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RESEARCH ARTICLE

3D-bioprinted osteochondral model based on hierarchical polymeric microarchitectures for in vitro osteoarthritis drug screening

Yi-Cheng Wang1† ,  Xiao-Jie Song1† ,  Xiao-Chang Lu1 ,  Zhou-Jiang Chen2 ,  Yue-Wei Li1 ,  Ranjith Kumar Kankala1 ,  Ai-Zheng Chen1 ,  Shi-Bin Wang1* ,  Chao-Ping Fu1*
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1 Institute of Biomaterials and Tissue Engineering & Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen, Fujian, China
2 Engineering Research Center for Pharmaceuticals and Equipment of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, Sichuan, China
†These authors contributed equally to this work.
IJB, 025290288 https://doi.org/10.36922/IJB025290288
Received: 14 July 2025 | Accepted: 10 September 2025 | Published online: 10 September 2025
(This article belongs to the Special Issue Advanced Strategies in 3D Bioprinting for Disease Modelling)
© 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

Compared to conventional two-dimensional (2D) or scaffold-free three-dimensional (3D) drug screening models, biomimetic osteochondral constructs offer superior physiological relevance for studying osteoarthritis (OA) and accelerating therapeutic discovery. This study reports the development of a polymeric microarchitecture (PM)- based 3D osteochondral model for drug screening applications. Microfluidics-assisted fabrication enabled the generation of cartilage-like and osteogenic microtissues by encapsulating chondrocytes and endothelial/osteoblast cells within PMs. These multicellular aggregates were embedded in gelatin methacryloyl and assembled via 3D bioprinting into a stratified osteochondral construct. The model exhibited favorable cell viability, high proliferation, and organized microtissue formation, validating its biological functionality. An OA-like microenvironment was induced using lipopolysaccharide, significantly elevating pro-inflammatory cytokines. Treatment with diclofenac, dexamethasone, or curcumin markedly attenuated this response, reducing tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6 to 42.1, 193.5, and 193.5 pg/mL, respectively, while elevating the anti-inflammatory cytokine IL-10 to 90.2 pg/mL. Overall, this PM-based 3D osteochondral platform reproduces key features of native joint tissue and holds promise for OA research, drug screening, and regenerative medicine.  

Graphical abstract
Keywords
3D osteochondral model
Curcumin
Drug screening
Microfluidics
Porous microspheres
Funding
This work was funded by the National Natural Science Foundation of China (grant numbers: 32271410), the Science and Technology Projects in Fujian Province (grant numbers: 2022FX1 and 2023Y4008), the Natural Science Foundation of Fujian Province (grant number: 2022J01297), the Fundamental Research Funds for the Central Universities (grant number: ZQN-1107), and the Program for Innovative Research Team in Science and Technology in Fujian Province, Scientific Research Funds of Huaqiao University (grant number: 24BS132).
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
References
  1. Bhardwaj N, Singh YP, Mandal BB. Silk fibroin scaffold-based 3D co-culture model formodulation of chondrogenesis without hypertrophy via reciprocal cross-talk and paracrine signaling. ACS Biomater Sci Eng. 2019;5(10):5240-5254. doi: 10.1021/acsbiomaterials.9b00573
  2. Wang D, Liu W, Venkatesan JK, Madry H, Cucchiarini M. Therapeutic controlled release strategies for human osteoarthritis. Adv Healthc Mater. 2024;14(2):e2402737. doi: 10.1002/adhm.202402737
  3. Samvelyan HJ, Hughes D, Stevens C, Staines KA. Models of osteoarthritis: relevance and new insights. Calcif Tissue Int. 2021;109(3):243-256. doi: 10.1007/s00223-020-00670-x
  4. Yessica Eduviges ZC, Martínez-Nava G, Reyes-Hinojosa D, et al. Impact of cadmium toxicity on cartilage loss in a 3D in vitro model. Environ Toxicol Pharmacol. 2020;74:103307. doi: 10.1016/j.etap.2019.103307
  5. Jones G, Winzenberg T. Osteoarthritis: a new short-term treatment option? Lancet. 2019;394(10213):1967-1968. doi: 10.1016/s0140-6736(19)32729-1
  6. Yang D, Xu J, Xu K, Xu P. Skeletal interoception in osteoarthritis. Bone Res. 2024;12(22). doi: 10.1038/s41413-024-00328-6
  7. Cowan KJ, Kleinschmidt-Dörr K, Gigout A, et al. Translational strategies in drug development for knee osteoarthritis. Drug Discov Today. 2020;25(6): 1054-1064. doi: 10.1016/j.drudis.2020.03.015
  8. Assi R, Quintiens J, Monteagudo S, Lories RJ. Innovation in targeted intra-articular therapies for osteoarthritis. Drugs. 2023;83(8):649-663. doi: 10.1007/s40265-023-01863-y
  9. Cao H, Deng S, Chen X, et al. An injectable cartilage-coating composite with long-term protection, effective lubrication and chondrocyte nourishment for osteoarthritis treatment. Acta Biomater. 2024;179:95-105. doi: 10.1016/j.actbio.2024.03.015
  10. Wu M, Zheng K, Li W, et al. Nature-inspired strategies for the treatment of osteoarthritis. Adv Funct Mater. 2023;34(4):2305603. doi: 10.1002/adfm.202305603
  11. Yeung P, Cheng KH, Yan CH, Chan BP. Collagen microsphere based 3D culture system for human osteoarthritis chondrocytes (hOACs). Sci Rep. 2019;9(1):12453. doi: 10.1038/s41598-019-47946-3
  12. Zou Z, Luo X, Chen Z, Zhang YS, Wen C. Emerging microfluidics-enabled platforms for osteoarthritis management: from benchtop to bedside. Theranostics. 2022;12(2):891-909. doi: 10.7150/thno.62685
  13. Liu H, Wu X, Liu R, Wang W, Zhang D, Jiang Q. Cartilage-on-a-chip with magneto-mechanical transformation for osteoarthritis recruitment. Bioact Mater. 2024; 33:61-68. doi: 10.1016/j.bioactmat.2023.10.030
  14. Chapman JH, Ghosh D, Attari S, Ude CC, Laurencin CT. Animal models of osteoarthritis: updated models and outcome measures 2016–2023. Regen Eng Transl Med. 2023;10(2):127-146. doi: 10.1007/s40883-023-00309-x
  15. Singh YP, Moses JC, Bhardwaj N, Mandal BB. Overcoming the dependence on animal models for osteoarthritis therapeutics – the promises and prospects of in vitro models. Adv Healthc Mater. 2021;10(20):2100961. doi: 10.1002/adhm.202100961
  16. Zhou M, Lozano N, Wychowaniec JK, et al. Graphene oxide: a growth factor delivery carrier to enhance chondrogenic differentiation of human mesenchymal stem cells in 3D hydrogels. Acta Biomater. 2019;96:271-280. doi: 10.1016/j.actbio.2019.07.027
  17. Ding SL, Zhao XY, Xiong W, et al. Cartilage lacuna‐inspired microcarriers drive hyaline neocartilage regeneration. Adv Mater. 2023;35(30):e2212114. doi: 10.1002/adma.202212114
  18. Hwang HS, Kim HA. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. In. J Mol Sci. 2015;16(11):26035-26054. doi: 10.3390/ijms161125943
  19. Ebata T, Terkawi MA, Kitahara K, et al. Noncanonical pyroptosis triggered by macrophage‐derived extracellular vesicles in chondrocytes leading to cartilage catabolism in osteoarthritis. Arthritis Rheumatol. 2023;75(8):1358-1369. doi: 10.1002/art.42505
  20. Maihemuti A, Zhang H, Lin X, et al. 3D-printed fish gelatin scaffolds for cartilage tissue engineering. Bioact. Mater. 2023;26:77-87. doi: 10.1016/j.bioactmat.2023.02.007
  21. Korpayev S, Kaygusuz G, Şen M, Orhan K, Oto Ç, Karakeçili A. Chitosan/collagen based biomimetic osteochondral tissue constructs: A growth factor-free approach. Int J Biol Macromol. 2020;156:681-690. doi: 10.1016/j.ijbiomac.2020.04.109
  22. Singh YP, Moses JC, Bandyopadhyay A, Mandal BB. 3D bioprinted silk‐based in vitro osteochondral model for osteoarthritis therapeutics. Adv Healthc Mater. 2022;11(24):200209. doi: 10.1002/adhm.202200209
  23. Salehi S, Brambilla S, Rasponi M, Lopa S, Moretti M. Development of a microfluidic vascularized osteochondral model as a drug testing platform for osteoarthritis. Adv Healthc Mater. 2024;13(31):e2402350. doi: 10.1002/adhm.202402350
  24. Ong LJY, Sun AR, Wang Z, Lee J, Prasadam I, Toh YC. Localized oxygen control in a microfluidic osteochondral interface model recapitulates bone–cartilage crosstalk during osteoarthritis. Adv Funct Mater. 2024;34(28):2315608. doi: 10.1002/adfm.202315608
  25. Wei Y, Deng Y, Ma S, et al. Local drug delivery systems as therapeutic strategies against periodontitis: a systematic review. J Control Release. 2021;333:269-282. doi: 10.1016/j.jconrel.2021.03.041
  26. Jo YK, Lee D. Biopolymer microparticles prepared by microfluidics for biomedical applications. Small. 2020;16(9):1903736. doi: 10.1002/smll.201903736
  27. Jin Z, Zhai Y, Zhou Y, et al. Regulation of mesenchymal stem cell osteogenic potential via microfluidic manipulation of microcarrier surface curvature. Chem Eng J. 2022;448:137739. doi: 10.1016/j.cej.2022.137739
  28. He Q, Zhang J, Liao Y, et al. Current advances in microsphere based cell culture and tissue engineering. Biotechnol Adv. 2020;39:107459. doi: 10.1016/j.biotechadv.2019.107459
  29. Hendow EK, Iacoviello F, Casajuana Ester M, Pellet‐Many C, Day RM. Hierarchically structured biodegradable microspheres promote therapeutic angiogenesis. Adv Healthc Mater. 2024;13(31):e2401832. doi: 10.1002/adhm.202401832
  30. Wang Y, Kankala RK, Zhang J, et al. Modeling endothelialized hepatic tumor microtissues for drug screening. Adv Sci. 2020;7(21):2002002. doi: 10.1002/advs.202002002
  31. Zhang Y, Ma C, Xie J, Ågren H, Zhang H. Black phosphorus/polymers: status and challenges. Adv Mater. 2021;37(33):2100113. doi: 10.1002/adma.202100113
  32. Bai L, Han Q, Han Z, et al. Stem cells expansion vector via bioadhesive porous microspheres for accelerating articular cartilage regeneration. Adv Healthc Mater. 2023;13(3):2302327. doi: 10.1002/adhm.202302327
  33. Dhanabalan KM, Gupta VK, Agarwal R. Rapamycin–PLGA microparticles prevent senescence, sustain cartilage matrix production under stress and exhibit prolonged retention in mouse joints. Biomater Sci. 2020;8(15):4308-4321. doi: 10.1039/D0BM00596G
  34. Wang Y, Yuan X, Yu K, et al. Fabrication of nanofibrous microcarriers mimicking extracellular matrix for functional microtissue formation and cartilage regeneration. Biomaterials. 2018;171:118-132. doi: 10.1016/j.biomaterials.2018.04.033
  35. Hu Z, Lin H, Wang Z, et al. 3D printing hierarchical porous nanofibrous scaffold for bone regeneration. Small. 2024; 21(2):2405406. doi: 10.1002/smll.202405406
  36. Dai W, Li S, Jia H, et al. Indirect 3D printing CDHA scaffolds with hierarchical porous structure to promote osteoinductivity and bone regeneration. J Mater Sci Technol. 2025;207:295-307. doi: 10.1016/j.jmst.2024.04.032
  37. He J, Sun Y, Gao Q, et al. Gelatin methacryloyl hydrogel, from standardization, performance, to biomedical application. Adv Healthc Mater. 2023;12(23):2300395. doi: 10.1002/adhm.202300395
  38. Huang Z, Kraus VB. Does lipopolysaccharide-mediated inflammation have a role in OA? Nat Rev Rheumatol. 2016;12(2):123-129. doi: 10.1038/nrrheum.2015.158
  39. Xue C, Tian J, Cui Z, et al. Reactive oxygen species (ROS)- mediated M1 macrophage-dependent nanomedicine remodels inflammatory microenvironment for osteoarthritis recession. Bioact Mater. 2024;33:545-561. doi: 10.1016/j.bioactmat.2023.10.032
  40. Yu X, Gholipourmalekabadi M, Wang X, Yuan C, Lin K. Three‐dimensional bioprinting biphasic multicellular living scaffold facilitates osteochondral defect regeneration. Interdiscip Mater. 2024;3(5):738-756. doi: 10.1002/idm2.12181
  41. Jhun J, Min H-K, Na HS, et al. Combinatmarion treatment with Lactobacillus acidophilus LA-1, vitamin B, and curcumin ameliorates the progression of osteoarthritis by inhibiting the pro-inflammatory mediators. Immunol Lett. 2020;228:112-121. doi: 10.1016/j.imlet.2020.10.008
  42. Luo W, Bai L, Zhang J, et al. Polysaccharides-based nanocarriers enhance the anti-inflammatory effect of curcumin. Carbohydr Polym. 2023;311:120718. doi: 10.1016/j.carbpol.2023.120718
  43. Liu X, Chen B, Chen J, et al. A cardiac‐targeted nanozyme interrupts the inflammation‐free radical cycle in myocardial infarction. Adv Mater. 2023;36(2):2308477. doi: 10.1002/adma.202308477
  44. Yao Q, Yang Y, Hu M, Qiu Y, Shi Y, Kou L. Liposomal dexamethasone for intra-articular therapy: Functional strategies and clinical progress. J Control Release. 2025;385:114040. doi: 10.1016/j.jconrel.2025.114040
  45. da Costa BR, Pereira TV, Saadat P, et al. Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis. BMJ. 2021;375:n2321. doi: 10.1136/bmj.n2321
  46. Chen Y, Chen L-F, Wang Y, et al. Engineered dECM-based microsystem promotes cartilage regeneration in osteoarthritis by synergistically enhancing chondrogenesis of BMSCs and anti-inflammatory effect. Compos B. 2025;290:111974. doi: 10.1016/j.compositesb.2024.111974
  47. Wu D, Yu Y, Zhao C, et al. NK cell-encapsulated porous microspheres via microfluidic electrospray for tumor immunotherapy. ACS Appl Mater Interfaces. 2019;11(37):33716-33724. doi: 10.1021/acsami.9b12816
  48. Chen X, Zhang D, Wang X, et al. Preparation of porous GelMA microcarriers by microfluidic technology for stem-cell culture. Chem Eng J. 2023;477:146444. doi: 10.1016/j.cej.2023.146444
  49. Long J, Yao Z, Zhang W, et al. Regulation of osteoimmune microenvironment and osteogenesis by 3D‐printed PLAG/ black phosphorus scaffolds for bone regeneration. Adv Sci. 2023;10(28):2302539. doi: 10.1002/advs.202302539
  50. Wei J, Xia X, Xiao S, et al. Sequential dual‐biofactor release from the scaffold of mesoporous HA microspheres and PLGA matrix for boosting endogenous bone regeneration. Adv Healthc Mater. 2023;12(20):2300624. doi: 10.1002/adhm.202300624
  51. Dong R, Kang M, Qu Y, Hou T, Zhao J, Cheng X. Incorporating hydrogel (with low polymeric content) into 3D‐printed PLGA scaffolds for local and sustained release of BMP2 in repairing large segmental bone defects. Adv Healthc Mater. 2024;14(2):2403613. doi: 10.1002/adhm.202403613
  52. Kamboj N, Kazantseva J, Rahmani R, Rodríguez MA, Hussainova I. Selective laser sintered bio-inspired silicon-wollastonite scaffolds for bone tissue engineering. Mater Sci Eng C. 2020;116:111223. doi: 10.1016/j.msec.2020.111223
  53. Zhu S, Bennett S, Kuek V, et al. Endothelial cells produce angiocrine factors to regulate bone and cartilage via versatile mechanisms. Theranostics. 2020;10(13):5957-5965. doi: 10.7150/thno.45422
  54. Sun T, Feng Z, He W, et al. Novel 3D-printing bilayer GelMA-based hydrogel containing BP, β-TCP and exosomes for cartilage–bone integrated repair. Biofabrication. 2023;16(1):015008. doi: 10.1088/1758-5090/ad04fe
  55. Liu S, Chen G, Chen Z, Wang F, Lv Y. Research progress on stiffness controllable scaffolds based on gelatin methacryloyl hydrogels for tissue repair and reconstruction. Int J Biol Macromol. 2025;321(Pt 3):146485. doi: 10.1016/j.ijbiomac.2025.146485
  56. Matai I, Kaur G, Seyedsalehi A, McClinton A, Laurencin CT. Progress in 3D bioprinting technology for tissue/organ regenerative engineering. Biomaterials. 2020;226:119536. doi: 10.1016/j.biomaterials.2019.119536
  57. Tong W, Chen X, Song X, et al. Resveratrol inhibits LPS-induced inflammation through suppressing the signaling cascades of TLR4-NF-κB/MAPKs/IRF3. Exp Ther Med. 2020;19(3):1824-1834. doi: 10.3892/etm.2019.8396
  58. Lei J, Fu Y, Zhuang Y, Zhang K. Sema4D aggravated LPS-Induced injury via activation of the MAPK signaling pathway in ATDC5 chondrocytes. Biomed Res Int. 2020;2020:8691534. doi: 10.1155/2020/8691534
  59. Peng K, Li Y, Lu C, Hu S. ABIN-1 protects chondrocytes from lipopolysaccharide-induced inflammatory injury through the inactivation of NF-κB signalling. Clin Exp Pharmacol Physiol. 2020;47(7):1212-1220. doi: 10.1111/1440-1681.13291
  60. Yan F, Li H, Zhong Z, et al. Co-delivery of prednisolone and curcumin in human serum albumin nanoparticles for effective treatment of rheumatoid arthritis. Int J Nanomedicine. 2019;14:9113-9125. doi: 10.2147/ijn.S219413

 

 

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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing
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