j.cobme.2024.100546
  144. Li ZA, Sant S, Cho SK, et al. Synovial joint-on-a-chip for modeling arthritis: progress, pitfalls, and potential. Trends Biotechnol. 2023;41(4):511-527. doi: 10.1016/j.tibtech.2022.07.011
  145. Zhang Y, Li G, Wang J, Zhou F, Ren X, Su J. Small Joint Organoids 3D Bioprinting: Construction Strategy and Application. Small. 2024;20(8):e2302506. doi: 10.1002/smll.202302506
  146. Zelinka A, Roelofs AJ, Kandel RA, De Bari C. Cellular therapy and tissue engineering for cartilage repair. Osteoarthritis Cartilage. 2022;30(12):1547-1560. doi: 10.1016/j.joca.2022.07.012
  147. Wang XH, Liu N, Zhang H, Yin ZS, Zha ZG. From cells to organs: progress and potential in cartilaginous organoids research. J Transl Med. 2023;21(1):926. doi: 10.1186/s12967-023-04591-9
  148. Jiao R, Lin X, Wang J, et al. 3D-printed constructs deliver bioactive cargos to expedite cartilage regeneration. J Pharm Anal. 2024;14(12):100925. doi: 10.1016/j.jpha.2023.12.015
  149. Dimaraki A, Díaz-Payno PJ, Minneboo M, et al. Bioprinting of a Zonal-Specific Cell Density Scaffold: A Biomimetic Approach for Cartilage Tissue Engineering. Appl Sci. 2021;11(17):7821. doi: 10.3390/app11177821
  150. Paggi CA, Hendriks J, Karperien M, Le Gac S. Emulating the chondrocyte microenvironment using multi-directional mechanical stimulation in a cartilage-on-chip. Lab Chip. 2022;22(9):1815-1828. doi: 10.1039/d1lc01069g
  151. Roehm KD, Chiesa I, Haithcock D, Gottardi R, Prabhakarpandian B. A vascularized microfluidic model of the osteochondral unit for modeling inflammatory response and therapeutic screening. Lab Chip. 2025;25(3):370-382. doi: 10.1039/d4lc00651h
  152. Mirazi H, Wood ST. Microfluidic chip-based co-culture system for modeling human joint inflammation in osteoarthritis research. Front Pharmacol. 2025;16:1579228. doi: 10.3389/fphar.2025.1579228
  153. Rydén M, Önnerfjord P. In Vitro Models and Proteomics in Osteoarthritis Research. Adv Exp Med Biol. 2023;1402:57-68. doi: 10.1007/978-3-031-25588-5_4
  154. Ma Z, Liu Y, Chen R, Fan H, Kong L, Cao X. A novel perspective on bone tumors: advances in organoid research. Front Pharmacol. 2025;16:1550163. doi: 10.3389/fphar.2025.1550163
  155. Wang X, Luo Y, Ma Y, Wang P, Yao R. Converging bioprinting and organoids to better recapitulate the tumor microenvironment. Trends Biotechnol. 2024;42(5):648-663. doi: 10.1016/j.tibtech.2023.11.006
  156. Cui X, Jiao J, Yang L, et al. Advanced tumor organoid bioprinting strategy for oncology research. Mater Today Bio. 2024;28:101198. doi: 10.1016/j.mtbio.2024.101198
  157. Puce A, Ferraresi V, Biagini R, Soddu S, Loria R. Three-dimensional preclinical models for Osteosarcoma: Advances and translational prospects. Biomed Pharmacother. 2025;191:118471. doi: 10.1016/j.biopha.2025.118471
  158. Frankenbach-Désor T, Niesner I, Ahmed P, et al. Tissue-engineered patient-derived osteosarcoma models dissecting tumour-bone interactions. Cancer Metastasis Rev. 2024;44(1):8. doi: 10.1007/s10555-024-10218-2
  159. Sandhu V, Bakkalci D, Wei S, Cheema U. Enhanced Biomimetics of Three-Dimensional Osteosarcoma Models: A Scoping Review. Cancers (Basel). 2023;16(1):164. doi: 10.3390/cancers16010164
  160. Lu Z, Miao X, Zhang C, et al. An osteosarcoma-on-a-chip model for studying osteosarcoma matrix-cell interactions and drug responses. Bioact Mater. 2024;34:1-16. doi: 10.1016/j.bioactmat.2023.12.005
  161. Lipreri MV, Totaro MT, Raimondi I, Cortini M, Baldini N, Avnet S. A customizable micropatterned platform for osteosarcoma spheroid generation, imaging, and drug screening. Biomater Adv. 2025;177:214419. doi: 10.1016/j.bioadv.2025.214419
  162. Madan A, Saini R, Dhiman N, Juan SH, Satapathy MK. Organoids as Next-Generation Models for Tumor Heterogeneity, Personalized Therapy, and Cancer Research: Advancements, Applications, and Future Directions. Organoids. 2025;4(4):23. doi: 10.3390/organoids4040023
  163. Cristini N, Tavakoli M, Sanati M, Yavari SA. Exploring bone-tumor interactions through 3D in vitro models: Implications for primary and metastatic cancers. J Bone Oncol. 2025;53:100698. doi: 10.1016/j.jbo.2025.100698
  164. Zeng G, Yu Y, Wang M, et al. Advancing cancer research through organoid technology. J Transl Med. 2024;22(1):1007. doi: 10.1186/s12967-024-05824-1
  165. Ahn J, Kim DH, Koo DJ, et al. 3D microengineered vascularized tumor spheroids for drug delivery and efficacy testing. Acta Biomater. 2023;165:153-167. doi: 10.1016/j.actbio.2022.10.009
  166. Tuladhar A, Guffroy M, Finnema SJ, et al. Investigation of bone toxicity in drug development: review of current and emerging technologies. Toxicol Sci. 2025;208(2):207-224. doi: 10.1093/toxsci/kfaf131
  167. Thorel L, Perréard M, Florent R, et al. Patient-derived tumor organoids: a new avenue for preclinical research and precision medicine in oncology. Exp Mol Med. 2024;56(7):1531-1551. doi: 10.1038/s12276-024-01272-5
  168. Nie JH, Wan CY, Li H, et al. Personalized prediction of chemotherapy efficacy in osteosarcoma through patient-derived organoids: correlation with survival and tumor proliferation potential. J Exp Clin Cancer Res. 2025;45(1):16. doi: 10.1186/s13046-025-03541-1
  169. Verstegen MMA, Coppes RP, Beghin A, et al. Clinical applications of human organoids. Nat Med. 2025;31(2):409-421. doi: 10.1038/s41591-024-03489-3
  170. Fois MG, van Griensven M, Giselbrecht S, Habibović P, Truckenmüller RK, Tahmasebi Birgani ZN. Mini-bones: miniaturized bone in vitro models. Trends Biotechnol. 2024;42(7):910-928. doi: 10.1016/j.tibtech.2024.01.004
  171. Xie C, Liang R, Ye J, et al. High-efficient engineering of osteo-callus organoids for rapid bone regeneration within one month. Biomaterials. 2022;288:121741. doi: 10.1016/j.biomaterials.2022.121741
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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing
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