Modern Cellular Therapies in Orthopedics

Radosław Zagożdżon; Ewa Olender; Piotr Strzelczyk; Marcin Kowalski; Sławomir Żarek; Robert Jopowicz

doi:10.56782/pps.822

Published : 2025-12-11

No. 2025 (Early Access)

Modern Cellular Therapies in Orthopedics

Radosław Zagożdżon

Ewa Olender

Piotr Strzelczyk

Marcin Kowalski

Sławomir Żarek

Robert Jopowicz

DOI: https://doi.org/10.56782/pps.822

Abstract

Cellular therapies, so-called “living drugs”, are reshaping the landscape of clinical and experimental medicine and are increasingly recognized as a new class of pharmaceutics. They provide unprecedented opportunities for treatment of a range of diseases, including orthopedic disorders, which represent a significant burden in global health. Traditional treatments in orthopedics often address symptoms rather than restore damaged tissues or target malignancies. Initially, cellular therapies, particularly those involving stem and progenitor cells, have emerged as a promising frontier in regenerative orthopedics. Additionally, genetically engineered immune cell therapies, such as chimeric antigen receptor (CAR)-T/NK cells, have been proposed for applications in onco-orthopedics, offering targeted approaches to bone and soft tissue sarcomas, but also, in parallel to CAR-bearing regulatory T cells, in a range of autoimmune diseases. This review provides an overview of current cellular therapies, either in clinical use or under investigation in orthopedics, with a focus on platelet-rich plasma- or chondrocyte-based approaches, mesenchymal stromal cells (MSC), induced pluripotent stem cells (iPSC), and potential applications of CAR-based immune cell therapies. Their biological basis, mechanisms of action, preclinical evidence, clinical applications, challenges, and future directions are discussed.

Keywords:

Orthopedics, Cellular Therapies, Regenerative Medicine, Chimeric Antigen Receptors

Similar Articles

Olga Ciepiela, Patrycja Dąbrowska, Helena Donica, A. Goliszek, Ireneusz P. Grudziński, J. Jedlińska, Maciej Korpysz, Paweł Kozłowski, Natalia Krześniak, Kamila Marciniec, D. Mika, K. Ołownia, Aleksandra Ozygała, Monika Paskudzka, J. Rachuna, Klaudia Radoszkiewicz, K. Rozmianiec, Mariusz Rozwandowicz, Anna Sarnowska, D. Sitarz, K. Szafraniec, Magdalena Szymańska, Monika Szymoniak, Marcin Śmiarowski, WARSZAWSKA JESIEŃ DIAGNOSTYCZNA , Prospects in Pharmaceutical Sciences: Vol. 21 No. S1 (2023): Konferencja naukowo-szkoleniowa Warszawska Jesień Diagnostyczna 28.09.-29.09.2023
Kinga Kocur, Katarzyna Camlet, Anna Ziobro, Mateusz Ziomek, Wojciech Kaźmierski, Paulina Lis, Jakub Jurek, Anna Lis, Renaissance of Ketamine , Prospects in Pharmaceutical Sciences: Vol. 22 No. 3 (2024)
Mateusz Sobczyk, Daria Żuraw, Paulina Oleksa, Kacper Jasiński, Mikołaj Porzak, Michał Dacka, SGLT2 inhibitors and their possible use in prevention and treatment of neurological diseases , Prospects in Pharmaceutical Sciences: Vol. 22 No. 1 (2024)
Katarzyna Łysiak, Anna Łysiak, Barbara Maziarz, Paulina Przywara, Natalia Bogumiłło, Kinga Ściurka, Julia Ignacak, Mikołaj Borek, The use of botulinum toxin in ophthalmology , Prospects in Pharmaceutical Sciences: Vol. 22 No. 4 (2024)
Kinga Sosnowicz, Monika Czerwińska, Plant materials used in eye diseases - from use in traditional medicine to research in antioxidant, anti - inflammatory, and antibacterial activity , Prospects in Pharmaceutical Sciences: Vol. 22 No. 3 (2024)
Elhassan Hussein Eltom, Bandar Theyab Alenezi, Mohamed Soliman, Muhammad Jan, Amro Soliman, Neglected Tropical Diseases: Current Treatment Challenges and Future Therapeutic Potentials , Prospects in Pharmaceutical Sciences: Vol. 23 No. 2 (2025)
Nour Mobayed, Dima Joujeh, The therapeutic potential of mesenchymal stromal cells and their secretome in sport-related injuries , Prospects in Pharmaceutical Sciences: Vol. 23 No. 1 (2025)
Joanna Warguła, Not only foils and packaging. Part 2: About the applications of polymers in orthopedics, surgery and dermatology , Prospects in Pharmaceutical Sciences: Vol. 23 No. 4 (2025)
Anna Szymanowska, Agnieszka Gornowicz, Anna Bielawska, Krzysztof Bielawski, PLANT STEM CELLS AND THEIR APPLICATION IN COSMETOLOGY AND REGENERATIVE MEDICINE , Prospects in Pharmaceutical Sciences: Vol. 17 No. 7 (2019)
Aleksandra Białczyk, Gabriela Leśniak, Filip Nadolny, Justyna Mrowiec, Antoni Otałęga, Exploring digital health horizons: a narrative review of e-health innovations in Poland, Spain, Romania and Estonia. , Prospects in Pharmaceutical Sciences: Vol. 22 No. 1 (2024)

1 2 3 4 5 6 7 8 9 > >>

You may also start an advanced similarity search for this article.

Details

References

Statistics

Authors

Download files

PDF

Citation rules

Zagożdżon, R., Olender, E., Strzelczyk, P., Kowalski, M., Żarek, S., & Jopowicz, R. (2025). Modern Cellular Therapies in Orthopedics. Prospects in Pharmaceutical Sciences, (2025 (Early Access). https://doi.org/10.56782/pps.822

Altmetric indicators

Cited by / Share

Licence

This work is licensed under a Creative Commons Attribution 4.0 International License.

References

1. Wiewiorska-Krata, N.; Foroncewicz, B.; Mucha, K.; Zagozdzon, R. Cell therapies for immune-mediated disorders. Front Med (Lausanne) 2025, 12, 1550527, DOI: 10.3389/fmed.2025.1550527 DOI: https://doi.org/10.3389/fmed.2025.1550527

2. Collaborators, G. B. D. O. M. D. Global, regional, and national burden of other musculoskeletal disorders, 1990-2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol 2023, 5 (11), e670-e682, DOI: 10.1016/S2665-9913(23)00232-1 DOI: https://doi.org/10.1016/S2665-9913(23)00232-1

3. Jiang, F.; Lu, C.; Zeng, Z.; Sun, Z.; Qiu, Y. Global burden of disease for musculoskeletal disorders in all age groups, from 2024 to 2050, and a bibliometric-based survey of the status of research in geriatrics, geriatric orthopedics, and geriatric orthopedic diseases. J Orthop Surg Res 2025, 20 (1), 179, DOI: 10.1186/s13018-025-05580-y DOI: https://doi.org/10.1186/s13018-025-05580-y

4. Das, S.; Thakur, A.; Datta, A.; Sahoo, A.; Bandyopadhyay, S.; Sah, A. K. Advances in Regenerative Medicine for Orthopedic Injuries: A Comprehensive Review. Cureus 2025, 17 (2), e79860, DOI: 10.7759/cureus.79860 DOI: https://doi.org/10.7759/cureus.79860

5. Parums, D. V. A Review of CAR T Cells and Adoptive T-Cell Therapies in Lymphoid and Solid Organ Malignancies. Med Sci Monit 2025, 31, e948125, DOI: 10.12659/MSM.948125 DOI: https://doi.org/10.12659/MSM.948125

6. Strzelec, M.; Detka, J.; Mieszczak, P.; Sobocinska, M. K.; Majka, M. Immunomodulation-a general review of the current state-of-the-art and new therapeutic strategies for targeting the immune system. Front Immunol 2023, 14, 1127704, DOI: 10.3389/fimmu.2023.1127704 DOI: https://doi.org/10.3389/fimmu.2023.1127704

7. Pittenger, M. F.; Discher, D. E.; Peault, B. M.; Phinney, D. G.; Hare, J. M.; Caplan, A. I. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med 2019, 4, 22, DOI: 10.1038/s41536-019-0083-6 DOI: https://doi.org/10.1038/s41536-019-0083-6

8. Trapana, J.; Weinerman, J.; Lee, D.; Sedani, A.; Constantinescu, D.; Best, T. M.; Hornicek, F. J., Jr.; Hare, J. M. Cell-based therapy in the treatment of musculoskeletal diseases. Stem Cells Transl Med 2024, 13 (10), 959-978, DOI: 10.1093/stcltm/szae049 DOI: https://doi.org/10.1093/stcltm/szae049

9. Pittenger, M. F.; Mackay, A. M.; Beck, S. C.; Jaiswal, R. K.; Douglas, R.; Mosca, J. D.; Moorman, M. A.; Simonetti, D. W.; Craig, S.; Marshak, D. R. Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284 (5411), 143-147, DOI: 10.1126/science.284.5411.143 DOI: https://doi.org/10.1126/science.284.5411.143

10. Rath, M.; Spinnen, J.; Kuhrt, L. D.; Priglinger, E.; Seika, P.; Runge, D.; Schubring, S.; Laue, D.; Wickert, M.; Erdem, M.; et al. Platelet-rich plasma - A comprehensive review of isolation, activation, and application. Acta Biomater 2025, 204, 52-75, DOI: 10.1016/j.actbio.2025.07.050 DOI: https://doi.org/10.1016/j.actbio.2025.07.050

11. Xiong, Y.; Gong, C.; Peng, X.; Liu, X.; Su, X.; Tao, X.; Li, Y.; Wen, Y.; Li, W. Efficacy and safety of platelet-rich plasma injections for the treatment of osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Front Med (Lausanne) 2023, 10, 1204144, DOI: 10.3389/fmed.2023.1204144 DOI: https://doi.org/10.3389/fmed.2023.1204144

12. Yue, L.; Lim, R.; Owens, B. D. Latest Advances in Chondrocyte-Based Cartilage Repair. Biomedicines 2024, 12 (6), DOI: 10.3390/biomedicines12061367 DOI: https://doi.org/10.3390/biomedicines12061367

13. Brittberg, M.; Lindahl, A.; Nilsson, A.; Ohlsson, C.; Isaksson, O.; Peterson, L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994, 331 (14), 889-895, DOI: 10.1056/NEJM199410063311401 DOI: https://doi.org/10.1056/NEJM199410063311401

14. Milliron, E. M.; Cavendish, P. A.; Carey, J.; Barker, T.; Flanigan, D. C. Use of MACI (Autologous Cultured Chondrocytes on Porcine Collagen Membrane) in the United States: Expanded Experience over 5,000 Cases. Cartilage 2025, 19476035251319404, DOI: 10.1177/19476035251319404 DOI: https://doi.org/10.1177/19476035251319404

15. Peterson, L.; Minas, T.; Brittberg, M.; Nilsson, A.; Sjogren-Jansson, E.; Lindahl, A. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Relat Res 2000, (374), 212-234, DOI: 10.1097/00003086-200005000-00020 DOI: https://doi.org/10.1097/00003086-200005000-00020

16. Ebert, J. R.; Edwards, P. K.; Klinken, S.; Fallon, M.; Wood, D. J.; Janes, G. C. 10-Year Clinical and MRI-Based Outcomes of a Randomized Controlled Trial Evaluating a 6-Week Return to Full Weightbearing After Matrix-Induced Autologous Chondrocyte Implantation. Orthop J Sports Med 2025, 13 (10), 23259671251383136, DOI: 10.1177/23259671251383136 DOI: https://doi.org/10.1177/23259671251383136

17. Bian, L.; Zhai, D. Y.; Mauck, R. L.; Burdick, J. A. Coculture of human mesenchymal stem cells and articular chondrocytes reduces hypertrophy and enhances functional properties of engineered cartilage. Tissue Eng Part A 2011, 17 (7-8), 1137-1145, DOI: 10.1089/ten.TEA.2010.0531 DOI: https://doi.org/10.1089/ten.tea.2010.0531

18. Cooke, M. E.; Allon, A. A.; Cheng, T.; Kuo, A. C.; Kim, H. T.; Vail, T. P.; Marcucio, R. S.; Schneider, R. A.; Lotz, J. C.; Alliston, T. Structured three-dimensional co-culture of mesenchymal stem cells with chondrocytes promotes chondrogenic differentiation without hypertrophy. Osteoarthritis Cartilage 2011, 19 (10), 1210-1218, DOI: 10.1016/j.joca.2011.07.005 DOI: https://doi.org/10.1016/j.joca.2011.07.005

19. Zuo, Q.; Cui, W.; Liu, F.; Wang, Q.; Chen, Z.; Fan, W. Co-cultivated mesenchymal stem cells support chondrocytic differentiation of articular chondrocytes. Int Orthop 2013, 37 (4), 747-752, DOI: 10.1007/s00264-013-1782-z DOI: https://doi.org/10.1007/s00264-013-1782-z

20. Esmaeili, A.; Hosseini, S.; Kamali, A.; Hosseinzadeh, M.; Shekari, F.; Baghaban Eslaminejad, M. Co-aggregation of MSC/chondrocyte in a dynamic 3D culture elevates the therapeutic effect of secreted extracellular vesicles on osteoarthritis in a rat model. Sci Rep 2022, 12 (1), 19827, DOI: 10.1038/s41598-022-22592-4 DOI: https://doi.org/10.1038/s41598-022-22592-4

21. Adkisson, H. D. t.; Martin, J. A.; Amendola, R. L.; Milliman, C.; Mauch, K. A.; Katwal, A. B.; Seyedin, M.; Amendola, A.; Streeter, P. R.; Buckwalter, J. A. The potential of human allogeneic juvenile chondrocytes for restoration of articular cartilage. Am J Sports Med 2010, 38 (7), 1324-1333, DOI: 10.1177/0363546510361950 DOI: https://doi.org/10.1177/0363546510361950

22. Lee, J.; Lee, J. Y.; Chae, B. C.; Jang, J.; Lee, E.; Son, Y. Fully Dedifferentiated Chondrocytes Expanded in Specific Mesenchymal Stem Cell Growth Medium with FGF2 Obtains Mesenchymal Stem Cell Phenotype In Vitro but Retains Chondrocyte Phenotype In Vivo. Cell Transplant 2017, 26 (10), 1673-1687, DOI: 10.1177/0963689717724794 DOI: https://doi.org/10.1177/0963689717724794

23. He, A.; Ye, A.; Song, N.; Liu, N.; Zhou, G.; Liu, Y.; Ye, X. Phenotypic redifferentiation of dedifferentiated microtia chondrocytes through a three-dimensional chondrogenic culture system. Am J Transl Res 2020, 12 (6), 2903-2915,

24. Lindberg, E. D.; Wu, T.; Cotner, K. L.; Glazer, A.; Jamali, A. A.; Sohn, L. L.; Alliston, T.; O'Connell, G. D. Priming chondrocytes during expansion alters cell behavior and improves matrix production in 3D culture. Osteoarthritis Cartilage 2024, 32 (5), 548-560, DOI: 10.1016/j.joca.2023.12.006 DOI: https://doi.org/10.1016/j.joca.2023.12.006

25. Matricali, G. A.; Dereymaeker, G. P.; Luyten, F. P. Donor site morbidity after articular cartilage repair procedures: a review. Acta Orthop Belg 2010, 76 (5), 669-674,

26. Peterson, L.; Vasiliadis, H. S.; Brittberg, M.; Lindahl, A. Autologous chondrocyte implantation: a long-term follow-up. Am J Sports Med 2010, 38 (6), 1117-1124, DOI: 10.1177/0363546509357915 DOI: https://doi.org/10.1177/0363546509357915

27. Malige, A.; Gates, C.; Cook, J. L. Mesenchymal stem cells in orthopaedics: A systematic review of applications to practice. J Orthop 2024, 58, 1-9, DOI: 10.1016/j.jor.2024.06.026 DOI: https://doi.org/10.1016/j.jor.2024.06.026

28. Ding, Q. X.; Wang, X.; Li, T. S.; Li, Y. F.; Li, W. Y.; Gao, J. H.; Liu, Y. R.; Zhuang, W. Comparative Analysis of Short-Term and Long-Term Clinical Efficacy of Mesenchymal Stem Cells from Different Sources in Knee Osteoarthritis: A Network Meta-Analysis. Stem Cells Int 2024, 2024, 2741681, DOI: 10.1155/2024/2741681 DOI: https://doi.org/10.1155/2024/2741681

29. Lee, S.; Chae, D. S.; Song, B. W.; Lim, S.; Kim, S. W.; Kim, I. K.; Hwang, K. C. ADSC-Based Cell Therapies for Musculoskeletal Disorders: A Review of Recent Clinical Trials. Int J Mol Sci 2021, 22 (19), DOI: 10.3390/ijms221910586 DOI: https://doi.org/10.3390/ijms221910586

30. Jeyaraman, M.; Muthu, S.; Jeyaraman, N.; Ranjan, R.; Jha, S. K.; Mishra, P. Synovium Derived Mesenchymal Stromal Cells (Sy-MSCs): A Promising Therapeutic Paradigm in the Management of Knee Osteoarthritis. Indian J Orthop 2022, 56 (1), 1-15, DOI: 10.1007/s43465-021-00439-w DOI: https://doi.org/10.1007/s43465-021-00439-w

31. Pico, O. A.; Espinoza, F.; Cadiz, M. I.; Sossa, C. L.; Becerra-Bayona, S. M.; Salgado, M. C. C.; Rodriguez, J. E. R.; Cardenas, O. F. V.; Cure, J. M. Q.; Khoury, M.; Arango-Rodriguez, M. L. Efficacy of a single dose of cryopreserved human umbilical cord mesenchymal stromal cells for the treatment of knee osteoarthritis:a randomized, controlled, double-blind pilot study. Cytotherapy 2025, 27 (2), 188-200, DOI: 10.1016/j.jcyt.2024.09.005 DOI: https://doi.org/10.1016/j.jcyt.2024.09.005

32. Bagno, L. L.; Salerno, A. G.; Balkan, W.; Hare, J. M. Mechanism of Action of Mesenchymal Stem Cells (MSCs): impact of delivery method. Expert Opin Biol Ther 2022, 22 (4), 449-463, DOI: 10.1080/14712598.2022.2016695 DOI: https://doi.org/10.1080/14712598.2022.2016695

33. Han, X.; Liao, R.; Li, X.; Zhang, C.; Huo, S.; Qin, L.; Xiong, Y.; He, T.; Xiao, G.; Zhang, T. Mesenchymal stem cells in treating human diseases: molecular mechanisms and clinical studies. Signal Transduct Target Ther 2025, 10 (1), 262, DOI: 10.1038/s41392-025-02313-9 DOI: https://doi.org/10.1038/s41392-025-02313-9

34. Wang, G.; Xing, D.; Liu, W.; Zhu, Y.; Liu, H.; Yan, L.; Fan, K.; Liu, P.; Yu, B.; Li, J. J.; Wang, B. Preclinical studies and clinical trials on mesenchymal stem cell therapy for knee osteoarthritis: A systematic review on models and cell doses. Int J Rheum Dis 2022, 25 (5), 532-562, DOI: 10.1111/1756-185X.14306 DOI: https://doi.org/10.1111/1756-185X.14306

35. Jancuska, J.; Matthews, J.; Miller, T.; Kluczynski, M. A.; Bisson, L. J. A Systematic Summary of Systematic Reviews on the Topic of the Rotator Cuff. Orthop J Sports Med 2018, 6 (9), 2325967118797891, DOI: 10.1177/2325967118797891 DOI: https://doi.org/10.1177/2325967118797891

36. Little, D.; Amadio, P. C.; Awad, H. A.; Cone, S. G.; Dyment, N. A.; Fisher, M. B.; Huang, A. H.; Koch, D. W.; Kuntz, A. F.; Madi, R.; et al. Preclinical tendon and ligament models: Beyond the 3Rs (replacement, reduction, and refinement) to 5W1H (why, who, what, where, when, how). J Orthop Res 2023, 41 (10), 2133-2162, DOI: 10.1002/jor.25678 DOI: https://doi.org/10.1002/jor.25678

37. Chang, C.; Yan, J.; Yao, Z.; Zhang, C.; Li, X.; Mao, H. Q. Effects of Mesenchymal Stem Cell-Derived Paracrine Signals and Their Delivery Strategies. Adv Healthc Mater 2021, 10 (7), e2001689, DOI: 10.1002/adhm.202001689 DOI: https://doi.org/10.1002/adhm.202001689

38. Knight, M. N.; Hankenson, K. D. Mesenchymal Stem Cells in Bone Regeneration. Adv Wound Care (New Rochelle) 2013, 2 (6), 306-316, DOI: 10.1089/wound.2012.0420 DOI: https://doi.org/10.1089/wound.2012.0420

39. Jiang, L.; Lu, J.; Chen, Y.; Lyu, K.; Long, L.; Wang, X.; Liu, T.; Li, S. Mesenchymal stem cells: An efficient cell therapy for tendon repair (Review). Int J Mol Med 2023, 52 (2), DOI: 10.3892/ijmm.2023.5273 DOI: https://doi.org/10.3892/ijmm.2023.5273

40. Acharya, S.; Shaha, S.; Bibbey, M. G.; Mukherji, M.; Zhao, Z.; Mitragotri, S. Stem cell therapies in the clinic. Bioeng Transl Med 2025, 10 (3), e70000, DOI: 10.1002/btm2.70000 DOI: https://doi.org/10.1002/btm2.70000

41. Martin, I.; Galipeau, J.; Kessler, C.; Le Blanc, K.; Dazzi, F. Challenges for mesenchymal stromal cell therapies. Sci Transl Med 2019, 11 (480), DOI: 10.1126/scitranslmed.aat2189 DOI: https://doi.org/10.1126/scitranslmed.aat2189

42. Yu, J.; Vodyanik, M. A.; Smuga-Otto, K.; Antosiewicz-Bourget, J.; Frane, J. L.; Tian, S.; Nie, J.; Jonsdottir, G. A.; Ruotti, V.; Stewart, R.; et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007, 318 (5858), 1917-1920, DOI: 10.1126/science.1151526 DOI: https://doi.org/10.1126/science.1151526

43. Ali, E. A. M.; Smaida, R.; Meyer, M.; Ou, W.; Li, Z.; Han, Z.; Benkirane-Jessel, N.; Gottenberg, J. E.; Hua, G. iPSCs chondrogenic differentiation for personalized regenerative medicine: a literature review. Stem Cell Res Ther 2024, 15 (1), 185, DOI: 10.1186/s13287-024-03794-1 DOI: https://doi.org/10.1186/s13287-024-03794-1

44. O'Brien, A.; Xu, M.; O'Connell, E.; Morrison, A. M.; Shaw, G.; Dutton, J. R.; Murphy, M.; Barry, F. Development of an iPSC-based screening platform identifying enhancers of chondrogenesis. Osteoarthr Cartil Open 2025, 7 (4), 100680, DOI: 10.1016/j.ocarto.2025.100680 DOI: https://doi.org/10.1016/j.ocarto.2025.100680

45. Lee, M. S.; Lin, E. C.; Sivapatham, A.; Leiferman, E. M.; Jiao, H.; Lu, Y.; Nemke, B. W.; Leiferman, M.; Markel, M. D.; Li, W. J. Autologous iPSC- and MSC-derived chondrocyte implants for cartilage repair in a miniature pig model. Stem Cell Res Ther 2025, 16 (1), 86, DOI: 10.1186/s13287-025-04215-7 DOI: https://doi.org/10.1186/s13287-025-04215-7

46. Wu, Q.; Yang, B.; Hu, K.; Cao, C.; Man, Y.; Wang, P. Deriving Osteogenic Cells from Induced Pluripotent Stem Cells for Bone Tissue Engineering. Tissue Eng Part B Rev 2017, 23 (1), 1-8, DOI: 10.1089/ten.TEB.2015.0559 DOI: https://doi.org/10.1089/ten.teb.2015.0559

47. Rosochowicz, M. A.; Lach, M. S.; Richter, M.; Suchorska, W. M.; Trzeciak, T. iPSC-conditioned medium mitigates the adverse effects of osteoarthritic synovial fluid on chondrocyte cultures. Biochem Biophys Res Commun 2025, 777, 152336, DOI: 10.1016/j.bbrc.2025.152336 DOI: https://doi.org/10.1016/j.bbrc.2025.152336

48. Berrigan, W.; Tao, F.; Kopcow, J.; Park, A. L.; Allen, I.; Tahir, P.; Reddy, A.; Bailowitz, Z. The Effect of Platelet Dose on Outcomes after Platelet Rich Plasma Injections for Musculoskeletal Conditions: A Systematic Review and Meta-Analysis. Curr Rev Musculoskelet Med 2024, 17 (12), 570-588, DOI: 10.1007/s12178-024-09922-x DOI: https://doi.org/10.1007/s12178-024-09922-x

49. Filardo, G.; Di Matteo, B.; Di Martino, A.; Merli, M. L.; Cenacchi, A.; Fornasari, P.; Marcacci, M.; Kon, E. Platelet-Rich Plasma Intra-articular Knee Injections Show No Superiority Versus Viscosupplementation: A Randomized Controlled Trial. Am J Sports Med 2015, 43 (7), 1575-1582, DOI: 10.1177/0363546515582027 DOI: https://doi.org/10.1177/0363546515582027

50. Bennell, K. L.; Paterson, K. L.; Metcalf, B. R.; Duong, V.; Eyles, J.; Kasza, J.; Wang, Y.; Cicuttini, F.; Buchbinder, R.; Forbes, A.; et al. Effect of Intra-articular Platelet-Rich Plasma vs Placebo Injection on Pain and Medial Tibial Cartilage Volume in Patients With Knee Osteoarthritis: The RESTORE Randomized Clinical Trial. JAMA 2021, 326 (20), 2021-2030, DOI: 10.1001/jama.2021.19415 DOI: https://doi.org/10.1001/jama.2021.19415

51. Mishra, A. K.; Skrepnik, N. V.; Edwards, S. G.; Jones, G. L.; Sampson, S.; Vermillion, D. A.; Ramsey, M. L.; Karli, D. C.; Rettig, A. C. Efficacy of platelet-rich plasma for chronic tennis elbow: a double-blind, prospective, multicenter, randomized controlled trial of 230 patients. Am J Sports Med 2014, 42 (2), 463-471, DOI: 10.1177/0363546513494359 DOI: https://doi.org/10.1177/0363546513494359

52. Ahmad, Z.; Ang, S.; Rushton, N.; Harvey, A.; Akhtar, K.; Dawson-Bowling, S.; Noorani, A. Platelet-Rich Plasma Augmentation of Arthroscopic Rotator Cuff Repair Lowers Retear Rates and Improves Short-Term Postoperative Functional Outcome Scores: A Systematic Review of Meta-Analyses. Arthrosc Sports Med Rehabil 2022, 4 (2), e823-e833, DOI: 10.1016/j.asmr.2021.12.012 DOI: https://doi.org/10.1016/j.asmr.2021.12.012

53. Zhu, C.; Wu, W.; Qu, X. Mesenchymal stem cells in osteoarthritis therapy: a review. Am J Transl Res 2021, 13 (2), 448-461,

54. Jayaram, P.; Danilkowicz, R. M.; Yuan, X. Ethical and Regulatory Considerations Related to Regenerative Medicine. HSS J 2025, 15563316251361511, DOI: 10.1177/15563316251361511 DOI: https://doi.org/10.1177/15563316251361511

55. Baker, D. J.; Arany, Z.; Baur, J. A.; Epstein, J. A.; June, C. H. CAR T therapy beyond cancer: the evolution of a living drug. Nature 2023, 619 (7971), 707-715, DOI: 10.1038/s41586-023-06243-w DOI: https://doi.org/10.1038/s41586-023-06243-w

56. Yu, T.; Jiang, W.; Wang, Y.; Zhou, Y.; Jiao, J.; Wu, M. Chimeric antigen receptor T cells in the treatment of osteosarcoma (Review). Int J Oncol 2024, 64 (4), DOI: 10.3892/ijo.2024.5628 DOI: https://doi.org/10.3892/ijo.2024.5628

57. Li, G.; Wang, H.; Meftahpour, V. Overall review of curative impact and barriers of CAR-T cells in osteosarcoma. EXCLI J 2024, 23, 364-383, DOI: 10.17179/excli2023-6760

58. Koksal, H.; Muller, E.; Inderberg, E. M.; Bruland, O.; Walchli, S. Treating osteosarcoma with CAR T cells. Scand J Immunol 2019, 89 (3), e12741, DOI: 10.1111/sji.12741 DOI: https://doi.org/10.1111/sji.12741

59. Mensali, N.; Koksal, H.; Joaquina, S.; Wernhoff, P.; Casey, N. P.; Romecin, P.; Panisello, C.; Rodriguez, R.; Vimeux, L.; Juzeniene, A.; et al. ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma. Nat Commun 2023, 14 (1), 3375, DOI: 10.1038/s41467-023-39097-x DOI: https://doi.org/10.1038/s41467-023-39097-x

60. Mitra, A.; Barua, A.; Huang, L.; Ganguly, S.; Feng, Q.; He, B. From bench to bedside: the history and progress of CAR T cell therapy. Front Immunol 2023, 14, 1188049, DOI: 10.3389/fimmu.2023.1188049 DOI: https://doi.org/10.3389/fimmu.2023.1188049

61. Hou, Y.; Hu, S.; Liu, C.; Chen, X.; Wang, Y.; Li, Y.; Fu, Z.; Feng, C.; Gong, Y.; Liu, Z.; Peng, S. Beyond CAR-T Cells: exploring CAR-NK, CAR-M, and CAR-gammadelta T strategies in solid tumor immunotherapy. Front Immunol 2025, 16, 1675807, DOI: 10.3389/fimmu.2025.1675807 DOI: https://doi.org/10.3389/fimmu.2025.1675807

62. Ahmed, N.; Brawley, V. S.; Hegde, M.; Robertson, C.; Ghazi, A.; Gerken, C.; Liu, E.; Dakhova, O.; Ashoori, A.; Corder, A.; et al. Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. J Clin Oncol 2015, 33 (15), 1688-1696, DOI: 10.1200/JCO.2014.58.0225 DOI: https://doi.org/10.1200/JCO.2014.58.0225

63. Lachota, M.; Vincenti, M.; Winiarska, M.; Boye, K.; Zagozdzon, R.; Malmberg, K. J. Prospects for NK Cell Therapy of Sarcoma. Cancers (Basel) 2020, 12 (12), DOI: 10.3390/cancers12123719 DOI: https://doi.org/10.3390/cancers12123719

64. Oei, V. Y. S.; Siernicka, M.; Graczyk-Jarzynka, A.; Hoel, H. J.; Yang, W.; Palacios, D.; Almasbak, H.; Bajor, M.; Clement, D.; Brandt, L.; et al. Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors. Cancer Immunol Res 2018, 6 (4), 467-480, DOI: 10.1158/2326-6066.CIR-17-0207 DOI: https://doi.org/10.1158/2326-6066.CIR-17-0207

65. Kailayangiri, S.; Altvater, B.; Spurny, C.; Jamitzky, S.; Schelhaas, S.; Jacobs, A. H.; Wiek, C.; Roellecke, K.; Hanenberg, H.; Hartmann, W.; et al. Targeting Ewing sarcoma with activated and GD2-specific chimeric antigen receptor-engineered human NK cells induces upregulation of immune-inhibitory HLA-G. Oncoimmunology 2017, 6 (1), e1250050, DOI: 10.1080/2162402X.2016.1250050 DOI: https://doi.org/10.1080/2162402X.2016.1250050

66. Fradin, J. J.; Charlson, J. A. Review of Adoptive Cellular Therapies for the Treatment of Sarcoma. Cancers (Basel) 2025, 17 (8), DOI: 10.3390/cancers17081302 DOI: https://doi.org/10.3390/cancers17081302

67. Anyfanti, P.; Evangelidis, P.; Kotsiou, N.; Papakonstantinou, A.; Eftychidis, I.; Sakellari, I.; Dimitroulas, T.; Gavriilaki, E. Chimeric Antigen Receptor T Cell Immunotherapy for Autoimmune Rheumatic Disorders: Where Are We Now? Cells 2025, 14 (16), DOI: 10.3390/cells14161242 DOI: https://doi.org/10.3390/cells14161242

68. Mackensen, A.; Muller, F.; Mougiakakos, D.; Boltz, S.; Wilhelm, A.; Aigner, M.; Volkl, S.; Simon, D.; Kleyer, A.; Munoz, L.; et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 2022, 28 (10), 2124-2132, DOI: 10.1038/s41591-022-02017-5 DOI: https://doi.org/10.1038/s41591-022-02017-5

69. Sakkas, L. I.; Katsiari, C.; Syrmou, V.; Chikanza, I. C. CAR-T cells in systemic sclerosis. Clin Rheumatol 2025, DOI: 10.1007/s10067-025-07554-1 DOI: https://doi.org/10.1007/s10067-025-07554-1

70. Haase, I.; Richter, J.; Holzer, M. T.; Fehse, B.; Ruffer, N.; Seibel, J.; Berger, S. C.; Gagelmann, N.; Borie, D.; Ayuk, F.; et al. A novel approach to refractory idiopathic inflammatory myopathy: CD19 CAR T-cell therapy-case report and literature review. Rheumatology (Oxford) 2025, 64 (9), 5101-5107, DOI: 10.1093/rheumatology/keaf190 DOI: https://doi.org/10.1093/rheumatology/keaf190

71. Hojati Shargh, M. M.; Mahmoudi, M.; Agah, S. A. A.; Forouzanfar, F.; Javanmardi, Z.; Fadaee, A.; Haghmorad, D.; Esmaeili, S. A. CAR T-cell therapy in autoimmune diseases: Opportunities and challenges, with implications for RA. Tissue Cell 2025, 98, 103164, DOI: 10.1016/j.tice.2025.103164 DOI: https://doi.org/10.1016/j.tice.2025.103164

72. Suri-Payer, E.; Fritzsching, B. Regulatory T cells in experimental autoimmune disease. Springer Semin Immunopathol 2006, 28 (1), 3-16, DOI: 10.1007/s00281-006-0021-8 DOI: https://doi.org/10.1007/s00281-006-0021-8

73. Komatsu, N.; Takayanagi, H. Regulatory T cells in Arthritis. Prog Mol Biol Transl Sci 2015, 136, 207-215, DOI: 10.1016/bs.pmbts.2015.07.021 DOI: https://doi.org/10.1016/bs.pmbts.2015.07.021

74. Pikor, L. A.; Arivazhagan, S.; Mendicino, M.; Sathiamoorthy, S. Navigating the manufacturing, testing and regulatory complexities of regulatory T cells for adoptive cell therapy. Front Immunol 2025, 16, 1626085, DOI: 10.3389/fimmu.2025.1626085 DOI: https://doi.org/10.3389/fimmu.2025.1626085

75. Hu, M.; Zhou, Y.; Yao, Z.; Tang, Y.; Zhang, Y.; Liao, J.; Cai, X.; Liu, L. T cell dysregulation in rheumatoid arthritis: Recent advances and natural product interventions. Int Immunopharmacol 2025, 153, 114499, DOI: 10.1016/j.intimp.2025.114499 DOI: https://doi.org/10.1016/j.intimp.2025.114499

76. Yan, S.; Kotschenreuther, K.; Deng, S.; Kofler, D. M. Regulatory T cells in rheumatoid arthritis: functions, development, regulation, and therapeutic potential. Cell Mol Life Sci 2022, 79 (10), 533, DOI: 10.1007/s00018-022-04563-0 DOI: https://doi.org/10.1007/s00018-022-04563-0

77. Bulliard, Y.; Freeborn, R.; Uyeda, M. J.; Humes, D.; Bjordahl, R.; de Vries, D.; Roncarolo, M. G. From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases. Front Immunol 2024, 15, 1509956, DOI: 10.3389/fimmu.2024.1509956 DOI: https://doi.org/10.3389/fimmu.2024.1509956

78. Zhang, Q.; Lu, W.; Liang, C. L.; Chen, Y.; Liu, H.; Qiu, F.; Dai, Z. Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance. Front Immunol 2018, 9, 2359, DOI: 10.3389/fimmu.2018.02359 DOI: https://doi.org/10.3389/fimmu.2018.02359

79. MacDonald, K. G.; Hoeppli, R. E.; Huang, Q.; Gillies, J.; Luciani, D. S.; Orban, P. C.; Broady, R.; Levings, M. K. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J Clin Invest 2016, 126 (4), 1413-1424, DOI: 10.1172/JCI82771 DOI: https://doi.org/10.1172/JCI82771

80. Dawson, N. A.; Lamarche, C.; Hoeppli, R. E.; Bergqvist, P.; Fung, V. C.; McIver, E.; Huang, Q.; Gillies, J.; Speck, M.; Orban, P. C.; et al. Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in regulatory T cells. JCI Insight 2019, 4 (6), DOI: 10.1172/jci.insight.123672 DOI: https://doi.org/10.1172/jci.insight.123672

81. Muller, Y. D.; Ferreira, L. M. R.; Ronin, E.; Ho, P.; Nguyen, V.; Faleo, G.; Zhou, Y.; Lee, K.; Leung, K. K.; Skartsis, N.; et al. Precision Engineering of an Anti-HLA-A2 Chimeric Antigen Receptor in Regulatory T Cells for Transplant Immune Tolerance. Front Immunol 2021, 12, 686439, DOI: 10.3389/fimmu.2021.686439 DOI: https://doi.org/10.3389/fimmu.2021.686439

82. Arjomandnejad, M.; Kopec, A. L.; Keeler, A. M. CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications. Biomedicines 2022, 10 (2), DOI: 10.3390/biomedicines10020287 DOI: https://doi.org/10.3390/biomedicines10020287

83. Beheshti, S. A.; Shamsasenjan, K.; Ahmadi, M.; Abbasi, B. CAR Treg: A new approach in the treatment of autoimmune diseases. Int Immunopharmacol 2022, 102, 108409, DOI: 10.1016/j.intimp.2021.108409 DOI: https://doi.org/10.1016/j.intimp.2021.108409

84. Riet, T.; Chmielewski, M. Regulatory CAR-T cells in autoimmune diseases: Progress and current challenges. Front Immunol 2022, 13, 934343, DOI: 10.3389/fimmu.2022.934343 DOI: https://doi.org/10.3389/fimmu.2022.934343

85. Asnagli, H.; Martire, D.; Belmonte, N.; Quentin, J.; Bastian, H.; Boucard-Jourdin, M.; Fall, P. B.; Mausset-Bonnefont, A. L.; Mantello-Moreau, A.; Rouquier, S.; et al. Type 1 regulatory T cells specific for collagen type II as an efficient cell-based therapy in arthritis. Arthritis Res Ther 2014, 16 (3), R115, DOI: 10.1186/ar4567 DOI: https://doi.org/10.1186/ar4567

86. Sun, G.; Hou, Y.; Gong, W.; Liu, S.; Li, J.; Yuan, Y.; Zhang, D.; Chen, Q.; Yan, X. Adoptive Induced Antigen-Specific Treg Cells Reverse Inflammation in Collagen-Induced Arthritis Mouse Model. Inflammation 2018, 41 (2), 485-495, DOI: 10.1007/s10753-017-0704-4 DOI: https://doi.org/10.1007/s10753-017-0704-4

87. Zavvar, M.; Abdolmaleki, M.; Farajifard, H.; Noorbakhsh, F.; Azadmanesh, K.; Vojgani, M.; Nikcnam, M. H. Collagen II-primed Foxp3 Transduced T Cells Ameliorate Collagen-induced Arthritis in Rats: The Effect of Antigenic Priming on T Regulatory Cell Function. Iran J Allergy Asthma Immunol 2018, 17 (4), 361-371, DOI: 10.18502/ijaai.v17i4.95 DOI: https://doi.org/10.18502/ijaai.v17i4.95

Radosław Zagożdżon

radoslaw.zagozdzon@wum.edu.pl
https://orcid.org/0000-0002-7957-2372

Affiliation:

Laboratory of Cellular and Genetic Therapies, Center for Preclinical Research, Medical University of Warsaw, Warsaw, Poland Poland

Ewa Olender

ewa.a.olender@gmail.com

Affiliation:

Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland Poland

Piotr Strzelczyk

piotr.strzelczyk@wum.edu.pl
https://orcid.org/0000-0003-0462-6134

Affiliation:

Department of Orthopedics and Musculoskeletal Traumatology, Medical University of Warsaw, Warsaw, Poland Poland

Marcin Kowalski

marcin.kowalski@wum.edu.pl

Affiliation:

Department of Orthopedics and Musculoskeletal Traumatology, Medical University of Warsaw, Warsaw, Poland Poland

Sławomir Żarek

slawomir.zarek@wum.edu.pl

Affiliation:

Department of Orthopedics and Musculoskeletal Traumatology, Medical University of Warsaw, Warsaw, Poland Poland

Robert Jopowicz

robert.jopowicz@wum.edu.pl

Affiliation:

Department of Mini-Invasive Orthopedics and Rehabilitation, Medical University of Warsaw, Warsaw, Poland Poland