·
REVIEW
·

Future perspectives: advances in bone/cartilage organoid technology and clinical potential

Jingtao Huang1,2 Aikang Li2,3 Rongji Liang1,2 Xiaohao Wu4 Shicheng Jia1,2 Jiayou Chen1,2 Zilu Jiao1 Canfeng Li1* Xintao Zhang1* Jianjing Lin1*
Show Less
1 Department of Sports Medicine and Rehabilitation, Peking University Shenzhen Hospital, Shenzhen, Gunagdong Province, China
2 Department of Clinical Medicine, Shantou University Medical College, Shantou, Gunagdong Province, China
3 Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, Gunagdong Province, China
4 Immunology and Rheumatology, School of Medicine, Stanford University, Palo Alto, CA, USA
Submitted: 28 September 2024 | Revised: 15 October 2024 | Accepted: 21 October 2024 | Published: 28 December 2024
Copyright © 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution–NonCommercial–ShareAlike 4.0 License.
Abstract

Bone and cartilage tissues are essential for movement and structure, yet diseases like osteoarthritis affect millions. Traditional therapies have limitations, necessitating innovative approaches. Organoid technology, leveraging stem cells’ regenerative potential, offers a novel platform for disease modelling and therapy. This review focuses on advancements in bone/cartilage organoid technology, highlighting the role of stem cells, biomaterials, and external factors in organoid development. We discuss the implications of these organoids for regenerative medicine, disease research, and personalised treatment strategies, presenting organoids as a promising avenue for enhancing cartilage repair and bone regeneration. Bone/cartilage organoids will play a greater role in the treatment of bone/cartilage diseases in the future, and promote the progress of biological tissue engineering.

Keywords
biomaterials; bone; cartilage; organoids; stem cells; tissue engineering
References

Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.

1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990 - 2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018, 392, 1789 - 1858.
2. Li, M.; Yin, H.; Yan, Z.; Li, H.; Wu, J.; Wang, Y.; Wei, F.; Tian, G.; Ning, C.; Li, H.; Gao, C.; Fu, L.; Jiang, S.; Chen, M.; Sui, X.; Liu, S.; Chen, Z.; Guo, Q. The immune microenvironment in cartilage injury and repair. Acta Biomater. 2022, 140, 23 - 42.
3. GBD 2021 Osteoarthritis Collaborators. Global, regional, and national burden of osteoarthritis, 1990 - 2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Rheumatology. 2023, 5, e508 - e522.
4. Li, H.; Kong, W.; Liang, Y.; Sun, H. Burden of osteoarthritis in China, 1990 - 2019: findings from the Global Burden of Disease Study 2019. Clin Rheumatol. 2024, 43, 1189 - 1197.
5. von Mentzer, U.; Corciulo, C.; Stubelius, A. Biomaterial integrationin the joint: pathological considerations, immunomodulation, and the extracellular matrix. Macromol Biosci. 2022, 22, e2200037.
6. Lin, A.; Sved Skottvoll, F.; Rayner, S.; Pedersen - Bjergaard, S.; Sullivan, G.; Krauss, S.; Ray Wilson, S.; Harrison, S. 3D cell culture models and organ - on - a - chip: meet separation science and mass spectrometry. Electrophoresis. 2020, 41, 56 - 64.
7. Ballard, D. H.; Boyer, C. J.; Alexander, J. S. Organoids - preclinical models of human disease. N Engl J Med. 2019, 380, 1981 - 1982.
8. Zhang, Y.; Li, G.; Wang, J.; Zhou, F.; Ren, X.; Su, J. Small joint organoids 3D bioprinting: construction strategy and application. Small. 2024, 20, e2302506.
9. Wu, M.; Zheng, K.; Li, W.; He, W.; Qian, C.; Lin, Z.; Xiao, H.; Yang, H.; Xu, Y.; Wei, M.; Bai, J.; Geng, D. Nature - inspired strategies for the treatment of osteoarthritis. Adv Funct Mater. 2024, 34, 2305603.
10. Abraham, D. M.; Herman, C.; Witek, L.; Cronstein, B. N.; Flores, R. L.; Coelho, P. G. Self - assembling human skeletal organoids for disease modeling and drug testing. J Biomed Mater Res B Appl Biomater. 2022, 110, 871 - 884.
11. Sánchez - Porras, D.; Durand - Herrera, D.; Paes, A. B.; Chato - Astrain, J.; Verplancke, R.; Vanfleteren, J.; Sánchez - López, J. D.; García - García Ó, D.; Campos, F.; Carriel, V. Ex vivo generation and characterization of human hyaline and elastic cartilaginous microtissues for tissue engineering applications. Biomedicines. 2021, 9, 292.
12. Manjula - Basavanna, A.; Duraj - Thatte, A. M.; Joshi, N. S. Robust self - regeneratable stiff living materials fabricated from microbial cells. Adv Funct Mater. 2021, 31, 2010784.
13. Kim, I. L.; Mauck, R. L.; Burdick, J. A. Hydrogel design for cartilage tissue engineering: a case study with hyaluronic acid. Biomaterials. 2011, 32, 8771 - 8782.
14. 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, 926.
15. Zhao, D.; Saiding, Q.; Li, Y.; Tang, Y.; Cui, W. Bone organoids: recent advances and future challenges. Adv Healthc Mater. 2024, 13, e2302088.
16. Huang, J.; Zhang, L.; Lu, A.; Liang, C. Organoids as innovative models for bone and joint diseases. Cells. 2023, 12, 1590.
17. Lin, J.; Huang, J.; Jiao, Z.; Nian, M.; Li, C.; Dai, Y.; Jia, S.; Zhang, X. Mesenchymal stem cells for osteoarthritis: recent advances in related cell therapy. Bioeng Transl Med. 2024, e10701.
18. Mendes - Pinheiro, B.; Campos, J.; Marote, A.; Soares - Cunha, C.; Nickels, S. L.; Monzel, A. S.; Cibrão, J. R.; Loureiro - Campos, E.; Serra, S. C.; Barata - Antunes, S.; Duarte - Silva, S.; Pinto, L.; Schwamborn, J. C.; Salgado, A. J. Treating Parkinson’s disease with human bone marrow mesenchymal stem cell secretome: a translational investigation using human brain organoids and different routes of in vivo administration. Cells. 2023, 12, 2565.
19. Brassard, J. A.; Lutolf, M. P. Engineering stem cell self - organization to build better organoids. Cell Stem Cell. 2019, 24, 860 - 876.
20. Aurora, M.; Spence, J. R. hPSC - derived lung and intestinal organoids as models of human fetal tissue. Dev Biol. 2016, 420, 230 - 238.
21. Yang, J.; Zhang, Y. S.; Yue, K.; Khademhosseini, A. Cell - laden hydrogels for osteochondral and cartilage tissue engineering. Acta Biomater. 2017, 57, 1 - 25.
22. Fatehullah, A.; Tan, S. H.; Barker, N. Organoids as an in vitro model of human development and disease. Nat Cell Biol. 2016, 18, 246 - 254.
23. Kleuskens, M. W. A.; Crispim, J. F.; van Donkelaar, C. C.; Janssen, R. P. A.; Ito, K. Evaluating initial integration of cell - based chondrogenic constructs in human osteochondral explants. Tissue Eng Part C Methods. 2022, 28, 34 - 44.
24. Xiahou, Z.; She, Y.; Zhang, J.; Qin, Y.; Li, G.; Zhang, L.; Fang, H.; Zhang, K.; Chen, C.; Yin, J. Designer hydrogel with intelligently switchable stem - cell contact for incubating cartilaginous microtissues. ACS Appl Mater Interfaces. 2020, 12, 40163 - 40175.
25. Yang, Z.; Wang, B.; Liu, W.; Li, X.; Liang, K.; Fan, Z.; Li, J. J.; Niu, Y.; He, Z.; Li, H.; Wang, D.; Lin, J.; Du, Y.; Lin, J.; Xing, D. In situ self - assembled organoid for osteochondral tissue regeneration with dual functional units. Bioact Mater. 2023, 27, 200 - 215.
26. Dai, K.; Zhang, Q.; Deng, S.; Yu, Y.; Zhu, F.; Zhang, S.; Pan, Y.; Long, D.; Wang, J.; Liu, C. A BMP - 2 - triggered in vivo osteo - organoid for cell therapy. Sci Adv. 2023, 9, eadd1541.
27. Li, Q.; Yu, H.; Sun, M.; Yang, P.; Hu, X.; Ao, Y.; Cheng, J. The tissue origin effect of extracellular vesicles on cartilage and bone regeneration. Acta Biomater. 2021, 125, 253 - 266.
28. Shimizu, H.; Yokoyama, S.; Asahara, H. Growth and differentiation of the developing limb bud from the perspective of chondrogenesis. Dev Growth Differ. 2007, 49, 449 - 454.
29. Gao, L.; Orth, P.; Cucchiarini, M.; Madry, H. Effects of solid acellular type - I/III collagen biomaterials on in vitro and in vivo chondrogenesis of mesenchymal stem cells. Expert Rev Med Devices. 2017, 14, 717 - 732.
30. Chamberlain, G.; Fox, J.; Ashton, B.; Middleton, J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007, 25, 2739 - 2749.
31. Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper - Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.; Keating, A.; Prockop, D.; Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006, 8, 315 - 317.
32. Sakaguchi, Y.; Sekiya, I.; Yagishita, K.; Muneta, T. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005, 52, 2521 - 2529.
33. Yoshimura, H.; Muneta, T.; Nimura, A.; Yokoyama, A.; Koga, H.; Sekiya, I. Comparison of rat mesenchymal stem cells derived from bone marrow, synovium, periosteum, adipose tissue, and muscle. Cell Tissue Res. 2007, 327, 449 - 462.
34. Xie, C.; Liang, R.; Ye, J.; Peng, Z.; Sun, H.; Zhu, Q.; Shen, X.; Hong, Y.; Wu, H.; Sun, W.; Yao, X.; Li, J.; Zhang, S.; Zhang, X.; Ouyang, H. High - efficient engineering of osteo - callus organoids for rapid bone regeneration within one month. Biomaterials. 2022, 288, 121741.
35. Scotti, C.; Piccinini, E.; Takizawa, H.; Todorov, A.; Bourgine, P.; Papadimitropoulos, A.; Barbero, A.; Manz, M. G.; Martin, I. Engineering of a functional bone organ through endochondral ossification. Proc Natl Acad Sci U S A. 2013, 110, 3997 - 4002.
36. Hamid, A. A.; Idrus, R. B.; Saim, A. B.; Sathappan, S.; Chua, K. H. Characterization of human adipose - derived stem cells and expression of chondrogenic genes during induction of cartilage differentiation. Clinics (Sao Paulo). 2012, 67, 99 - 106.
37. Baksh, D.; Yao, R.; Tuan, R. S. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells. 2007, 25, 1384 - 1392.
38. Han, Y.; Wu, Y.; Wang, F.; Li, G.; Wang, J.; Wu, X.; Deng, A.; Ren, X.; Wang, X.; Gao, J.; Shi, Z.; Bai, L.; Su, J. Heterogeneous DNA hydrogel loaded with Apt02 modified tetrahedral framework nucleic acid accelerated critical - size bone defect repair. Bioact Mater. 2024, 35, 1 - 16.
39. 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.
40. Vail, D. J.; Somoza, R. A.; Caplan, A. I. MicroRNA regulation of bone marrow mesenchymal stem cell chondrogenesis: toward articular cartilage. Tissue Eng Part A. 2022, 28, 254 - 269.
41. Lemarié, L.; Dargar, T.; Grosjean, I.; Gache, V.; Courtial, E. J.; Sohier, J. Human induced pluripotent spheroids’ growth is driven by viscoelastic properties and macrostructure of 3D hydrogel environment. Bioengineering (Basel). 2023, 10, 1418.
42. Adkar, S. S.; Brunger, J. M.; Willard, V. P.; Wu, C. L.; Gersbach, C. A.; Guilak, F. Genome engineering for personalized arthritis therapeutics. Trends Mol Med. 2017, 23, 917 - 931.
43. Narsinh, K. H.; Plews, J.; Wu, J. C. Comparison of human induced pluripotent and embryonic stem cells: fraternal or identical twins? Mol Ther. 2011, 19, 635 - 638.
44. Hirschi, K. K.; Li, S.; Roy, K. Induced pluripotent stem cells for regenerative medicine. Annu Rev Biomed Eng. 2014, 16, 277 - 294.
45. Zhao, J.; Jiang, W. J.; Sun, C.; Hou, C. Z.; Yang, X. M.; Gao, J. G. Induced pluripotent stem cells: origins, applications, and future perspectives. J Zhejiang Univ Sci B. 2013, 14, 1059 - 1069.
46. O’Connor, S. K.; Katz, D. B.; Oswald, S. J.; Groneck, L.; Guilak, F. Formation of osteochondral organoids from murine induced pluripotent stem cells. Tissue Eng Part A. 2021, 27, 1099 - 1109.
47. Larson, B. L.; Yu, S. N.; Park, H.; Estes, B. T.; Moutos, F. T.; Bloomquist, C. J.; Wu, P. B.; Welter, J. F.; Langer, R.; Guilak, F.; Freed, L. E. Chondrogenic, hypertrophic, and osteochondral differentiation of human mesenchymal stem cells on three - dimensionally woven scaffolds. J Tissue Eng Regen Med. 2019, 13, 1453 - 1465.
48. Liu, Z.; Tang, Y.; Lü, S.; Zhou, J.; Du, Z.; Duan, C.; Li, Z.; Wang, C. The tumourigenicity of iPS cells and their differentiated derivates. J Cell Mol Med. 2013, 17, 782 - 791.
49. Tam, W. L.; Freitas Mendes, L.; Chen, X.; Lesage, R.; Van Hoven, I.; Leysen, E.; Kerckhofs, G.; Bosmans, K.; Chai, Y. C.; Yamashita, A.; Tsumaki, N.; Geris, L.; Roberts, S. J.; Luyten, F. P. Human pluripotent stem cell - derived cartilaginous organoids promote scaffold - free healing of critical size long bone defects. Stem Cell Res Ther. 2021, 12, 513.
50. Hall, G. N.; Tam, W. L.; Andrikopoulos, K. S.; Casas - Fraile, L.; Voyiatzis, G. A.; Geris, L.; Luyten, F. P.; Papantoniou, I. Patterned, organoid - based cartilaginous implants exhibit zone specific functionality forming osteochondral - like tissues in vivo. Biomaterials. 2021, 
51. Liu, H.; Yang, L.; Yu, F. F.; Wang, S.; Wu, C.; Qu, C.; Lammi, M. J.; Guo, X. The potential of induced pluripotent stem cells as a tool to study skeletal dysplasias and cartilage - related pathologic conditions. Osteoarthritis Cartilage. 2017, 25, 616 - 624.
52. Abe, K.; Yamashita, A.; Morioka, M.; Horike, N.; Takei, Y.; Koyamatsu, S.; Okita, K.; Matsuda, S.; Tsumaki, N. Engraftment of allogeneic iPS cell - derived cartilage organoid in a primate model of articular cartilage defect. Nat Commun. 2023, 14, 804.
53. Nilsson Hall, G.; Mendes, L. F.; Gklava, C.; Geris, L.; Luyten, F. P.; Papantoniou, I. Developmentally engineered callus organoid bioassemblies exhibit predictive in vivo long bone healing. Adv Sci (Weinh). 2020, 7, 1902295.
54. Tsumaki, N.; Okada, M.; Yamashita, A. iPS cell technologies and cartilage regeneration. Bone. 2015, 70, 48 - 54.
55. Rodríguez Ruiz, A.; van Hoolwerff, M.; Sprangers, S.; Suchiman, E.; Schoenmaker, T.; Dibbets - Schneider, P.; Bloem, J. L.; Nelissen, R.; Freund, C.; Mummery, C.; Everts, V.; de Vries, T. J.; Ramos, Y. F. M.; Meulenbelt, I. Mutation in the CCAL1 locus accounts for bidirectional process of human subchondral bone turnover and cartilage mineralization. Rheumatology (Oxford). 2022, 62, 360 - 372.
56. Han, B.; Fang, W.; Yang, Z.; Wang, Y.; Zhao, S.; Hoang, B. X.; Vangsness, C. T., Jr. Enhancement of chondrogenic markers by exosomes derived from cultured human synovial fluid - derived cells: a comparative analysis of 2D and 3D conditions. Biomedicines. 2023, 11, 3145.
57. Amarasekara, D. S.; Kim, S.; Rho, J. Regulation of osteoblast differentiation by cytokine networks. Int J Mol Sci. 2021, 22, 2851.
58. Breslin, S.; O’Driscoll, L. Three - dimensional cell culture: the missing link in drug discovery. Drug Discov Today. 2013, 18, 240 - 249.
59. Fang, Y.; Eglen, R. M. Three - dimensional cell cultures in drug discovery and development. SLAS Discov. 2017, 22, 456 - 472.
60. Fuller, J.; Lefferts, K. S.; Shah, P.; Cottrell, J. A. Methodology and characterization of a 3D bone organoid model derived from murine cells. Int J Mol Sci. 2024, 25, 4225.
61. Iordachescu, A.; Hughes, E. A. B.; Joseph, S.; Hill, E. J.; Grover, L. M.; Metcalfe, A. D. Trabecular bone organoids: a micron - scale ‘humanised’ prototype designed to study the effects of microgravity and degeneration. NPJ Microgravity. 2021, 7, 17.
62. Park, Y.; Cheong, E.; Kwak, J. G.; Carpenter, R.; Shim, J. H.; Lee, J. Trabecular bone organoid model for studying the regulation of localized bone remodeling. Sci Adv. 2021, 7, eabd6495.
63. Knowles, H. J.; Chanalaris, A.; Koutsikouni, A.; Cribbs, A. P.; Grover, L. M.; Hulley, P. A. Mature primary human osteocytes in mini organotypic cultures secrete FGF23 and PTH1 - 34 - regulated sclerostin. Front Endocrinol (Lausanne). 2023, 14, 1167734.
64. Kleuskens, M. W. A.; Crispim, J. F.; van Doeselaar, M.; van Donkelaar, C. C.; Janssen, R. P. A.; Ito, K. Neo - cartilage formation using human nondegenerate versus osteoarthritic chondrocyte - derived cartilage organoids in a viscoelastic hydrogel. J Orthop Res. 2023, 41, 1902 - 1915.
65. Crispim, J. F.; Ito, K. De novo neo - hyaline - cartilage from bovine organoids in viscoelastic hydrogels. Acta Biomater. 2021, 128, 236 - 249.
66. Wei, W.; Dai, H. Articular cartilage and osteochondral tissue engineering techniques: recent advances and challenges. Bioact Mater. 2021, 6, 4830 - 4855.
67. D’Costa, K.; Kosic, M.; Lam, A.; Moradipour, A.; Zhao, Y.; Radisic, M. Biomaterials and culture systems for development of organoid and organ - on - a - chip models. Ann Biomed Eng. 2020, 48, 2002 - 2027.
68. Haghwerdi, F.; Khozaei Ravari, M.; Taghiyar, L.; Shamekhi, M. A.; Jahangir, S.; Haririan, I.; Baghaban Eslaminejad, M. Application of bone and cartilage extracellular matrices in articular cartilage regeneration. Biomed Mater. 2021, 16, 042014.
69. Chen, L.; Ren, W. Three - dimensional (3D) and drug - eluting nanofiber coating for prosthetic implants. In Racing for the surface: antimicrobial and interface tissue engineering, Li, B.; Moriarty, T. F.; Webster, T.; Xing, M., eds.; Springer International Publishing: Cham, 2020; pp 91 - 114.
70. Wang, Z.; Wang, Y.; Yan, J.; Zhang, K.; Lin, F.; Xiang, L.; Deng, L.; Guan, Z.; Cui, W.; Zhang, H. Pharmaceutical electrospinning and 3D printing scaffold design for bone regeneration. Adv Drug Deliv Rev. 2021, 174, 504 - 534.
71. Zhou, J.; Xiong, S.; Liu, M.; Yang, H.; Wei, P.; Yi, F.; Ouyang, M.; Xi, H.; Long, Z.; Liu, Y.; Li, J.; Ding, L.; Xiong, L. Study on the influence of scaffold morphology and structure on osteogenic performance. Front Bioeng Biotechnol. 2023, 11, 1127162.
72. 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.
73. Chae, S.; Lee, H.; Ryu, D.; Kim, G. Macroscale pseudo - spheroids fabricated using methacrylated collagen - coated cells. Theranostics. 2024, 14, 924 - 939.
74. Nerger, B. A.; Sinha, S.; Lee, N. N.; Cheriyan, M.; Bertsch, P.; Johnson, C. P.; Mahadevan, L.; Bonventre, J. V.; Mooney, D. J. 3D hydrogel encapsulation regulates nephrogenesis in kidney organoids. Adv Mater. 2024, 36, e2308325.
75. Cullier, A.; Cassé, F.; Manivong, S.; Contentin, R.; Legendre, F.; Garcia Ac, A.; Sirois, P.; Roullin, G.; Banquy, X.; Moldovan, F.; Bertoni, L.; Audigié, F.; Galéra, P.; Demoor, M. Functionalized nanogels with endothelin - 1 and bradykinin receptor antagonist peptides decrease inflammatory and cartilage degradation markers of osteoarthritis in a horse organoid model of cartilage. Int J Mol Sci. 2022, 23, 8949.
76. Cardier, J. E.; Diaz - Solano, D.; Wittig, O.; Sierra, G.; Pulido, J.; Moreno, R.; Fuentes, S.; Leal, F. Osteogenic organoid for bone regeneration: Healing of bone defect in congenital pseudoarthrosis of the tibia. Int J Artif Organs. 2024, 47, 107 - 114.
77. Shehzad, A.; Mukasheva, F.; Moazzam, M.; Sultanova, D.; Abdikhan, B.; Trifonov, A.; Akilbekova, D. Dual - crosslinking of gelatin - based hydrogels: promising compositions for a 3D printed organotypic bone model. Bioengineering (Basel). 2023, 10, 704.
78. Luo, Z.; Xian, B.; Li, K.; Li, K.; Yang, R.; Chen, M.; Xu, C.; Tang, M.; Rong, H.; Hu, D.; Ye, M.; Yang, S.; Lu, S.; Zhang, H.; Ge, J. Biodegradable scaffolds facilitate epiretinal transplantation of hiPSC - Derived retinal neurons in nonhuman primates. Acta Biomater. 2021, 134, 289 - 301.
79. Qiao, F.; Zou, Y.; Bie, B.; Lv, Y. Dual siRNA - loaded cell membrane functionalized matrix facilitates bone regeneration with angiogenesis and neurogenesis. Small. 2024, 20, e2307062.
80. Majumder, J.; Torr, E. E.; Aisenbrey, E. A.; Lebakken, C. S.; Favreau, P. F.; Richards, W. D.; Yin, Y.; Chang, Q.; Murphy, W. L. Human induced pluripotent stem cell - derived planar neural organoids assembled on synthetic hydrogels. J Tissue Eng. 2024, 15, 20417314241230633.
81. Zhang, F. X.; Liu, P.; Ding, W.; Meng, Q. B.; Su, D. H.; Zhang, Q. C.; Lian, R. X.; Yu, B. Q.; Zhao, M. D.; Dong, J.; Li, Y. L.; Jiang, L. B. Injectable mussel - inspired highly adhesive hydrogel with exosomes for endogenous cell recruitment and cartilage defect regeneration. Biomaterials. 2021, 278, 121169.
82. Eiraku, M.; Takata, N.; Ishibashi, H.; Kawada, M.; Sakakura, E.; Okuda, S.; Sekiguchi, K.; Adachi, T.; Sasai, Y. Self - organizing optic - cup morphogenesis in three - dimensional culture. Nature. 2011, 472, 51 - 56.
83. Banihashemian, S. A.; Zamanlui Benisi, S.; Hosseinzadeh, S.; Shojaei, S.; Abbaszadeh, H. A. Chitosan/hyaluronan and alginate - nanohydroxyapatite biphasic scaffold as a promising matrix for osteoarthritis disorders. Adv Pharm Bull. 2024, 14, 176 - 191.
84. Dai, K.; Zhang, W.; Deng, S.; Wang, J.; Liu, C. Sulfated polysaccharide regulates the homing of HSPCs in a BMP - 2 - triggered in vivo osteo - organoid. Adv Sci (Weinh). 2023, 10, e2301592.
85. Vasvani, S.; Kulkarni, P.; Rawtani, D. Hyaluronic acid: A review on its biology, aspects of drug delivery, route of administrations and a special emphasis on its approved marketed products and recent clinical studies. Int J Biol Macromol. 2020, 151, 1012 - 1029.
86. Paggi, C. A.; Teixeira, L. M.; Le Gac, S.; Karperien, M. Joint - on - chip platforms: entering a new era of in vitro models for arthritis. Nat Rev Rheumatol. 2022, 18, 217 - 231.
87. Deng, S.; Zhu, F.; Dai, K.; Wang, J.; Liu, C. Harvest of functional mesenchymal stem cells derived from in vivo osteo - organoids. Biomater Transl. 2023, 4, 270 - 279.
88. Wang, J.; Wu, Y.; Li, G.; Zhou, F.; Wu, X.; Wang, M.; Liu, X.; Tang, H.; Bai, L.; Geng, Z.; Song, P.; Shi, Z.; Ren, X.; Su, J. Engineering large - scale self - mineralizing bone organoids with bone matrix - inspired hydroxyapatite hybrid bioinks. Adv Mater. 2024, 36, e2309875.
89. Sun, Y.; You, Y.; Wu, Q.; Hu, R.; Dai, K. Senescence - targeted MicroRNA/Organoid composite hydrogel repair cartilage defect and prevention joint degeneration via improved chondrocyte homeostasis. Bioact Mater. 2024, 39, 427 - 442.
90. Zhang, L.; Tang, H.; Xiahou, Z.; Zhang, J.; She, Y.; Zhang, K.; Hu, X.; Yin, J.; Chen, C. Solid multifunctional granular bioink for constructing chondroid basing on stem cell spheroids and chondrocytes. Biofabrication. 2022, 14, 035003.
91. Toni, R.; Barbaro, F.; Di Conza, G.; Zini, N.; Remaggi, G.; Elviri, L.; Spaletta, G.; Quarantini, E.; Quarantini, M.; Mosca, S.; Caravelli, S.; Mosca, M.; Ravanetti, F.; Sprio, S.; Tampieri, A. A bioartificial and vasculomorphic bone matrix - based organoid mimicking microanatomy of flat and short bones. J Biomed Mater Res B Appl Biomater. 2024, 112, e35329.
92. Ma, C.; Peng, Y.; Li, H.; Chen, W. Organ - on - a - chip: a new paradigm for drug development. Trends Pharmacol Sci. 2021, 42, 119 - 133.
93. Klotz, B. J.; Oosterhoff, L. A.; Utomo, L.; Lim, K. S.; Vallmajo - Martin, Q.; Clevers, H.; Woodfield, T. B. F.; Rosenberg, A.; Malda, J.; Ehrbar, M.; Spee, B.; Gawlitta, D. A versatile biosynthetic hydrogel platform for engineering of tissue analogues. Adv Healthc Mater. 2019, 8, e1900979.
94. Shen, C.; Wang, J.; Li, G.; Hao, S.; Wu, Y.; Song, P.; Han, Y.; Li, M.; Wang, G.; Xu, K.; Zhang, H.; Ren, X.; Jing, Y.; Yang, R.; Geng, Z.; Su, J. Boosting cartilage repair with silk fibroin - DNA hydrogel - based cartilage organoid precursor. Bioact Mater. 2024, 35, 429 - 444.
95. Pina, S.; Rebelo, R.; Correlo, V. M.; Oliveira, J. M.; Reis, R. L. Bioceramics for osteochondral tissue engineering and regeneration. Adv Exp Med Biol. 2018, 1058, 53 - 75.
96. Li, Z. A.; Shang, J.; Xiang, S.; Li, E. N.; Yagi, H.; Riewruja, K.; Lin, H.; Tuan, R. S. Articular tissue - mimicking organoids derived from mesenchymal stem cells and induced pluripotent stem cells. Organoids. 2022, 1, 135 - 148.
97. Li, L.; Li, H.; Wang, Q.; Xue, Y.; Dai, Y.; Dong, Y.; Shao, M.; Lyu, F. Hydroxyapatite nanoparticles promote the development of bone microtissues for accelerated bone regeneration by activating the FAK/Akt pathway. ACS Biomater Sci Eng. 2024, 10, 4463 - 4479.
98. He, T.; Hausdorf, J.; Chevalier, Y.; Klar, R. M. Trauma induced tissue survival in vitro with a muscle - biomaterial based osteogenic organoid system: a proof of concept study. BMC Biotechnol. 2020, 20, 8.
99. Chung, C.; Kim, Y. K.; Shin, D.; Ryoo, S. R.; Hong, B. H.; Min, D. H. Biomedical applications of graphene and graphene oxide. Acc Chem Res. 2013, 46, 2211 - 2224.
100. Park, S. Y.; Park, J.; Sim, S. H.; Sung, M. G.; Kim, K. S.; Hong, B. H.; Hong, S. Enhanced differentiation of human neural stem cells into neurons on graphene. Adv Mater. 2011, 23, H263 - 267.
101. Chen, H.; Müller, M. B.; Gilmore, K. J.; Wallace, G. G.; Li, D. Mechanically strong, electrically conductive, and biocompatible graphene paper. Adv Mater. 2008, 20, 3557 - 3561.
102. Lee, W. C.; Lim, C. H.; Shi, H.; Tang, L. A.; Wang, Y.; Lim, C. T.; Loh, K. P. Origin of enhanced stem cell growth and differentiation on graphene and graphene oxide. ACS Nano. 2011, 5, 7334 - 7341.
103. Nayak, T. R.; Andersen, H.; Makam, V. S.; Khaw, C.; Bae, S.; Xu, X.; Ee, P. L.; Ahn, J. H.; Hong, B. H.; Pastorin, G.; Özyilmaz, B. Graphene for controlled and accelerated osteogenic differentiation of human mesenchymal stem cells. ACS Nano. 2011, 5, 4670 - 4678.
104. Marrella, A.; Lagazzo, A.; Barberis, F.; Catelani, T.; Quarto, R.; Scaglione, S. Enhanced mechanical performances and bioactivity of cell - laden graphene oxide/alginate hydrogels open new scenario for articular tissue engineering applications. Carbon. 2017, 115, 608 - 616.
105. Choe, G.; Oh, S.; Seok, J. M.; Park, S. A.; Lee, J. Y. Graphene oxide/alginate composites as novel bioinks for three - dimensional mesenchymal stem cell printing and bone regeneration applications. Nanoscale. 2019, 11, 23275 - 23285.
106. Kang, S.; Park, J. B.; Lee, T.-J.; Ryu, S.; Bhang, S. H.; La, W.-G.; Noh, M.-K.; Hong, B. H.; Kim, B.-S. Covalent conjugation of mechanically stiff graphene oxide flakes to three - dimensional collagen scaffolds for osteogenic differentiation of human mesenchymal stem cells. Carbon. 2015, 83, 162 - 172.
107. Shin, S. R.; Aghaei - Ghareh - Bolagh, B.; Dang, T. T.; Topkaya, S. N.; Gao, X.; Yang, S. Y.; Jung, S. M.; Oh, J. H.; Dokmeci, M. R.; Tang, X. S.; Khademhosseini, A. Cell - laden microengineered and mechanically tunable hybrid hydrogels of gelatin and graphene oxide. Adv Mater. 2013, 25, 6385 - 6391.
108. Zhang, J.; Wehrle, E.; Adamek, P.; Paul, G. R.; Qin, X. H.; Rubert, M.; Müller, R. Optimization of mechanical stiffness and cell density of 3D bioprinted cell - laden scaffolds improves extracellular matrix mineralization and cellular organization for bone tissue engineering. Acta Biomater. 2020, 114, 307 - 322.
109. Zhang, J.; Eyisoylu, H.; Qin, X. H.; Rubert, M.; Müller, R. 3D bioprinting of graphene oxide - incorporated cell - laden bone - mimicking scaffolds for promoting scaffold fidelity, osteogenic differentiation and mineralization. Acta Biomater. 2021, 121, 637 - 652.
110. Zhang, J.; Griesbach, J.; Ganeyev, M.; Zehnder, A. K.; Zeng, P.; Schädli, G. N.; Leeuw, A.; Lai, Y.; Rubert, M.; Müller, R. Long - term mechanical loading is required for the formation of 3D bioprinted functional osteocyte bone organoids. Biofabrication. 2022, 14, 035018.
111. Rossi, G.; Manfrin, A.; Lutolf, M. P. Progress and potential in organoid research. Nat Rev Genet. 2018, 19, 671 - 687.
112. Li, J.; Dong, S. The signaling pathways involved in chondrocyte differentiation and hypertrophic differentiation. Stem Cells Int. 2016, 2016, 2470351.
113. Mendes, L. F.; Tam, W. L.; Chai, Y. C.; Geris, L.; Luyten, F. P.; Roberts, S. J. Combinatorial analysis of growth factors reveals the contribution of bone morphogenetic proteins to chondrogenic differentiation of human periosteal cells. Tissue Eng Part C Methods. 2016, 22, 473 - 486.
114. Murphy, M. K.; Huey, D. J.; Hu, J. C.; Athanasiou, K. A. TGF - β1, GDF - 5, and BMP - 2 stimulation induces chondrogenesis in expanded human articular chondrocytes and marrow - derived stromal cells. Stem Cells. 2015, 33, 762 - 773.
115. Matta, C.; Mobasheri, A. Regulation of chondrogenesis by protein kinase C: Emerging new roles in calcium signalling. Cell Signal. 2014, 26, 979 - 1000.
116. Min, S. K.; Kim, M.; Park, J. B. Bone morphogenetic protein 2 - enhanced osteogenic differentiation of stem cell spheres by regulation of Runx2 expression. Exp Ther Med. 2020, 20, 79.
117. Lin, W.; Zhu, X.; Gao, L.; Mao, M.; Gao, D.; Huang, Z. Osteomodulin positively regulates osteogenesis through interaction with BMP2. Cell Death Dis. 2021, 12, 147.
118. Limraksasin, P.; Kondo, T.; Zhang, M.; Okawa, H.; Osathanon, T.; Pavasant, P.; Egusa, H. In vitro fabrication of hybrid bone/cartilage complex using mouse induced pluripotent stem cells. Int J Mol Sci. 2020, 21, 581.
119. Dicks, A. R.; Steward, N.; Guilak, F.; Wu, C. L. Chondrogenic differentiation of human - induced pluripotent stem cells. Methods Mol Biol. 2023, 2598, 87 - 114.
120. Belluzzi, E.; Todros, S.; Pozzuoli, A.; Ruggieri, P.; Carniel, E. L.; Berardo, A. Human cartilage biomechanics: experimental and theoretical approaches towards the identification of mechanical properties in healthy and osteoarthritic conditions. Processes. 2023, 11, 1014.
121. Ansari, S.; Khorshidi, S.; Karkhaneh, A. Engineering of gradient osteochondral tissue: From nature to lab. Acta Biomater. 2019, 87, 41 - 54.
122. Bilic, J.; Izpisua Belmonte, J. C. Concise review: Induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart? Stem Cells. 2012, 30, 33 - 41.
123. Juhász, K. Z.; Hajdú, T.; Kovács, P.; Vágó, J.; Matta, C.; Takács, R. Hypoxic conditions modulate chondrogenesis through the circadian clock: the role of hypoxia - inducible factor - 1α. Cells. 2024, 13, 512.
124. Arai, Y.; Cha, R.; Nakagawa, S.; Inoue, A.; Nakamura, K.; Takahashi, K. Cartilage homeostasis under physioxia. Int J Mol Sci. 2024, 25, 9398.
125. Yu, Y.; Jiang, Y.; Ge, H.; Fan, X.; Gao, H.; Zhou, Z. HIF - 1α in cartilage homeostasis, apoptosis, and glycolysis in mice with steroid - induced osteonecrosis of the femoral head. J Cell Physiol. 2024, 239, e31224.
126. Bolander, J.; Mota, C.; Ooi, H. W.; Agten, H.; Baker, M. B.; Moroni, L.; Luyten, F. P. Bioinspired development of an in vitro engineered fracture callus for the treatment of critical long bone defects. Adv Funct Mater. 2021, 31, 2104159.
127. Li, Z.; Lin, Z.; Liu, S.; Yagi, H.; Zhang, X.; Yocum, L.; Romero - Lopez, M.; Rhee, C.; Makarcyzk, M. J.; Yu, I.; Li, E. N.; Fritch, M. R.; Gao, Q.; Goh, K. B.; O’Donnell, B.; Hao, T.; Alexander, P. G.; Mahadik, B.; Fisher, J. P.; Goodman, S. B.; Bunnell, B. A.; Tuan, R. S.; Lin, H. Human mesenchymal stem cell - derived miniature joint system for disease modeling and drug testing. Adv Sci (Weinh). 2022, 9, e2105909.
128. Paggi, C. A.; 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, 1815 - 1828.
129. Alamán - Díez, P.; García - Gareta, E.; Arruebo, M.; Pérez, M. A bone - on - a - chip collagen hydrogel - based model using pre - differentiated adipose - derived stem cells for personalized bone tissue engineering. J Biomed Mater Res A. 2023, 111, 88 - 105.
130. Bahmaee, H.; Owen, R.; Boyle, L.; Perrault, C. M.; Garcia - Granada, A. A.; Reilly, G. C.; Claeyssens, F. Design and evaluation of an osteogenesis - on - a - chip microfluidic device incorporating 3D cell culture. Front Bioeng Biotechnol. 2020, 8, 557111.
131. Zhang, W.; Wei, X.; Wang, Q.; Dai, K.; Wang, J.; Liu, C. In vivo osteo - organoid approach for harvesting therapeutic hematopoietic stem/progenitor cells. J Vis Exp. 2024, e66026.
132. Yu, L.; Lin, Y. L.; Yan, M.; Li, T.; Wu, E. Y.; Zimmel, K.; Qureshi, O.; Falck, A.; Sherman, K. M.; Huggins, S. S.; Hurtado, D. O.; Suva, L. J.; Gaddy, D.; Cai, J.; Brunauer, R.; Dawson, L. A.; Muneoka, K. Hyaline cartilage differentiation of fibroblasts in regeneration and regenerative medicine. Development. 2022, 149, dev200249.
133. Wilson, H. V. A new method by which sponges may be artificially reared. Science. 1907, 25, 912 - 915.
134. Wu, Y.; Wang, K.; Karapetyan, A.; Fernando, W. A.; Simkin, J.; Han, M.; Rugg, E. L.; Muneoka, K. Connective tissue fibroblast properties are position - dependent during mouse digit tip regeneration. PLoS One. 2013, 8, e54764.
135. Yan, H. H. N.; Siu, H. C.; Law, S.; Ho, S. L.; Yue, S. S. K.; Tsui, W. Y.; Chan, D.; Chan, A. S.; Ma, S.; Lam, K. O.; Bartfeld, S.; Man, A. H. Y.; Lee, B. C. H.; Chan, A. S. Y.; Wong, J. W. H.; Cheng, P. S. W.; Chan, A. K. W.; Zhang, J.; Shi, J.; Fan, X.; Kwong, D. L. W.; Mak, T. W.; Yuen, S. T.; Clevers, H.; Leung, S. Y. A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening. Cell Stem Cell. 2018, 23, 882 - 897.e11.
136. Li, Z.; Yu, D.; Zhou, C.; Wang, F.; Lu, K.; Liu, Y.; Xu, J.; Xuan, L.; Wang, X. Engineering vascularised organoid - on - a - chip: strategies, advances and future perspectives. Biomater Transl. 2024, 5, 21 - 32.
137. Dönges, L.; Damle, A.; Mainardi, A.; Bock, T.; Schönenberger, M.; Martin, I.; Barbero, A. Engineered human osteoarthritic cartilage organoids. Biomaterials. 2024, 308, 122549.
138. van Hoolwerff, M.; Rodríguez Ruiz, A.; Bouma, M.; Suchiman, H. E. D.; Koning, R. I.; Jost, C. R.; Mulder, A. A.; Freund, C.; Guilak, F.; Ramos, Y. F. M.; Meulenbelt, I. High - impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II. Sci Adv. 2021, 7, eabg8583.
139. Liu, H.; Su, J. Organoid and organoid extracellular vesicles for osteoporotic fractures therapy: current status and future perspectives. Interdiscip Med. 2023, 1, e20230011.

Conflict of interest
The authors declare they have no competing interests.
Share
Back to top