Cartilage-on-chip for osteoarthritis drug screening

Abstract

Osteoarthritis (OA) is a common disease characterized by degenerative changes in joint cartilage, manifesting clinically as joint pain, stiffness, and functional impairment. At present, the variety of drugs available for OA is relatively limited, and these primarily serve to alleviate symptoms rather than effectuate actual cartilage repair. The complex cellular environment and biochemical reactions within cartilage tissue further complicate the screening of effective drugs. Organ-on-a-chip is increasingly being applied in the field of drug screening with its ability to mimic the microenvironment and physiological functions of human organs. Herein, we developed a cartilage-on-chip by culturing primary chondrocytes in three dimensions within a microfluidic system. This novel design could maintain the cartilage phenotype and replicate its microenvironment. This cartilage-on-chip cultured under interleukin-1 beta for 3 days displayed a distinct OA-like phenotype, serving as an OA model. Furthermore, we tested different types of drugs, and the outcomes indicated that each tested drug was effective in alleviating OA using the OA-like cartilage-on-chip. Notably, the results obtained were consistent with in vivo findings, thereby validating the utility of the cartilage-on-chip as a reliable platform for drug screening. This study underscores the potential of organ-on-a-chip in advancing OA research and drug development, offering a more physiologically relevant and ethically sustainable alternative to traditional models to reduce costs and enhance efficiency.

Keywords

Osteoarthritis / Organ-on-a-chip / Cartilage / Drug screening

References

[1] Xie R, Pal V, Yu Y, et al. A comprehensive review on 3D tissue models: Biofabrication technologies and preclinical applications. Biomaterials. 2024;304:122408. doi: 10.1016/j.biomaterials.2023.122408

[2] Xu H, Zhang S, Song K, et al. Droplet-based 3D bioprinting for drug delivery and screening. Adv Drug Deliv Rev. 2025;217:115486. doi: 10.1016/j.addr.2024.115486

[3] Bramhe P, Rarokar N, Kumbhalkar R, et al. Natural and synthetic polymeric hydrogel: A bioink for 3D bioprinting of tissue models. J Drug Deliv Sci Technol. 2024;101:106204. doi: 10.1016/j.jddst.2024.106204

[4] Nithin R, Aggarwal A, Sravani AB, et al. Organ-on-a-chip: An emerging research platform. Organogenesis. 2023; 19(1):2278236. doi: 10.1080/15476278.2023.2278236

[5] Wang Y, Gao Y, Pan Y, et al. Emerging trends in organ-on-a-chip systems for drug screening. Acta Pharm Sin B. 2023; 13(6):2483-2509. doi: 10.1016/j.apsb.2023.02.006

[6] Kimura H, Sakai Y, Fujii T. Organ/body-on-a-chip based on microfluidic technology for drug discovery. Drug Metab Pharmacokinet. 2018; 33(1):43-48. doi: 10.1016/j.dmpk.2017.11.003

[7] Piluso S, Li Y, Texeira LM, et al. Effect of fluid flow-induced shear stress on the behavior of synovial fibroblasts in a bioinspired synovium-on-chip model. J Cartil Joint Preserv. 2025;2025:100233. doi: 10.1016/j.jcjp.2025.100233

[8] Ko J, Park D, Lee S, et al. Engineering organ-on-a-chip to accelerate translational research. Micromachines (Basel). 2022; 13(8):1200. doi: 10.3390/mi13081200

[9] Zhou C, Li Z, Lu K, et al. Advances in human organs-on-chips and applications for drug screening and personalized medicine. Fundam Res. 2024. doi: 10.1016/j.fmre.2023.12.019

[10] Monteiro MV, Zhang YS, Gaspar VM, et al. 3D-bioprinted cancer-on-a-chip: Level-up organotypic in vitro models. Trends Biotechnol. 2022; 40(4):432-447. doi: 10.1016/j.tibtech.2021.08.007

[11] Danku AE, Dulf EH, Braicu C, et al. Organ-on-a-chip: A survey of technical results and problems. Front Bioeng Biotechnol. 2022;10:840674. doi: 10.3389/bioe.2022.840674

[12] Li Z, Hui J, Yang P, et al. Microfluidic organ-on-a-chip system for disease modeling and drug development. Biosensors (Basel). 2022; 12(6):370. doi: 10.3390/bios12060370

[13] Nguyen VV, Ye S, Gkouzioti V, et al. A human kidney and liver organoid-based multi-organ-on-a-chip model to study the therapeutic effects and biodistribution of mesenchymal stromal cell-derived extracellular vesicles. J Extracell Vesicles. 2022; 11(11):e12280. doi: 10.1002/jev2.12280

[14] Lipreri MV, Di Pompo G, Boanini E, et al. Bone on-a-chip: A 3D dendritic network in a screening platform for osteocyte-targeted drugs. Biofabrication. 2023; 15(4). doi: 10.1088/1758-5090/acee23

[15] Liao Y, He Y, Liao L. The Invention Relates to A Multi-Organ Chip Series System and A Multi-Organ Chip Construction Method. Patent no: CN116179353A.

[16] Zhu L, Du H, He Y, et al. Re-evaluation of the safety of commonly used traditional Chinese medicine injection in liver based on bioprinting 3D cell microfluidic chip. Cent S Pharm. 2021; 19(11):2304-2310. doi: 10.7539/j.issn.1672 2981.2021.11.011

[17] Shen F, Liao L, Wang W, et al. Construction of microfluidic organ chip and its application in simulating subchondral bone remodeling. Chin J Traumatol. 2024; 40(2):179-189. doi: 10.3760/cma.j.cn501098-20240112-00057

[18] Li Z, Lin Z, Liu S, et al. Human mesenchymal stem cell-derived miniature joint system for disease modeling and drug testing. Adv Sci (Weinh). 2022; 9(21):e2105909. doi: 10.1002/advs.202105909

[19] Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: Structure, composition, and function. Sports Health. 2009; 1(6):461-468. doi: 10.1177/1941738109350438

[20] Hölzl K, Fürsatz M, Göcerler H, et al. Gelatin methacryloyl as environment for chondrocytes and cell delivery to superficial cartilage defects. J Tissue Eng Regener Med. 2022; 16(2):207-222. doi: 10.1002/term.3273

[21] Shen J, Song W, Liu J, et al. 3D bioprinting by reinforced bioink based on photocurable interpenetrating networks for cartilage tissue engineering. Int J Biol Macromol. 2024;254:127671. doi: 10.1016/j.ijbiomac.2023.127671

[22] Cao Y, Cheng P, Sang S, et al. 3D printed PCL/GelMA biphasic scaffold boosts cartilage regeneration using co-culture of mesenchymal stem cells and chondrocytes: In vivo study. Mater Des. 2021;210:110065. doi: 10.1016/j.matdes.2021.110065

[23] Burdick JA, Murphy WL. Moving from static to dynamic complexity in hydrogel design. Nat Commun. 2012;3:1269. doi: 10.1038/ncomms2271

[24] Huh D, Hamilton GA, Ingber DE. From 3D cell culture to organs-on-chips. Trends Cell Biol. 2011; 21(12):745-754. doi: 10.1016/j.tcb.2011.09.005

[25] Goldring MB, Otero M.Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011; 23(5):471-478. doi: 10.1097/BOR.0b013e328349c2b1

[26] Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010; 6(11):625-635. doi: 10.1038/nrrheum.2010.159

[27] Kapoor M, Martel-Pelletier J, Lajeunesse D, et al. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011; 7(1):33-42. doi: 10.1038/nrrheum.2010.196

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

[29] Jhun J, Cho KH, Lee DH, et al. Oral administration of Lactobacillus rhamnosus ameliorates the progression of osteoarthritis by inhibiting joint pain and inflammation. Cells. 2021; 10(5):1057. doi: 10.3390/cells10051057

[30] Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019; 393(10182):1745-1759. doi: 10.1016/s0140-6736(19)30417-9

[31] Paggi CA, Hendriks J, Karperien M, et al. Emulating the chondrocyte microenvironment using multi-directional mechanical stimulation in a cartilage-on-chip. Lab Chip. 2022; 22(9):1815-1828. doi: 10.1039/d1lc01069g

[32] Lin Z, Li Z, Li EN, et al. Osteochondral tissue chip derived from iPSCs: Modeling OA pathologies and testing drugs. Front Bioeng Biotechnol. 2019;7:411. doi: 10.3389/bioe.2019.00411

[33] Liu H, Wu X, Liu R, et al. 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

[34] Sun Q, Zhang Y, Hu B, et al. Development of a dual-responsive injectable GelMA/F127DA hydrogel for enhanced cartilage regeneration in osteoarthritis: Harnessing MMP-triggered and mechanical stress-induced release of therapeutic agents. Int J Biol Macromol. 2025;2025:140823. doi: 10.1016/j.ijbiomac.2025.140823

[35] Paggi C, Venzac B, Leijten J, et al. Cartilage-on-chip: A multi-modal platform to study human chondrocyte’s response to mechanical stimuli. Osteoarthritis Cartil. 2020;28:S176-S177. doi: 10.1016/j.joca.2020.02.287

[36] Banh L, Cheung K, Perera K, et al. Development of a novel synovial joint-on-a-chip to model the complex osteoarthritic knee microenvironment. Osteoarthritis Cartil. 2023;31:S57. doi: 10.1016/j.joca.2023.01.552

[37] Reihs EI, Hayer S, Toegel S, et al. 405 -Advancing synovial tissue models with animal-free organs-on-a-chip -a matter of synovial structure and function in the context of osteoarthritic remodelling. Osteoarthritis Cartil. 2024;32:S287-S288. doi: 10.1016/j.joca.2024.02.418

[38] Kahraman E, Vasconcelos D, Ribeiro B, et al. Deciphering cartilage neuro-immune interactions and innervation profile through 3D engineered osteoarthritic micropathophysiological system. Mater Today Bio. 2025;31:101491. doi: 10.1016/j.mtbio.2025.101491

[39] Nahak BK, Mishra A, Preetam S, et al. Advances in organ-on-a-chip materials and devices. ACS Appl Bio Mater. 2022; 5(8):3576-3607. doi: 10.1021/acsabm.2c00041

[40] Ying-Jin S, Yuste I, González-Burgos E, et al. Fabrication of organ-on-a-chip using microfluidics. Bioprinting. 2025;46:e00394. doi: 10.1016/j.bprint.2025.e00394

[41] Sun L, Bian F, Xu D, et al. Tailoring biomaterials for biomimetic organs-on-chips. Mater Horiz. 2023; 10(11):4724-4745. doi: 10.1039/d3mh00755c

[42] Feng J, Neuzil J, Manz A, et al. Microfluidic trends in drug screening and drug delivery. TrAC Trends Anal Chem. 2023;158:116821. doi: 10.1016/j.trac.2022.116821

[43] Mousavi Shaegh SA, De Ferrari F, Zhang YS, et al. A microfluidic optical platform for real-time monitoring of pH and oxygen in microfluidic bioreactors and organ-on-chip devices. Biomicrofluidics. 2016; 10(4):044111. doi: 10.1063/1.4955155