Benjamin Langford

Background: Articular cartilage forms the outside layer of bones at every joint in the human body. Having healthy articular cartilage is integral for movement and overall musculoskeletal health. There are multiple disease processes associated with this tissue type, the most common being osteoarthritis (OA) and rheumatoid arthritis (RA). Some estimates say that 25% of the adult population is affected by OA, another study reports more than 32.5 million Americans are impacted.^1,2,3,9 Conservative treatment for these diseases is physical therapy, lifestyle modification, and NSAIDs. Currently there is no way to completely reverse cartilage degeneration associated with OA and RA. The most reliable long-term solution to these problems is joint arthroplasty. Over 1 million of these procedures are performed in the US each year.⁴ Thus, a modern medical challenge is to discover a reliable way to regenerate this tissue type, improving joint health and quality of life as people age.

Methods: An initial PubMed database search was conducted with the key words “articular cartilage.” Further refined searches included partner keywords and modifiers including “orthopedic surgery”, “regeneration”, “osteoarthritis”, and “stem cell.” Resulting publications were investigated for discoveries and experiments attempting to regenerate articular cartilage.

Results: Studies have investigated the makeup of cartilage, what the components do, and what cell types and genes contribute to its makeup.^2,3,5,6 Experiments have also been performed attempting to regenerate cartilage through various methods. These studies have been done in mice, rabbits, human stem cell models, and living humans.^6,7,8,9 Some of the methods that have been used in cartilage regeneration include mechanical stimulation^6,9, agonists of drug receptors⁸, injectable biomaterials,¹⁰ platelet lysates with microfracture,¹¹ and biphasic cartilage repair implants.¹² All of these methods showed cartilage regeneration and improved outcomes in their respective studies. Future research should validate the long-term effects of these methods and their efficacy in humans to determine if they are viable alternatives to current treatment.

Conclusions: This review outlines the complex nature of articular cartilage, and the difficulty in long term regeneration and healing of this unique tissue type. The long term efficacy of these various methods would need to be validated for any of them to emerge as a disruptive therapy to conventional treatment. Future innovation could include facilitating the sampling or evaluation of articular cartilage, which would improve monitoring of musculoskeletal health and future attempts at cartilage regeneration.

Works Cited:

1. Żylińska, B., Sobczyńska-Rak, A., Lisiecka, U., Jarosz, S., & Szponder, T. (2021). Structure and pathologies of articular cartilage. In Vivo, 35(3), 1355–1363. https://doi.org/10.21873/invivo.12388
2. Pueyo Moliner, A., Ito, K., Zaucke, F., et al. (2025). Restoring articular cartilage: Insights from structure, composition and development. Nature Reviews Rheumatology, 21, 291–308. https://doi.org/10.1038/s41584-025-01236-7
3. Ouyang, Z., Dong, L., Yao, F., Wang, K., Chen, Y., Li, S., Zhou, R., Zhao, Y., & Hu, W. (2023). Cartilage-related collagens in osteoarthritis and rheumatoid arthritis: From pathogenesis to therapeutics. International Journal of Molecular Sciences, 24(12), 9841. https://doi.org/10.3390/ijms24129841
4. American College of Rheumatology. (2023). Joint replacement surgery. Rheumatology.org. https://rheumatology.org/patients/joint-replacement-surgery
5. Ambrosi, T. H., Sinha, R., Steininger, H. M., Hoover, M. Y., Murphy, M. P., Koepke, L. S., Wang, Y., Lu, W.-J., Morri, M., Neff, N. F., Weissman, I. L., Longaker, M. T., & Chan, C. K. F. (2021). Distinct skeletal stem cell types orchestrate long bone skeletogenesis. eLife, 10, e66063.
6. Xu, H., Fang, W., Liu, Y., et al. (2025). Procr+ chondroprogenitors sense mechanical stimuli to govern articular cartilage maintenance and regeneration. Cell, 194(3), xxx–xxx. https://doi.org/10.1016/j.cell.2025.03.012
7. Park, Y.-B., Ha, C.-W., Lee, C.-H., Yoon, Y. C., & Park, Y.-G. (2017). Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: Results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up. Stem Cells Translational Medicine, 6(2), 613–621.
8. Zhu, Y., Zhang, X., Li, J., et al. (2024). A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration. Cell Reports Medicine, 5(8), 100123. https://doi.org/10.1016/j.xcrm.2024.100123
9. Liu, Y., et al. (2022). Exercise-induced piezoelectric stimulation for cartilage regeneration in rabbits. Science Translational Medicine, 14, eabi7282. https://doi.org/10.1126/scitranslmed.abi7282
10. Kalairaj, M. S., Pradhan, R, Saleem, W., Smith, M. M., & Gaharwar, A. K. (2024). Intra-articular injectable biomaterials for cartilage repair and regeneration. Advanced Healthcare Materials, 13(17), e2303794. https://doi.org/10.1002/adhm.202303794
11. Zhang, H., Li, D., Zheng, W., et al. (2025). Enhancing cartilage repair in osteoarthritis using platelet lysates and arthroscopic microfracture. Drug Design, Development and Therapy, 19, 3827–3843. https://doi.org/10.2147/DDDT.S502935
12. Tseng, T. H., Chen, C. P., Jiang, C. C., et al. (2024). Biphasic cartilage repair implant versus microfracture in the treatment of focal chondral and osteochondral lesions of the knee: A prospective, multi-center, randomized clinical trial. Journal of Orthopaedics and Traumatology, 25(1), 62. https://doi.org/10.1186/s10195-024-00802-1
13. Gandhi, N., Qadeer, A. S., Meher, A., et al. (2023). Costs and models used in the economic analysis of total knee replacement (TKR): A systematic review. PLOS ONE, 18(7), e0280371. https://doi.org/10.1371/journal.pone.0280371