AccScience Publishing / OR / Online First / DOI: 10.36922/OR026110017
REVIEW ARTICLE

Reconstructing intra-articular cell communication networks: Bionic design and research progress of cartilage organoids

Neng Lai1† Siyu Fan2† Haoshaqiang Zhang3* Yuling Li1,4*
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1 Department of Orthopedics, Laboratory of Biological Tissue Engineering and Digital Medicine, Institute of Nanomedicine Innovation and Translational Research, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
2 Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, United Kingdom
3 Department of Orthopedic Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang Uyghur Autonomous Region, China
4 Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, North Sichuan Medical College, Nanchong, Sichuan, China
†These authors contributed equally to this work.
Received: 11 March 2026 | Revised: 23 April 2026 | Accepted: 28 April 2026 | Published online: 22 May 2026
© 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/ )
Abstract

Osteoarthritis is a chronic disease characterized by progressive degeneration of articular cartilage, with onset and progression strongly associated with dysregulation of complex intracellular communication networks within the joint. Existing therapeutic strategies struggle to precisely regulate cell–cell interactions within the microenvironment, and current in vitro research models still exhibit limitations in simulating multicellular composition, dynamic stimuli, and the natural tissue environment. Organoids, as emerging bionic three-dimensional models, offer a novel approach to reconstructing intercellular communication within joint cavities. In this review, we aimed to summarize advances in the intercellular interactions, construction strategies, and potential applications of cartilage organoids. We discuss the communication networks between chondrocytes, synovial cells, immune cells, and subchondral osteoblasts. Moreover, we analyze the various components and construction techniques for cartilage organoids and explore the potential applications of cartilage organoids in disease modeling, drug screening, and regenerative medicine. We explore innovative directions such as artificial intelligence and integrated organoids, aiming to provide theoretical guidance for advancing cartilage organoids toward higher bionic fidelity and clinical translation.

Keywords
Cartilage organoids
Intercellular communication
Extracellular matrix
Osteoarthritis
Regenerative medicine
Funding
This work was supported by the National Natural Science Foundation of China (82472404), Special Research Project for Chronic Disease of Sichuan Medical Association (2024HR139), Special Program for Regional Collaborative Innovation of the Xinjiang Uygur Autonomous Region— Science and Technology Assistance to Xinjiang Project (2026E01047), Research Innovation Team for Degenerative Joint Diseases and Regenerative Medicine of North Sichuan Medical College (CBYTD-2025A01), and Research Project of the Affiliated Hospital of North Sichuan Medical College (2023-2ZD001, 2024JB001, 2025MSZK001).
Conflict of interest
The authors declare they have no competing interests.
References
  1. Statham P, Jones E, Jennings LM, Fermor HL. Reproducing the biomechanical environment of the chondrocyte for cartilage tissue engineering. Tissue Eng Part B Rev. 2022;28(2):405-420. doi: 10.1089/ten.TEB.2020.0373
  2. Semenistaja S, Skuja S, Kadisa A, Groma V. Healthy and osteoarthritis-affected joints facing the cellular crosstalk. Int J Mol Sci. 2023;24(4):4120. doi: 10.3390/ijms24044120
  3. Molnar V, Matišić V, Kodvanj I, et al. Cytokines and chemokines involved in osteoarthritis pathogenesis. Int J Mol Sci. 2021;22(17):9208. doi: 10.3390/ijms22179208
  4. Giusti V, Scotlandi K. CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology. J Cell Commun Signal. 2021;15(4):545-566. doi: 10.1007/s12079-021-00631-5
  5. Tang Sa, Zhang C, Oo WM, et al. Osteoarthritis. Nat Rev Dis Primers. 2025;11(1):1-22. doi: 10.1038/s41572-025-00594-6
  6. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol. 2020;72(2):220-233. doi: 10.1002/art.41142
  7. Foster NC, Hall NM, Haj AJE. Two-dimensional and three-dimensional cartilage model platforms for drug evaluation and high-throughput screening assays. Tissue Eng Part B Rev. 2022;28(2):421-436. doi: 10.1089/ten.teb.2020.0354
  8. Yeung P, Cheng K, Yan C, Chan B. Collagen microsphere based 3D culture system for human osteoarthritis chondrocytes (hOACs). Sci Rep. 2019;9(1):12453. doi: 10.1038/s41598-019-47946-3
  9. 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
  10. Nath S, Toda S, Okuda S. Intestinal and optic-cup organoids as tools for unveiling mechanics of self-organizing morphogenesis. Biophys Phys. 2022;19:e190048. doi: 10.2142/biophysico.bppb-v19.0048
  11. Shen C, Zhang Z-j, Li X-x, et al. Intersection of nanomaterials and organoids technology in biomedicine. Front Immunol. 2023;14:1172262. doi: 10.3389/fimmu.2023.1172262
  12. Zeng D, Chen Y, Liao Z, et al. Cartilage organoids and osteoarthritis research: a narrative review. Front Bioeng Biotechnol. 2023;11:1278692. doi: 10.3389/fbioe.2023.1278692
  13. Liu S-J, Li J-P, Wang Y-Z, Li K-Z, Zhu Y-T, Feng W-S. Mechanism of Cyathulae Radix in treatment of knee osteoarthritis based on metabolomics. Zhongguo Zhong yao za zhi= Zhongguo Zhongyao Zazhi= China J Chin Mater Med. 2022;47(22):6199-6206. doi: 10.19540/j.cnki.cjcmm.20220706.703
  14. Kang X, Zhang K, Wang Y, Zhao Y, Lu Y. Single-cell RNA sequencing analysis of human chondrocytes reveals cell– cell communication alterations mediated by interactive signaling pathways in osteoarthritis. Front Cell Dev Biol. 2023;11:1099287. doi: 10.3389/fcell.2023.1099287
  15. Wang J, Liu C, Wang T, et al. Single-cell communication patterns and their intracellular information flow in synovial fibroblastic osteoarthritis and rheumatoid arthritis. Immunol Lett. 2023;263:1-13. doi: 10.1016/j.imlet.2023.09.005
  16. Hsiung N, Ju Y, Yang K, et al. Organoid-based tissue engineering for advanced tissue repair and reconstruction. Mater Today Bio. 2025:102093. doi: 10.1016/j.mtbio.2025.102093
  17. Chen B, Sun Y, Xu G, et al. Role of crosstalk between synovial cells and chondrocytes in osteoarthritis. Exp Ther Med. 2024;27(5):201. doi: 10.3892/etm.2024.12490
  18. Liu Z, Sun Y, Pan J, Guo K, Tang Z, Wang X. Single-cell profiling uncovers synovial fibroblast subpopulations associated with chondrocyte injury in osteoarthritis. Front Endocrinol. 2024;15:1479909. doi: 10.3389/fendo.2024.1479909
  19. Platzer H, Nees TA, Reiner T, et al. Impact of mononuclear cell infiltration on chondrodestructive MMP/ADAMTS production in osteoarthritic knee joints—an ex vivo study. J Clin Med. 2020;9(5):1279. doi: 10.3390/jcm9051279
  20. Han W, Xu T, He Z, Luo H, Guo C, Meng J. Single‐Cell RNA Sequencing Study on Two Synovial Derived Tumors in the Temporomandibular Joint. Oral Dis. 2025;31(12):3372-3382. doi: 10.1111/odi.70003
  21. Liu B, Xian Y, Shen T, et al. Targeted Blockage of Pathological Extracellular Vesicles and Particles From Fibroblast‐Like Synoviocytes for Osteoarthritis Relief: Proteomic Analysis and Cellular Effect. J Extracell Vesicles. 2025;14(9):e70162. doi: 10.1002/jev2.70162
  22. Wang H, Shu J, Zhang C, et al. Extracellular vesicle-mediated miR-150-3p delivery in joint homeostasis: a potential treatment for osteoarthritis? Cells. 2022;11(17):2766. doi: 10.3390/cells11172766
  23. Danzeng L, Sun Y, He Z, Hou X, Li L. Single-cell sequencing reveals the immune microenvironment in osteoarthritis: from heterogeneity to therapeutic targets. Int Immunopharmacol. 2025;165:115521. doi: 10.1016/j.intimp.2025.115521
  24. Liao S, Yang M, Li D, et al. Comprehensive bulk and single-cell transcriptome profiling give useful insights into the characteristics of osteoarthritis associated synovial macrophages. Front Immunol. 2023;13:1078414. doi: 10.3389/fimmu.2022.1078414
  25. Chen B, Hong H, Sun Y, et al. Role of macrophage polarization in osteoarthritis. Exp Ther Med. 2022;24(6):757. doi: 10.3892/etm.2022.11693
  26. Troshina EA, Panevin TS, Briskman TD. The role of obesity in the development and progression of osteoarthritis: the influence of medical and surgical therapies for obesity on the course of inflammatory arthritis: A review. Ter Arkhiv 2025;97(5):449-454. doi: 10.26442/00403660.2025.05.203230
  27. Li M, Yin H, Yan Z, et al. The immune microenvironment in cartilage injury and repair. Acta Biomater. 2022;140:23-42. doi: 10.1016/j.actbio.2021.12.006
  28. Wang X-Q, Wang T-T, Fang X-X, Shen W-X, Peng Y-P, Qiu Y-H. Intervention of tyrosine hydroxylase expression alters joint inflammation and Th17/Treg imbalance in Collagen- Induced arthritis. Neuro-Signals. 2021;29(1):1-13. doi: 10.33594/000000328
  29. Fennen M, Weinhage T, Kracke V, et al. A myostatin-CCL20– CCR6 axis regulates Th17 cell recruitment to inflamed joints in experimental arthritis. Sci Rep. 2021;11(1):14145. doi: 10.1038/s41598-021-93599-6
  30. Guo Z, Chen T, Wen X, et al. Harnessing the dual immunomodulatory function of myeloid-derived suppressor cells to reshape the inflammatory microenvironment for osteoarthritis therapy. Mater Today Bio. 2025:102332. doi: 10.1016/j.mtbio.2025.102332
  31. Liu Z, Zhuang Y, Fang L, Yuan C, Wang X, Lin K. Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis. Bioact Mater. 2023;22:423-452. doi: 10.1016/j.bioactmat.2022.10.012
  32. Fang F, Hua M, Yu G. Study of the mechanism of fibroblast-like synoviocytes-derived exosomes inducing macrophages M1 polarization and CD8+ T cells immune regulation ferroptosis and autophagy in rheumatoid arthritis. Immunol Lett. 2024;270:106936. doi: 10.1016/j.imlet.2024.106936
  33. Knights AJ, Farrell EC, Ellis OM, Song MJ, Appleton CT, Maerz T. Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis. eLife. 2025;12:RP93283. doi: 10.7554/eLife.93283
  34. Xiao P, Han X, Huang Y, et al. Reprogramming macrophages via immune cell mobilized hydrogel microspheres for osteoarthritis treatments. Bioact Mater. 2024;32:242-259. doi: 10.1016/j.bioactmat.2023.09.010
  35. Sengprasert P, Kamenkit O, Tanavalee A, Reantragoon R. The immunological facets of chondrocytes in osteoarthritis: a narrative review. J Rheumatol. 2024;51(1):13-24. doi: 10.3899/jrheum.2023-0816
  36. Jiang A, Xu P, Sun S, et al. Cellular alterations and crosstalk in the osteochondral joint in osteoarthritis and promising therapeutic strategies. Connect Tissue Res. 2021;62(6):709- 719. doi: 10.1080/03008207.2020.1870969
  37. Qiangqiang L, Bojing C, Faming T. The role of Wnt signaling pathway in osteoarthritis via the dual-targeted regulation of cartilage and subchondral bone. Chin J Reparative Reconstr Surg. 2020;34(6):797. doi: 10.7507/1002-1892.201909088
  38. Wu X, Crawford R, Xiao Y, Mao X, Prasadam I. Osteoarthritic subchondral bone release exosomes that promote cartilage degeneration. Cells. 2021;10(2):251. doi: 10.3390/cells10020251
  39. Wang X, Lu X, Tian D, et al. Transcriptomic integration and ligand–receptor crosstalk reveal the underlying molecular mechanisms between hip cartilage and subchondral bone in osteonecrosis of femoral head. Gene. 2025;939:149179. doi: 10.1016/j.gene.2024.149179
  40. Li J, Fu X, Zhang D, et al. Co-culture with osteoblasts up-regulates glycolysis of chondrocytes through MAPK/ HIF-1 pathway. Tissue Cell. 2022;78:101892. doi: 10.1016/j.tice.2022.101892
  41. Wang W, Ye R, Xie W, et al. Roles of the calcified cartilage layer and its tissue engineering reconstruction in osteoarthritis treatment. Front Bioeng Biotechnol. 2022;10. doi: 10.3389/fbioe.2022.911281
  42. Wang H, Li M, Wang X, Han J, Zhang X-a. The Notch signaling pathway in regulating bone and cartilage homeostasis: novel insights into the pathogenesis and therapeutics of osteoarthritis. Cell Commun Signal. 2025. doi: 10.1186/s12964-025-02584-3
  43. Chen P, Zeng L, Wang T, et al. The communication role of extracellular vesicles in the osteoarthritis microenvironment. Front Immunol. 2025;16:1549833. doi: 10.3389/fimmu.2025.1549833
  44. Clarke EJ, Chabronova A, Peffers MJ. Extracellular vesicles in cartilage homeostasis, osteoarthritis, and biomarker discovery. Connect Tissue Res. 2025;66(5):428-434. doi: 10.1080/03008207.2025.2524064
  45. Li T, Liu B, Chen K, Lou Y, Jiang Y, Zhang D. Small molecule compounds promote the proliferation of chondrocytes and chondrogenic differentiation of stem cells in cartilage tissue engineering. Biomed Pharmacother. 2020;131:110652. doi: 10.1016/j.biopha.2020.110652
  46. Le H, Xu W, Zhuang X, Chang F, Wang Y, Ding J. Mesenchymal stem cells for cartilage regeneration. J Tissue Eng. 2020;11:2041731420943839. doi: 10.1177/2041731420943839
  47. Theodoridis K, Aggelidou E, Manthou M-E, Kritis A. Hypoxia promotes cartilage regeneration in cell-seeded 3D-printed bioscaffolds cultured with a bespoke 3D culture device. Int J Mol Sci. 2023;24(7):6040. doi: 10.3390/ijms24076040
  48. Levingstone TJ, Moran C, Almeida HV, Kelly DJ, O’Brien FJ. Layer-specific stem cell differentiation in tri-layered tissue engineering biomaterials: Towards development of a single-stage cell-based approach for osteochondral defect repair. Mater Today Bio. 2021;12:100173. doi: 10.1016/j.mtbio.2021.100173
  49. Lee M-S, Stebbins MJ, Jiao H, et al. Comparative evaluation of isogenic mesodermal and ectomesodermal chondrocytes from human iPSCs for cartilage regeneration. Sci Adv. 2021;7(21):eabf0907. doi: 10.1126/sciadv.abf0907
  50. Lach MS, Rosochowicz MA, Richter M, Jagiełło I, Suchorska WM, Trzeciak T. The induced pluripotent stem cells in articular cartilage regeneration and disease modelling: are we ready for their clinical use? Cells. 2022;11(3):529. doi: 10.3390/cells11030529
  51. Larijani L, Rancourt D, Krawetz RJ. Teratoma-free cartilage regeneration using p21−/− iPSCs engineered with iCasp9. Stem Cells Transl Med. 2025;14(11):szaf056. doi: 10.1093/stcltm/szaf056
  52. Xue M, Zheng K, Chen J, et al. Comparative analysis of scaffold-free tissue-engineered cartilage derived from different seed cells: in vitro and in vivo studies. Stem Cells Transl Med. 2025;14(12):szaf057. doi: 10.1093/stcltm/szaf057
  53. Hou M, Bai B, Tian B, et al. Cartilage regeneration characteristics of human and goat auricular chondrocytes. Front Bioeng Biotechnol. 2021;9:766363. doi: 10.3389/fbioe.2021.766363
  54. Zheng R, Wang X, Xue J, et al. Regeneration of subcutaneous cartilage in a swine model using autologous auricular chondrocytes and electrospun nanofiber membranes under conditions of varying gelatin/PCL ratios. Front Bioeng Biotechnol. 2021;9:752677. doi: 10.3389/fbioe.2021.752677
  55. You Q, Liu Z, Zhang J, et al. Human amniotic mesenchymal stem cell sheets encapsulating cartilage particles facilitate repair of rabbit osteochondral defects. Am J Sports Med. 2020;48(3):599-611. doi: 10.1177/0363546519897912
  56. Zha K, Li X, Yang Z, et al. Heterogeneity of mesenchymal stem cells in cartilage regeneration: from characterization to application. NPJ Regen Med. 2021;6(1):14. doi: 10.1038/s41536-021-00122-6
  57. Bai B, Hou M, Hao J, Liu Y, Ji G, Zhou G. Research progress in seed cells for cartilage tissue engineering. Regen Med. 2022;17(9):659-675. doi: 10.2217/rme-2022-0023
  58. Yang Z, Wu Y, Neo SH, et al. Size-based microfluidic-enriched mesenchymal stem cell subpopulations enhance articular cartilage repair. Am J Sports Med. 2024;52(2):503- 515. doi: 10.1177/03635465231214431
  59. Wang X-h, Liu N, Zhang H, Yin Z-s, Zha Z-G. 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
  60. Azain CM, Santamaría Durán AN, Castañeda TC, et al. Interaction Between Human Skeletal and Mesenchymal Stem Cells Under Physioxia Enhances Cartilage Organoid Formation: A Phenotypic, Molecular, and Functional Characterization. Cells. 2025;14(18):1423. doi: 10.3390/cells14181423
  61. Dönges L, Damle A, Mainardi A, et al. Engineered human osteoarthritic cartilage organoids. Biomaterials. 2024;308:122549. doi: 10.1016/j.biomaterials.2024.122549
  62. Valenta T, Degirmenci B, Moor AE, et al. Wnt ligands secreted by subepithelial mesenchymal cells are essential for the survival of intestinal stem cells and gut homeostasis. Cell Rep. 2016;15(5):911-918. doi: 10.1016/j.celrep.2016.03.088
  63. Chen M, Jiang Z, Zou X, You X, Cai Z, Huang J. Advancements in tissue engineering for articular cartilage regeneration. Heliyon. 2024;10(3). doi: 10.1016/j.heliyon.2024.e25400
  64. Fang K, Ueda M, Ren X, et al. Osteogenesis enhancement by immobilized DOPA-BMP-2 in combination with ultrasonic stimulation. RSC Adv. 2025;15(25):19860-19869. doi: 10.1039/d5ra02354h
  65. Ao R, Liang W, Wang Z, et al. Delivery strategies of growth factors in cartilage tissue engineering. Tissue Eng Part B Rev. 2025;31(4):374-389. doi: 10.1089/ten.teb.2024.0158
  66. Kwon H, Paschos NK, Hu JC, Athanasiou K. Articular cartilage tissue engineering: the role of signaling molecules. Cell Mol Life Sci. 2016;73(6):1173-1194. doi: 10.1007/s00018-015-2115-8
  67. Leung HKJ, Huang N, Chen AD, Yan CH, Chan BP. Epidermal growth factor (EGF) enhances chondrocyte chondrogenic expression and phenotype maintenance. Osteoarthr Cartil. 2024;32:S286-S287. doi: 10.1016/j.joca.2024.02.416
  68. Jiang H, Liu W, Chen J, et al. Construction of cartilaginous organoids based on cartilage extracellular matrix microcarriers to promote articular cartilage regeneration through immune regulation. J Orthop Transl. 2025;53:82-98. doi: 10.1016/j.jot.2025.05.005
  69. Ashammakhi N, Ahadian S, Xu C, et al. Bioinks and bioprinting technologies to make heterogeneous and biomimetic tissue constructs. Mater Today Bio. 2019;1:100008. doi: 10.1016/j.mtbio.2019.100008
  70. He M, Li L, Liu Y, et al. Decellularized extracellular matrix coupled with polycaprolactone/laponite to construct a biomimetic barrier membrane for bone defect repair. Int J Biol Macromol. 2024;276:133775. doi: 10.1016/j.ijbiomac.2024.133775
  71. Liu Q, Chen M, Gu P, et al. Covalently grafted biomimetic matrix reconstructs the regenerative microenvironment of the porous gradient polycaprolactone scaffold to accelerate bone remodeling. Small. 2023;19(19):2206960. doi: 10.1002/smll.202206960
  72. Tomaszewski CE, DiLillo KM, Baker BM, Arnold KB, Shikanov A. Sequestered cell-secreted extracellular matrix proteins improve murine folliculogenesis and oocyte maturation for fertility preservation. Acta Biomater. 2021;132:313-324. doi: 10.1016/j.actbio.2021.03.041
  73. Xu Z, Cao J, Zhao Z, et al. A functional extracellular matrix biomaterial enriched with VEGFA and bFGF as vehicle of human umbilical cord mesenchymal stem cells in skin wound healing. Biomed Mater. 2022;17(1):014103. doi: 10.1088/1748-605X/ac37b0
  74. Abune L, Lee K, Wang Y. Development of a biomimetic extracellular matrix with functions of protein sequestration and cell attachment using dual aptamer-functionalized hydrogels. ACS Biomater Sci Eng. 2022;8(3):1279-1289. doi: 10.1021/acsbiomaterials.1c01544
  75. Ren Y, Zhang H, Qin W, Du B, Liu L, Yang J. A collagen mimetic peptide-modified hyaluronic acid hydrogel system with enzymatically mediated degradation for mesenchymal stem cell differentiation. Mater Sci Eng C. 2020;108:110276. doi: 10.1016/j.msec.2019.110276
  76. Wang Y, Cao Z, Li B, Huang Y, Wang G, Chen Q. Hydrogel design for intestinal organoids: principles governing translational regenerative medicine. Biomater Sci. 2025. doi: 10.1039/d5bm00926j
  77. Liu X, Wang B, Ma J, Hu H. 3D-printed heterogeneous biomimetic scaffold utilizing TEMPO-oxidized and mineralized bacterial cellulose nanofibers for osteochondral regeneration. Carbohydr Polym. 2025:124366. doi: 10.1016/j.carbpol.2025.124366
  78. Yang B, Li Z, Yang Z, et al. Recapitulating hypoxic metabolism in cartilaginous organoids via adaptive cell-matrix interactions enhances histone lactylation and cartilage regeneration. Nature Commun. 2025;16(1):2711. doi: 10.1038/s41467-025-57779-6
  79. Farag A, Vaquette C, Hutmacher DW, Bartold PM, Ivanovski S. Fabrication and Characterization of Decellularized Periodontal Ligament Cell Sheet Constructs. In: Oral Biology: Molecular Techniques and Applications. Springer; 2022:429-438.
  80. Borzacchiello A, Gloria A, Mayol L, et al. Natural/synthetic porous scaffold designs and properties for fibro-cartilaginous tissue engineering. J Bioact Compat Polym. 2011;26(5):437- 451. doi: 10.1177/0883911511420149
  81. Gloria A, Russo T, D’Amora U, Santin M, De Santis R, Ambrosio L. Customised multiphasic nucleus/annulus scaffold for intervertebral disc repair/regeneration. Connect Tissue Res. 2020;61(2):152-162. doi: 10.1080/03008207.2019.1650037
  82. Du X, Gu H, Ouyang X, et al. Advanced 3D bioprinting technology for cartilage engineering and regeneration. ACS Biomater Sci Eng. 2025;11(10):5780-5804. doi: 10.1021/acsbiomaterials.5c01107
  83. Chen H, Gonnella G, Huang J, Di-Silvio L. Fabrication of 3D bioprinted bi-phasic scaffold for bone–cartilage interface regeneration. Biomimetics. 2023;8(1):87. doi: 10.3390/biomimetics8010087
  84. Yang X, Wang L, Chen X, Ling B, Xiao J. Digital light processing 3D bioprinting of collagen-based gradient osteochondral scaffold for cartilage-bone regeneration. Int J Biol Macromol. 2025;331(1):148403. doi: 10.1016/j.ijbiomac.2025.148403.
  85. Ruiz-Cantu L, Gleadall A, Faris C, Segal J, Shakesheff K, Yang J. Multi-material 3D bioprinting of porous constructs for cartilage regeneration. Mater Sci Eng C. 2020;109:110578. doi: 10.1016/j.msec.2019.110578.
  86. Sun Y, You Y, Jiang W, Wang B, Wu Q, Dai K. 3D bioprinting dual-factor releasing and gradient-structured constructs ready to implant for anisotropic cartilage regeneration. Sci Adv. 2020;6(37):eaay1422. doi: 10.1126/sciadv.aay1422
  87. Özder MN, Yelkenci A, Kucak M, Altinbay A, Ustündag CB, Ciftci F. Development and characterization of a polycaprolactone/graphene oxide scaffold for meniscus cartilage regeneration using 3D bioprinting. Pharmaceutics. 2025;17(3):346. doi: 10.3390/pharmaceutics17030346
  88. Zhang Y, Li D, Liu Y, et al. 3D-bioprinted anisotropic bicellular living hydrogels boost osteochondral regeneration via reconstruction of cartilage–bone interface. Innov. 2024;5(1). doi: 10.1016/j.xinn.2023.100542
  89. Noh S, Jin YJ, Shin DI, et al. High-performance cartilage tissue bioink for 3D bioprinting with minimal post-processing for articular cartilage regeneration. Biomaterials. 2025:123873. doi: 10.1016/j.biomaterials.2025.123873
  90. Sang S, Mao X, Cao Y, et al. 3D bioprinting using synovium-derived MSC-laden photo-cross-linked ECM bioinkfor cartilage regeneration. ACS Appl Mater Interfaces. 2023;15(7):8895-8913. doi: 10.1021/acsami.2c19058
  91. McGivern S, Boutouil H, Al-Kharusi G, Little S, Dunne NJ, Levingstone TJ. Translational application of 3D bioprinting for cartilage tissue engineering. Bioengineering. 2021;8(10):144. doi: 10.3390/bioengineering8100144
  92. Boretti G, Amirfallah A, Edmunds KJ, Hamzehpour H, Sigurjónsson ÓE. Advancing cartilage tissue engineering: a review of 3D bioprinting approaches and bioink properties. Tissue Eng Part B Rev. 2025;31(4):357-373. doi: 10.1089/ten.TEB.2024.0168
  93. Chauhdari T, Zaidi SA, Su J, Ding Y. Organoids meet microfluidics: recent advancements, challenges, and future of organoids-on-chip. Vitr Models. 2025;4(1):71-88. doi: 10.1007/s44164-025-00086-7
  94. Aubry R, Salmon I, Ranga A. Microfluidic Device Manufacturing by Light-Based 3D Printing for Organoid Vascularization. Springer; 2025.
  95. Su X, Wang M, Yuan R, et al. Organoids in dynamic culture: microfluidics and 3D printing technologies. ACS Biomater Sci Eng. 2025;11(6):3165-3181. doi: 10.1021/acsbiomaterials.4c02245
  96. Liu H, Gan Z, Qin X, Wang Y, Qin J. Advances in microfluidic technologies in organoid research. Adv Healthc Mater. 2024;13(21):2302686. doi: 10.1002/adhm.202302686
  97. Pinho D, Santos D, Vila A, Carvalho S. Establishment of colorectal cancer organoids in microfluidic-based system. Micromachines. 2021;12(5):497. doi: 10.3390/mi12050497
  98. Fang G, Lu H, Al-Nakashli R, et al. Enabling peristalsis of human colon tumor organoids on microfluidic chips. Biofabrication. 2021;14(1):015006. doi: 10.1088/1758-5090/ac2ef9
  99. Atif AR, Aramesh M, Carter S-S, Tenje M, Mestres G. Universal Biomaterial-on-Chip: A versatile platform for evaluating cellular responses on diverse biomaterial substrates. J Mater Sci Mater Med. 2024;35(1):2. doi: 10.1007/s10856-023-06771-x
  100. Saorin G, Caligiuri I, Rizzolio F. Microfluidic organoids-on-a-chip: The future of human models. Elsevier. 2023:41-54.
  101. Yang Y, Qu Y, Wang J, et al. Exploring microfluidics-based organoid interactions through analysis of albumin secretion. Lab Chip. 2025;25(4):487-499. doi: 10.1039/d4lc01085j
  102. Lee M, Song BR, Kim DH, et al. Up-regulation of superoxide dismutase 2 in 3D spheroid formation promotes therapeutic potency of human umbilical cord blood-derived mesenchymal stem cells. Antioxidants. 2020;9(1):66. doi: 10.3390/antiox9010066
  103. Liu H, Zhao C, Liang J, Fan Y, Sun Y, Zhang X. Three-dimensional cell spheroid technology: Recent advances and emerging strategies in cartilage regeneration. Acta Biomater. 2025. doi: 10.1016/j.actbio.2025.10.001
  104. Li H, Chen H, Du C, et al. Effect of hydroxyapatite nanowires on formation and bioactivity of osteoblastic cell spheroid. ACS Biomater Sci Eng. 2024;10(12):7413-7428. doi: 10.1021/acsbiomaterials.4c01159
  105. Hall GN, Fan Y, Viellerobe B, et al. Laser-assisted bioprinting of targeted cartilaginous spheroids for high density bottom-up tissue engineering. Biofabrication. 2024;16(4):045029. doi: 10.1088/1758-5090/ad6e1a
  106. Ramos-Rodriguez DH, Fok SW, Dorais CJ, Filler AC, Caserta M, Leach JK. Decellularized extracellular matrix improves mesenchymal stromal cell spheroid response to chondrogenic stimuli. Tissue Eng Part A. 2025;31(3-4):139- 151. doi: 10.1089/ten.tea.2024.0267
  107. Menssen DM, Feenstra JC, Janssen RP, Abinzano F, Ito K. Cartilage organoids from articular chondroprogenitor cells and their potential to produce neo-hyaline cartilage. Cartilage. 2025:19476035241313179. doi: 10.1177/19476035241313179
  108. Zhang Y, Fang Q, Peng Y, et al. Establishment and characterization of an inflammatory cartilaginous organoids model for organoid transplantation study. J Orthop Transl. 2025;52:376-386. doi: 10.1016/j.jot.2025.05.002
  109. Yang X, Wang L, Chen X, Ling B, Xiao J. Digital light processing 3D bioprinting of collagen-based gradient osteochondral scaffold for cartilage-bone regeneration. Int J Biol Macromol. 2025:148403. doi: 10.1016/j.ijbiomac.2025.148403
  110. Lu J, Gao Y, Cao C, et al. 3D bioprinted scaffolds for osteochondral regeneration: advancements and applications. Mater Today Bio. 2025;32:101834. doi: 10.1016/j.mtbio.2025.101834
  111. Thompson CL, Hopkins T, Bevan C, Screen HR, Wright KT, Knight MM. Human vascularised synovium-on-a-chip: a mechanically stimulated, microfluidic model to investigate synovial inflammation and monocyte recruitment. Biomed Mater. 2023;18(6):065013. doi: 10.1088/1748-605X/acf976
  112. Man Y, Liu Y, Chen Q, et al. Organoids‐On‐a‐Chip for Personalized Precision Medicine. Adv Healthc Mater. 2024;13(30):2401843. doi: 10.1002/adhm.202401843
  113. Kopinski-Grünwald O, Guillaume O, Ferner T, Schädl B, Ovsianikov A. Scaffolded spheroids as building blocks for bottom-up cartilage tissue engineering show enhanced bioassembly dynamics. Acta Biomater. 2024;174:163-176. doi: 10.1016/j.actbio.2023.12.001
  114. Zhang W, Chen L, Li Y, Zhang D, Wang N, Liu X. Cartilage organoids from basic research to clinical translation. iScience. 2025;28(12):114083. doi: 10.1016/j.isci.2025.114083
  115. Jiao Y, Lu S, Zhang J, Zhen J. Applications in osteochondral organoids for osteoarthritis research: from pathomimetic modeling to tissue engineering repair. Front Bioeng Biotechnol. 2025;13:1629608. doi: 10.3389/fbioe.2025.1629608
  116. Rochoux Q, Sopkova-de Oliveira Santos J, Marcelli C, et al. Description of joint alterations observed in a family carrying p. Asn453Ser COMP variant: clinical phenotypes, in silico prediction of functional impact on COMP protein and stability, and review of the literature. Biomolecules. 2021;11(10):1460. doi: 10.3390/biom11101460
  117. Wang L, Xu H, Li X, et al. Cucurbitacin E reduces IL-1β- induced inflammation and cartilage degeneration by inhibiting the PI3K/Akt pathway in osteoarthritic chondrocytes. J Transl Med. 2023;21(1):880. doi: 10.1186/s12967-023-04771-7
  118. Zou Y, Huang P, Lin H, et al. The dynamic progression of temporomandibular joint osteoarthritis-like lesions elicited by mandibular shift in a rat model. Ann Anat Anat Anz. 2024;255:152301. doi: 10.1016/j.aanat.2024.152301
  119. Jariyasakulroj S, Shu Y, Lin Z, et al. Mapping cell diversity and dynamics in inflammatory temporomandibular joint osteoarthritis with pain at single-cell resolution. JCI Insight. 2025;10(3):e184379. doi: 10.1172/jci.insight.184379
  120. Du J, Zhang Z, Bai D, Zhu T, Jiang D. Mechanical response microRNA-145a-5p alleviates osteoarthritis by inhibiting inflammation and promoting chondrogenesis. PeerJ. 2025;13:e19905. doi: 10.7717/peerj.19905
  121. Li Y, Rong Y, Jiang K, Zhang J, Li J, Li G. Regulatory roles of 13 types of RNA modifications in osteoarthritis: based on bulk and single-cell RNA analysis. 3 Biotech. 2025;15(9):279. doi: 10.1007/s13205-025-04448-6
  122. Luo J, Wu L, Liu D, et al. Gene regulatory network analysis identifies key genes and regulatory mechanisms involved in acute myocardial infarction using bulk and single cell RNA-seq data. bioRxiv. 2021:2021.08. 26.457775. doi: 10.3934/mbe.2021386
  123. Luan W, Fan S, Jiang H, Jiang D, Yang J, He L. IL-6 signaling is required for the development and regeneration of ear cartilage in microtia. Front Cell Dev Biol. 2025;13:1625058. doi: 10.3389/fcell.2025.1625058
  124. Yuan X, Li H, Guo F. Temperature cues are integrated in a flexible circadian neuropeptidergic feedback circuit to remodel sleep-wake patterns in flies. PLoS Biol. 2024;22(12):e3002918. doi: 10.1371/journal.pbio.3002918
  125. Francisquini R, Berton R, Soares SG, et al. Community-based network analyses reveal emerging connectivity patterns of protein-protein interactions in murine melanoma secretome. J Proteom. 2021;232:104063. doi: 10.1016/j.jprot.2020.104063.
  126. Chen N, Fan B, He Z, Yu X, Wang J. Identification of HBEGF+ fibroblasts in the remission of rheumatoid arthritis by integrating single-cell RNA sequencing datasets and bulk RNA sequencing datasets. Arthritis Res Ther. 2022;24(1):215. doi: 10.1186/s13075-022-02902-x
  127. Zheng Y-X, Wang K-X, Chen S-J, et al. Decoding the key functional combined components group and uncovering the molecular mechanism of longdan xiegan decoction in treating uveitis. Drug Des Dev Ther. 2022:3991-4011. doi: 10.2147/DDDT.S385136
  128. Yavuz BR, Jang H, Nussinov R. Discovering anticancer drug target combinations via network-informed signaling-based approach. Commun Med. 2025;5(1):428. doi: 10.1038/s43856-025-01150-9
  129. Yang K, Zhang T, Niu R, et al. Unveiling the role of IGF1R in autism spectrum disorder: a multi-omics approach to decipher common pathogenic mechanisms in the IGF signaling pathway. Front Genet. 2024;15:1483574. doi: 10.3389/fgene.2024.1483574
  130. Hayashida Y, Oosawa C, Yasunaga T, Morimoto YV. Cell-to-cell signaling in cell populations with large cell size variability. Biophys J. 2025;124(6):954-962. doi: 10.1016/j.bpj.2024.07.017
  131. Lyu X, Wang J, Su J. Intelligent manufacturing for osteoarthritis organoids. Cell Prolif. 2025;58(7):e70043. doi: 10.1111/cpr.70043
  132. Gao B, Chen Z, Long Y, et al. Cartilage organoids: an emerging platform for novel osteoarthritis therapies. Front Cell Dev Biol. 2025;13:1668766. doi: 10.3389/fcell.2025.1668766
  133. Fang G, Lu H, Rodriguez de la Fuente L, et al. Mammary tumor organoid culture in non‐adhesive alginate for luminal mechanics and high‐throughput drug screening. Adv Sci. 2021;8(21):2102418. doi: 10.1002/advs.202102418
  134. Ali EAM, Smaida R, Meyer M, et al. iPSCs chondrogenic differentiation for personalized regenerative medicine: a literature review. Stem Cell Res Ther. 2024;15(1):185. doi: 10.1186/s13287-024-03794-1
  135. Takahashi Y, Morimura R, Tsukamoto K, et al. In vitro throughput screening of anticancer drugs using patient-derived cell lines cultured on vascularized three-dimensional stromal tissues. Acta Biomater. 2024;183:111-129. doi: 10.1016/j.actbio.2024.05.037
  136. Gilazieva Z, Ponomarev A, Rutland C, Rizvanov A, Solovyeva V. Promising applications of tumor spheroids and organoids for personalized medicine. Cancers. 2020;12(10):2727. doi: 10.3390/cancers12102727
  137. Hu W, Cao M, Liao L, et al. An automated digital microfluidic system based on inkjet printing. Micromachines. 2024;15(11):1285. doi: 10.3390/mi15111285
  138. Xing F, Liu Y-C, Huang S, et al. Accelerating precision anti-cancer therapy by time-lapse and label-free 3D tumor slice culture platform. Theranostics. 2021;11(19):9415. doi: 10.7150/thno.59533
  139. Yang D, Yu Z, Zheng M, et al. Artificial intelligence-accelerated high-throughput screening of antibiotic combinations on a microfluidic combinatorial droplet system. Lab Chip. 2023;23(18):3961-3977. doi: 10.1039/d3lc00647f
  140. Shen C-Y, Zhou Q-R, Wu X, et al. Accelerating cartilage regeneration with DNA-SF hydrogel sustained release system-based cartilage organoids. Mil Med Res. 2025;12(1):39. doi: 10.1186/s40779-025-00625-z
  141. Cho J, Park JJ, Seo E, et al. Self-assembled organoid-tissue modules for scalable organoid engineering: Application to chondrogenic regeneration. Acta Biomater. 2025;197:152- 166. doi: 10.1016/j.actbio.2025.03.028
  142. Sun H, Wu Z, Liu L, et al. Construction and performance evaluation of fully biomimetic hyaline cartilage matrix scaffolds for joint defect regeneration. Biomed Mater. 2024;19(6):065035. doi: 10.1088/1748-605X/ad884f
  143. Chu B, Chu Y-F, He J-M, et al. A nature-inspired multifunctional adhesive for cartilage tissue—biomaterial integration. Soft Matter. 2024;20(9):2017-2023. doi: 10.1039/d4sm00065j
  144. Shen C, Wang J, Li G, et al. Boosting cartilage repair with silk fibroin-DNA hydrogel-based cartilage organoid precursor. Bioact Mater. 2024;35:429-444. doi: 10.1016/j.bioactmat.2024.02.016
  145. Dai M, Sui B, Hua Y, et al. A well defect-suitable and high-strength biomimetic squid type II gelatin hydrogel promoted in situ costal cartilage regeneration via dynamic immunomodulation and direct induction manners. Biomaterials. 2020;240:119841. doi: 10.1016/j.biomaterials.2020.119841
  146. Chen H, Huang J, Li X, et al. Trilayered biomimetic hydrogel scaffolds with dual-differential microenvironment for articular osteochondral defect repair. Mater Today Bio. 2024;26:101051. doi: 10.1016/j.mtbio.2024.101051
  147. Kronemberger GS, Spagnuolo FD, Karam AS, Chattahy K, Storey KJ, Kelly DJ. Rapidly degrading hydrogels to support biofabrication and 3D bioprinting using cartilage microtissues. ACS Biomater Sci Eng. 2024;10(10):6441-6450. doi: 10.1021/acsbiomaterials.4c00819
  148. Kowalczewski A, Sun S, Mai NY, et al. Design optimization of geometrically confined cardiac organoids enabled by machine learning techniques. Cell Rep Methods. 2024;4(6). doi: 10.1016/j.crmeth.2024.100798
  149. Sinha S, McLaren E, Mullick M, et al. FORWARD: A Data- Driven Framework for Network-Based Target Prioritization in Drug Discovery. bioRxiv. 2024:2024.07. 16.602603. doi: 10.1101/2024.07.16.602603
  150. Ronzetti M, Simeonov A. A comprehensive update on the application of high-throughput fluorescence imaging for novel drug discovery. Expert Opin Drug Discov. 2025;20(6):785-797. doi: 10.1080/17460441.2025.2499123
  151. Iftode L, Danceanu CMZ, Cumpata AJ, Popa M, Labusca L, Radulescu L. Computer models and artificial intelligence increase the fidelity and efficiency of the in vitro models for hearing loss. BioMedical Eng OnLine. 2025. doi: 10.1186/s12938-025-01467-5
  152. Biondi-Zoccai G, Frati G, Carnevale R, Booz GW. Human-based technologies in cardiovascular pharmacology research. J Cardiovasc Pharmacol. 2022;86(5):413-419. doi: 10.1097/FJC.0000000000001745
  153. Wang A, Liu J, Wen J, et al. A Multi-Layered Framework for Modeling Human Biology: From Basic AI Agents to a Full- Body AI Agent. 2025. doi: 10.48550/ARXIV.2508.19800
  154. Banh L, Cheung K, Chan M, Young E, Viswanathan S. Advances in organ-on-a-chip systems for modelling joint tissue and osteoarthritic diseases. Osteoarthr Cartil. 2022;30(8):1050-1061. doi: 10.1016/j.joca.2022.03.012
  155. 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/s41584-021-00736-6
  156. Rothbauer M, Byrne RA, Schobesberger S, et al. Establishment of a human three-dimensional chip-based chondro-synovial coculture joint model for reciprocal cross talk studies in arthritis research. Lab Chip. 2021;21(21):4128-4143. doi: 10.1039/d1lc00130b
  157. Han M, Lin W, Cao Y, et al. Microphysiological Systems for Comorbidity Studies: Chronic Kidney Disease and Osteoarthritis. Adv Healthc Mater. 2025;14(31):2500550. doi: 10.1002/adhm.202500550
  158. Pak H-U, Wang D, Qin J, Li H. Microengineering the synovial membrane microenvironment for osteoarthritis research. Connect Tissue Res. 2025:1-9. doi: 10.1080/03008207.2025.2534723
  159. Miao X, Kong K, Rong K, et al. Construction of biomimetic gradient-structured cartilage organoids and mechanistic study of their application for cartilage rejuvenation. Bioact Mater. 2026;59:579-594. doi: 10.1016/j.bioactmat.2025.12.052
  160. Labusca L. Next-generation osteoarthritis models: integrating biological, computational, and engineering approaches. Stem Cell Res Ther. 2025;16(1):686. doi: 10.1186/s13287-025-04790-9
  161. Owaidah AY. Induced pluripotent stem cells in cartilage tissue engineering: a literature review. Biosci Rep. 2024;44(5):BSR20232102. doi: 10.1042/BSR20232102
  162. Xing D, Liu W, Li JJ, et al. Engineering 3D functional tissue constructs using self-assembling cell-laden microniches. Acta Biomater. 2020;114:170-182. doi: 10.1016/j.actbio.2020.07.058
  163. Eguchi T, Okusha Y, Lu Y, Ono K, Taha EA, Fukuoka S. Comprehensive method for exosome isolation and proteome analysis for detection of CCN factors in/on exosomes. CCN Proteins: Methods and Protocols. Springer; 2022:59-76.
  164. Lin W, Wang M, Xu L, Tortorella M, Li G. Cartilage organoids for cartilage development and cartilage-associated disease modeling. Front Cell Dev Biol. 2023;11:1125405. doi: 10.3389/fcell.2023.1125405
  165. Wang M, Wu Y, Li G, et al. Articular cartilage repair biomaterials: strategies and applications. Mater Today Bio. 2024;24:100948. doi: 10.1016/j.mtbio.2024.100948
  166. Wei Y, Li Z, Yu T, et al. Ultrasound-activated piezoelectric biomaterials for cartilage regeneration. Ultrason Sonochemistry. 2025;117:107353. doi: 10.1016/j.ultsonch.2025.107353
  167. Wang Z, Zhu P, Li H, Cheng J, Cai Y. PDGF-BB inhibits F-actin formation and chondrocyte dedifferentiation in osteoarthritis via oxygen-dependent HIF-1α/SCIN regulation and RhoA/ROCK signaling inhibition. Eur J Pharmacol. 2025:178280. doi: 10.1016/j.ejphar.2025.178280
  168. Gao Y, Li Q, Du Z, et al. HAMA-SBMA hydrogel with anti-inflammatory properties delivers cartilage organoids, boosting cartilage regeneration. J Nanobiotechnol. 2025;23(1):401. doi: 10.1186/s12951-025-03475-y
  169. Gao D, Li R, Pan J, et al. 3D bioprinting bone/cartilage organoids: construction, applications, and challenges. J Orthop Transl. 2025;55:75-93. doi: 10.1016/j.jot.2025.08.008
  170. Nilsson Hall G, Mendes LF, Gklava C, Geris L, Luyten FP, Papantoniou I. Developmentally engineered callus organoid bioassemblies exhibit predictive in vivo long bone healing. Adv Sci. 2020;7(2):1902295. doi: 10.1002/advs.201902295
  171. Decoene I, Svitina H, Hamed MB, et al. Callus organoids reveal distinct cartilage to bone transition mechanisms across donors and a role for biological sex. Bone Res. 2025;13(1):41. doi: 10.1038/s41413-025-00418-z
  172. Huang J, Jia S, Liang R, et al. Construction of organoids using bioprinting technology: a frontier exploration of cartilage repair. J Orthop Transl. 2025;54:37-50. doi: 10.1016/j.jot.2025.06.020
  173. Abe K, Yamashita A, Morioka M, et al. Engraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect. Nature Commun. 2023;14(1):804. doi: 10.1038/s41467-023-36408-0
  174. Chen Z, Bo Q, Wang C, Xu Y, Fei X, Chen R. Single BMSC-derived cartilage organoids for gradient heterogeneous osteochondral regeneration by leveraging native vascular microenvironment. J Nanobiotechnol. 2025;23(1):325. doi: 10.1186/s12951-025-03403-0
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