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ORIGINAL RESEARCH ARTICLE

Self-organizing vascularized subchondral bone organoids from stromal vascular fraction enable functional osteochondral interface regeneration

Tao Qian1 ,  Jiazhou Wu2 ,  Zexian Liu2,3 ,  Aiyuan Wang2 ,  Yanbin Wu2 ,  Junli Wang1 ,  Hongyu Jiang2 ,  Zhengrui Zhou2 ,  Cheng Huang2 ,  Yazhou Li2 ,  Junming Zhang1 ,  Biao Ma1 ,  Yun Bai1 ,  Jialiang You2 ,  Endong Luo2 ,  Dingkai Wang2 ,  Ying He2* ,  Jiang Peng1,2*
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1 Jinzhou Medical University, Linghe, Jinzhou, Liaoning, China
2 Institute of Orthopedics, Beijing Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries, PLA, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, China
3 Institute of Orthopedics, Graduate School, Chinese People’s Liberation Army General Hospital, Beijing, China
OR 2025, 1(4), 025480037 https://doi.org/10.36922/OR025480037
Received: 30 November 2025 | Revised: 22 December 2025 | Accepted: 25 December 2025 | Published online: 31 December 2025
© 2025 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

Osteoarthritis is closely associated with subchondral bone (SCB) degeneration; however, current models fail to adequately mimic its complex microenvironment. Here, we developed a self-organizing SCB organoid (SSBO) by co-culturing stromal vascular fraction (SVF) cells with decellularized cartilage extracellular matrix (CECM). SVF provided cellular heterogeneity, including adipose-derived stem cells (ADSCs), endothelial cells, pericytes, and macrophages, while CECM served as a native scaffold with tissue-specific cues. SSBO exhibited spontaneous spheroid formation, active cellular infiltration, and dynamic matrix remodeling. Compared to ADSC-only controls, SSBO showed enhanced cell viability, vascularization, collagen remodeling, and spatial organization. Immunostaining and quantitative real-time polymerase chain reaction analyses confirmed an endochondral ossification-like process, characterized by the sequential expression of SOX9, COL2A1, RUNX2, COL1A1, and OCN. In vivo implantation into immunodeficient mice demonstrated robust angiogenesis, bone-like tissue formation, and integration with host vasculature. Furthermore, in a mouse osteochondral defect model, SSBO significantly promoted repair, as evidenced by increased bone volume, improved trabecular architecture, and enhanced cartilage regeneration. Collectively, this study presents a novel strategy for constructing vascularized, immunomodulatory, and osteogenic SCB organoids, offering a promising platform for regenerative medicine and bone–cartilage interface repair.

Graphical abstract
Keywords
Stromal vascular fraction
Organoids
Tissue engineering
Subchondral bone
Funding
This study was supported by the National Key Research and Development Program of China (Grant No. 2024YFA1108600).
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: An update with relevance for clinical practice. Lancet. 2011;377(9783):2115-2126. doi: 10.1016/s0140-6736(11)60243-2

 

  1. James SL, Abate D, Abate KH, et al. 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. The Lancet. 2018;392(10159):1789-1858. doi: 10.1016/s0140-6736(18)32279-7

 

  1. Reichenbach S, Felson DT, Hincapié CA, et al. Effect of biomechanical footwear on knee pain in people with knee osteoarthritis: The BIOTOK randomized clinical trial. JAMA. 2020;323(18):1802-1812. doi: 10.1001/jama.2020.3565

 

  1. Martel-Pelletier J, Barr AJ, Cicuttini FM, et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2:16072. doi: 10.1038/nrdp.2016.72

 

  1. Grynpas MD, Alpert B, Katz I, Lieberman I, Pritzker KP. Subchondral bone in osteoarthritis. Calcif Tissue Int. 1991;49(1):20-26. doi: 10.1007/bf02555898

 

  1. Burr DB, Gallant MA. Bone remodelling in osteoarthritis. Nat Rev Rheumatol. 2012;8(11):665-673. doi: 10.1038/nrrheum.2012.130 7. Suri S, Walsh DA. Osteochondral alterations in osteoarthritis. Bone. 2012;51(2):204-211. doi: 10.1016/j.bone.2011.10.010

 

  1. Goldring SR, Goldring MB. Changes in the osteochondral unit during osteoarthritis: Structure, function and cartilage-bone crosstalk. Nat Rev Rheumatol. 2016;12(11):632-644. doi: 10.1038/nrrheum.2016.148

 

  1. Karsdal MA, Bay-Jensen AC, Lories RJ, et al. The coupling of bone and cartilage turnover in osteoarthritis: Opportunities for bone antiresorptives and anabolics as potential treatments? Ann Rheum Dis. 2014;73(2):336-348. doi: 10.1136/annrheumdis-2013-204111

 

  1. Zhang H, Wang L, Cui J, et al. Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression. Sci Adv. 2023;9(14):eabo7868. doi: 10.1126/sciadv.abo7868

 

  1. 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

 

  1. Lyu X, Wang J, Su J. Intelligent manufacturing for osteoarthritis organoids. Cell Prolif. 2025;58(7):e70043. doi: 10.1111/cpr.70043

 

  1. Day JS, Ding M, Van Der Linden JC, Hvid I, Sumner DR, Weinans H. A decreased subchondral trabecular bone tissue elastic modulus is associated with pre-arthritic cartilage damage. J Orthop Res. 2001;19(5):914-918. doi: 10.1016/s0736-0266(01)00012-2

 

  1. Hu W, Chen Y, Dou C, Dong S. Microenvironment in subchondral bone: Predominant regulator for the treatment of osteoarthritis. Ann Rheum Dis. 2021;80(4):413-422. doi: 10.1136/annrheumdis-2020-218089

 

  1. 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

 

  1. Song H, Li X, Zhao Z, et al. Reversal of osteoporotic activity by endothelial cell-secreted bone targeting and biocompatible exosomes. Nano Lett. 2019;19(5):3040-3048. doi: 10.1021/acs.nanolett.9b00287

 

  1. Castañeda S, Roman-Blas JA, Largo R, Herrero-Beaumont G. Subchondral bone as a key target for osteoarthritis treatment. Biochem Pharmacol. 2012;83(3):315-323. doi: 10.1016/j.bcp.2011.09.018

 

  1. Li G, Yin J, Gao J, et al. Subchondral bone in osteoarthritis: Insight into risk factors and microstructural changes. Arthritis Res Ther. 2013;15(6):223. doi: 10.1186/ar4405

 

  1. Henrotin Y, Pesesse L, Sanchez C. Subchondral bone and osteoarthritis: Biological and cellular aspects. Osteoporos Int. 2012;23(Suppl 8):847-851. doi: 10.1007/s00198-012-2162-z

 

  1. Kim W, Gwon Y, Park S, Kim H, Kim J. Therapeutic strategies of three-dimensional stem cell spheroids and organoids for tissue repair and regeneration. Bioact Mater. 2023;19:50-74. doi: 10.1016/j.bioactmat.2022.03.039

 

  1. Hofer M, Lutolf MP. Engineering organoids. Nat Rev Mater. 2021;6(5):402-420. doi: 10.1038/s41578-021-00279-y

 

  1. Takebe T, Sekine K, Enomura M, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature. 2013;499(7459):481-484. doi: 10.1038/nature12271

 

  1. Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501(7467):373-379. doi: 10.1038/nature12517

 

  1. Takasato M, Er PX, Chiu HS, et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature. 2015;526(7574):564-568. doi: 10.1038/nature15695

 

  1. Zhang C, Jing Y, Wang J, et al. Skeletal organoids. Biomater Transl. 2024;5(4):390-410. doi: 10.12336/biomatertransl.2024.04.005

 

  1. Zakhari JS, Zabonick J, Gettler B, Williams SK. Vasculogenic and angiogenic potential of adipose stromal vascular fraction cell populations in vitro. In Vitro Cell Dev Biol Anim. 2018;54(1):32-40. doi: 10.1007/s11626-017-0213-7

 

  1. Reid G, Cerino G, Melly L, Fusco D, Zhang C, Reuthebuch O, et al. Harnessing the angiogenic potential of adipose-derived stromal vascular fraction cells with perfusion cell seeding. Stem Cell Res Ther. 2025;16(1):220. doi: 10.1186/s13287-025-04286-6

 

  1. Moreira HR, Rodrigues DB, Freitas-Ribeiro S, et al. Spongy-like hydrogels prevascularization with the adipose tissue vascular fraction delays cutaneous wound healing by sustaining inflammatory cell influx. Mater Today Bio. 2022;17:100496. doi: 10.1016/j.mtbio.2022.100496

 

  1. Liu W, Jiang H, Chen J, et al. High paracrine activity of hADSCs cartilage microtissues inhibits extracellular matrix degradation and promotes cartilage regeneration. Mater Today Bio. 2025;30:101372. doi: 10.1016/j.mtbio.2024.101372

 

  1. Kim YS, Majid M, Melchiorri AJ, Mikos AG. Applications of decellularized extracellular matrix in bone and cartilage tissue engineering. Bioeng Transl Med. 2019;4(1):83-95. doi: 10.1002/btm2.10110

 

  1. Morris AH, Stamer DK, Kyriakides TR. The host response to naturally-derived extracellular matrix biomaterials. Semin Immunol. 2017;29:72-91. doi: 10.1016/j.smim.2017.01.002

 

  1. Liu C, Pei M, Li Q, Zhang Y. Decellularized extracellular matrix mediates tissue construction and regeneration. Front Med. 2022;16(1):56-82. doi: 10.1007/s11684-021-0900-3

 

  1. Zhang X, Chen X, Hong H, Hu R, Liu J, Liu C. Decellularized extracellular matrix scaffolds: Recent trends and emerging strategies in tissue engineering. Bioact Mater. 2022;10:15-31. doi: 10.1016/j.bioactmat.2021.09.014

 

  1. Guo X, Liu B, Zhang Y, et al. Decellularized extracellular matrix for organoid and engineered organ culture. J Tissue Eng. 2024;15:1-31. doi: 10.1177/20417314241300386

 

  1. Pan J, Zhou X, Li W, Novotny JE, Doty SB, Wang L. In situ measurement of transport between subchondral bone and articular cartilage. J Orthop Res. 2009;27(10):1347-1352. doi: 10.1002/jor.20883

 

  1. 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

 

  1. 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

 

  1. Zhang X, Jiang W, Wu X, Xie C, Zhang Y, Li L, 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

 

  1. Bora P, Majumdar AS. Adipose tissue-derived stromal vascular fraction in regenerative medicine: A brief review on biology and translation. Stem Cell Res Ther. 2017;8(1):145. doi: 10.1186/s13287-017-0598-y

 

  1. Rehman J, Traktuev D, Li J, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109(10):1292-1298. doi: 10.1161/01.Cir.0000121425.42966.F1

 

  1. Wu J, He Y, Qian T, et al. Stromal vascular fraction self-assembles vascularized osteogenic organoids with immunomodulatory functions. Bioact Mater. 2026;57:323-343. doi: 10.1016/j.bioactmat.2025.10.030

 

  1. Ahmad N, Anker A, Klein S, et al. Autologous fat grafting-a panacea for scar tissue therapy? Cells. 2024;13(16):1384. doi: 10.3390/cells13161384

 

  1. Airuddin SS, Halim AS, Wan Sulaiman WA, Kadir R, Nasir NAM. Adipose-derived stem cell: “Treat or trick.” Biomedicines. 2021;9(11):1624. doi: 10.3390/biomedicines9111624

 

  1. Guan F, Wang R, Yi Z, et al. Tissue macrophages: Origin, heterogeneity, biological functions, diseases and therapeutic targets. Signal Transduct Target Ther. 2025;10(1):93. doi: 10.1038/s41392-025-02124-y

 

  1. Uribe-Querol E, Rosales C. Phagocytosis: Our current understanding of a universal biological process. Front Immunol. 2020;11:1066. doi: 10.3389/fimmu.2020.01066

 

  1. Blanchard L, Girard JP. High endothelial venules (HEVs) in immunity, inflammation and cancer. Angiogenesis. 2021;24(4):719-753. doi: 10.1007/s10456-021-09792-8

 

  1. Mohan SP, Priya SP, Tawfig N, et al. The potential role of adipose-derived stem cells in regeneration of peripheral nerves. Neurol Int. 2025;17(2):23. doi: 10.3390/neurolint17020023

 

  1. Xiong J, Qiang H, Li T, et al. Human adipose-derived stem cells promote seawater-immersed wound healing via proangiogenic effects. Aging (Albany NY). 2021;13(13):17118-17136. doi: 10.18632/aging.202773

 

  1. Li J, Liu Y, Zhang R, et al. Insights into the role of mesenchymal stem cells in cutaneous medical aesthetics: From basics to clinics. Stem Cell Res Ther. 2024;15(1):169. doi: 10.1186/s13287-024-03774-5

 

  1. Vanderstichele S, Vranckx JJ. Anti-fibrotic effect of adipose-derived stem cells on fibrotic scars. World J Stem Cells. 2022;14(2):200-213. doi: 10.4252/wjsc.v14.i2.200
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