Umbilical cord mesenchymal stem cells and their secretome: a new frontier in orthopedic medicine

Main Article Content

Tito Sumarwoto
Romaniyanto
Sholahuddin Rhamtomy
Mujaddid Idulhaq
Asep Santoso

Abstract

Umbilical cord mesenchymal stem cells (UC-MSCs) have gained significant attention in regenerative medicine due to their unique biological properties, including high proliferation capacity, low immunogenicity, and potent immunomodulatory effects. These characteristics make UC-MSCs particularly promising for orthopedic applications, where the repair and regeneration of musculoskeletal tissues such as bone, cartilage, tendons, ligaments, and nerves are critical for restoring function. The secretome of UC-MSCs—comprising bioactive molecules such as exosomes, cytokines, and growth factors—offers a powerful, cell-free therapeutic option through paracrine signaling, further enhancing their therapeutic potential. A literature search was conducted in major databases (PubMed, ScienceDirect, SpringerLink, Google Scholar) for English articles from 2010–2025 using keywords related to UC‑MSCs and orthopedic regeneration. This review explores the role of UC-MSCs and their secretome in orthopedic tissue repair, focusing on their application in bone healing, cartilage regeneration, tendon-ligament repair, and nerve regeneration with their innovative delivery. Despite the promising potential of UC-MSC therapies, several challenges remain, including regulatory hurdles, long-term safety concerns, and the scalability of cell-based and secretome-based therapies for widespread clinical use. Although umbilical cord MSCs are not yet widely applied in clinical practice, increasing evidence suggests that they offer significant therapeutic potential, especially in the treatment of autoimmune and neurodegenerative diseases. The UC-MSCs and their secretome represent a transformative approach in orthopedics, offering new avenues for treating complex musculoskeletal injuries and degenerative diseases. Ongoing advancements in this field will likely unlock their full potential, making them viable options for clinical use in the near future.

Article Details

Section

Review Article

Author Biographies

Tito Sumarwoto, Department of Orthopaedics and Traumatology Soeharso Orthopaedic Hospital and Faculty of Medicine, Sebelas Maret University, Surakarta

1Department of Orthopaedics and Traumatology Soeharso Orthopaedic Hospital - Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia

2Division of Hand, Upper Limb, and Microsurgery, Soeharso Orthopaedic Hospital, Surakarta, Indonesia

Romaniyanto, Department of Orthopaedics and Traumatology Soeharso Orthopaedic Hospital and Faculty of Medicine, Sebelas Maret University, Surakarta

1Department of Orthopaedics and Traumatology Soeharso Orthopaedic Hospital - Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia

3Division of Spine, Dr. Soeharso Orthopaedic Hospital, Surakarta, Indonesia

Sholahuddin Rhamtomy, Soeradji Tirtonegoro Central General Hospital and Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia

4Division of Adult Reconstruction, Soeradji Tirtonegoro Central General Hospital, Klaten - Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia

Mujaddid Idulhaq, Soeharso Orthopaedic Hospital and Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia

1Department of Orthopaedics and Traumatology, Soeharso Orthopaedic Hospital - Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia

5Division of Musculoskeletal Tumor, Soeharso Orthopaedic Hospital, Surakarta, Indonesia

Asep Santoso, Soeharso Orthopaedic Hospital and Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia

1Department of Orthopaedics and Traumatology, Soeharso Orthopaedic Hospital - Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia

6Division of Adult Reconstruction, Orthopaedic Hospital, Surakarta, Indonesia

How to Cite

Umbilical cord mesenchymal stem cells and their secretome: a new frontier in orthopedic medicine. (2026). Universa Medicina, 45(1). https://doi.org/10.18051/UnivMed.2026.v45.%p

References

1. Das S, Thakur A, Datta A, Sahoo A, Bandyopadhyay S, Sah AK. Advances in regenerative medicine for orthopedic injuries: a comprehensive review. Cureus 2025;17:e79860. doi: 10.7759/cureus.79860.

2. Bulut D, Sharabidze Z. Regenerative medicine in orthopaedic surgery: pioneering advances and their applications. EMJ Innov 2025;9:82-94. doi: 10.33.590/emjinnov/FGDS3814

3. Liang W, Zhou C, Bai J, et al. Current advancements in therapeutic approaches in orthopedic surgery: a review of recent trends. Front Bioeng Biotechnol 2024;12:1328997. doi: 10.3389/fbioe.2024.1328997.

4. Trapana J, Weinerman J, Lee D, et al. Cell-based therapy in the treatment of musculoskeletal diseases. Stem Cells Transl Med 2024;13:959-78. doi: 10.1093/stcltm/szae049.

5. Drobiova H, Sindhu S, Ahmad R, Haddad D, Al-Mulla F, Al Madhoun A. Wharton’s jelly mesenchymal stem cells: a concise review of their secretome and prospective clinical applications. Front Cell Dev Biol 2023;11:1211217. doi: 10.3389/fcell.2023.1211217.

6. Szabłowska-Gadomska I, Rudziński S, Dymowska M. Secretome of mesenchymal stromal cells as a possible innovative therapeutic tool in facial nerve injury treatment. Biomed Res Int 2023;2023:8427200. doi: 10.1155/2023/8427200.

7. Smolinska V, Csobonyeiova M, Zamborsky R, Danisovic L. Stem cells and their derivatives: an implication for the regeneration of nonunion fractures. Cell Transplant 2023;32:9636897231183530. doi: 10.1177/09636897231183530

8. Advani D, Barragan JV, Statache G, Kadri N, Kohli N. Upcycled mesenchymal stem cells : repurposing biological waste towards sustainable. Cell Engineering Connect 2025;1:1–14. doi : 10.69709/CellEngC.2025.101060.

9. Xu M, Xu J, Cheng D, et al. Isolation of umbilical cord-derived mesenchymal stem cells with high yields and low damage. J Vis Exp 2024;209:e66835. doi: 10.3791/66835.

10. Kestendjieva S, Chervenkov M, Oreshkova T, Mourdjeva M, Stoyanova E. Mesenchymal stromal/stem cells isolated by explant culture method from Wharton’s jelly and subamnion possess similar biological characteristics. Appl. Sci 2024;14:8036. doi: 10.3390/app14178036.

11. Vohra M, Arora SK. Mesenchymal stem cells—the master immunomodulators. Explor Immunol 2023;3:104–22. doi: 10.37349/ei.2023.00092.

12. Rehman A, Nigam A, Laino L, et al. Mesenchymal stem cells in soft tissue regenerative medicine: a comprehensive review. Medicina (Lithuania) 2023;59:1–20. doi: 10.3390/medicina59081449.

13. Choi SJ, Park SY, Shin YH, et al. Mesenchymal stem cells derived from Wharton’s jelly can differentiate into Schwann cell-like cells and promote peripheral nerve regeneration in acellular nerve grafts. Tissue Eng Regen Med 2021;18:467–78. doi: 10.1007/s13770-020-00329-6.

14. Xu Q, Hou W, Zhao B, et al. Mesenchymal stem cells lineage and their role in disease development. Mol Med 2024;30:207. doi: 10.1186/s10020-024-00967-9.

15. Wei C, Guo Y, Ci Z, Li M, Zhang Y, Zhou Y. Advances of Schwann cells in peripheral nerve regeneration: from mechanism to cell therapy. Biomed Pharmacother 2024;175:116645. doi :10.1016/j.biopha.2024.116645.

16. Cequier A, Vázquez FJ, Vitoria A, et al. The systemic cellular immune response against allogeneic mesenchymal stem cells is influenced by inflammation, differentiation and MHC compatibility: in vivo study in the horse. Front Vet Sci 2024;11:1391872. doi: 10.3389/fvets.2024.1391872.

17. Hori A, Takahashi A, Miharu Y, et al. Superior migration ability of umbilical cord-derived mesenchymal stromal cells (MSCs) toward activated lymphocytes in comparison with those of bone marrow and adipose-derived MSCs. Front Cell Dev Biol 2024;12:1–13. doi: 10.3389/fcell.2024.1329218.

18. Tian L, Wang W, Li X, et al. Whole transcriptome scanning and validation of negatively related genes in UC-MSCs. Heliyon 2024;10:e27996. doi: 10.1016/j.heliyon.2024.e27996.

19. Li P. Comparative breakthrough: Umbilical cord mesenchymal stem cells vs bone marrow mesenchymal stem cells in heart failure treatment. World J Cardiol 2024;16:776–80. doi: 10.4330/wjc.v16.i12.776.

20. García‑Guerrero CA, Fuentes P, Araya MJ, et al. How to enhance mscs therapeutic properties? an insight on potentiation methods. Stem Cell Res Ther 2024;15:331. doi: 10.1186/s13287-024-03935-6.

21. Seok J, Park H, Cetin E, Ghasroldasht MM, Liakath FB, Al-Hendy A. The potent paracrine effect of umbilical cord mesenchymal stem cells mediates mitochondrial quality control to restore chemotherapy-induced damage in ovarian granulosa cells. Biomed Pharmacother 2024;172:116263. doi: 10.1016/j.biopha.2024.116263.

22. Shan Y, Zhang M, Tao E, et al. Pharmacokinetic characteristics of mesenchymal stem cells in translational challenges. Signal Transduct Target Ther 2024;9:1–27. doi: 10.1038/s41392-024-01936-8.

23. Prado-Yupanqui JW, Ramírez-Orrego L, Cortez D, et al. The hidden power of the secretome: therapeutic potential on wound healing and cell-free regenerative medicine—a systematic review. Int J Mol Sci 2025;26:1–20. doi: 10.3390/ijms26051926.

24. Zhidu S, Ying T, Rui J, Chao Z. Translational potential of mesenchymal stem cells in regenerative therapies for human diseases: challenges and opportunities. Stem Cell Res Ther 2024;15:266. doi : 10.1186/s13287-024-03885-z.

25. Wang L, Ruan M, Bu Q, Zhao C. Signaling pathways driving MSC osteogenesis: mechanisms, regulation, and translational applications. Int J Mol Sci 2025;26:1311. doi: 10.3390/ijms26031311.

26. Cui C, Lin F, Xia L, Zhang X. Mesenchymal stem cells therapy for the treatment of non-union fractures: a systematic review and meta-analysis. BMC Musculoskelet Disord 2025;26:245. doi: 10.1186/s12891-025-08365-w.

27. Kangari P, Talaei-Khozani T, Razeghian-Jahromi I, Razmkhah M. Mesenchymal stem cells: amazing remedies for bone and cartilage defects. Stem Cell Res Ther 2020;11:1–21. doi: 10.1186/s13287-020-02001-1.

28. Trigo CM, Rodrigues JS, Camões SP, Solá S, Miranda JP. Mesenchymal stem cell secretome for regenerative medicine: where do we stand? J Adv Res 2024;70:103–24. doi: 10.1016/j.jare.2024.05.004.

29. Bian D, Wu Y, Song G, Azizi R, Zamani A. The application of mesenchymal stromal cells (MSCs) and their derivative exosome in skin wound healing: a comprehensive review. Stem Cell Res Ther 2022;13:1–17. doi: 10.1186/s13287-021-02697-9.

30. Zhang Y, Fan M, Zhang Y. Revolutionizing bone defect healing: the power of mesenchymal stem cells as seeds. Front Bioeng Biotechnol 2024;12:1–18. doi: 10.3389/fbioe.2024.1421674.

31. Householder NA, Raghuram A, Agyare K, Thipaphay S, Zumwalt M. A review of recent innovations in cartilage regeneration strategies for the treatment of primary osteoarthritis of the knee: intra-articular injections. Orthop J Sports Med 2023;11:1–20. doi: 10.1177/23259671231155950.

32. Liu Y, Shah KM, Luo J. Strategies for articular cartilage repair and regeneration. Front Bioeng Biotechnol 2021;9:1–10. doi: 10.3389/fbioe.2021.770655.

33. Liao ZK. Clinical research progress of umbilical cord blood mesenchymal stem cells in knee articular cartilage repair: a review. Medicine (United States) 2025;104:e41402. doi: 10.1097/MD.0000000000041402.

34. Piñeiro-Ramil M, Gómez-Seoane I, Rodríguez-Cendal AI, Fuentes-Boquete I, Díaz-Prado S. Mesenchymal stromal cells-derived extracellular vesicles in cartilage regeneration: potential and limitations. Stem Cell Res Ther 2025;16:11. doi: 10.1186/s13287-025-04135-6.

35. Wu KC, Chang YH, Ding DC, Lin SZ. Mesenchymal stromal cells for aging cartilage regeneration: a review. Int J Mol Sci 2024;25:12911. doi : 10.3390/ijms252312911.

36. Cho GH, Bae HC, Lee YJ, et al. Insulin-like growth factor 2 secreted from mesenchymal stem cells with high glutathione levels alleviates osteoarthritis via paracrine rejuvenation of senescent chondrocytes. Biomater Res 2025;29:1–16. doi: 10.34133/bmr.0152.

37. Anatolitou A, Sideri K, Mavrogenis A, et al. Cartilage extracellular matrix collagen type II and aggrecan expressions in rabbit cartilage following mesenchymal stem cell implantation. German J Vet Res 2024;4:197–207. doi: 10.51585/gjvr.2024.3.0110.

38. Peshkova M, Korneev A, Suleimanov S, et al. MSCs’ conditioned media cytokine and growth factor profiles and their impact on macrophage polarization. Stem Cell Res Ther 2023;14:1–16. doi: 10.1186/s13287-023-03381-w.

39. Chen Y, Cheng RJ, Wu Y, Huang D, Li Y, Liu Y. Advances in stem cell-based therapies in the treatment of osteoarthritis. Int J Mol Sci 2024;25:394. doi : 10.3390/ijms25010394.

40. Leong NL, Kator JL, Clemens TL, James A, Enamoto-Iwamoto M, Jiang J. Tendon and ligament healing and current approaches to tendon and ligament regeneration. J Orthop Res 2020;38:7–12. doi: 10.1002/jor.24475.

41. Shen Y, Wang Y, Xu Y, et al. Therapeutic potential and mechanisms of umbilical cord mesenchymal stem cells differentiating into tendon cells and promotion of rotator cuff tendon-bone healing. J Tissue Eng 2025;16:20417314251315185. doi: 10.1177/20417314251315185.

42. Augustin G, Jeong JH, Kim MK, Hur SS, Lee JH, Hwang Y. Stem cell-based therapies and tissue engineering innovations for tendinopathy: a comprehensive review of current strategies and future directions. Adv Ther (Weinh) 2024;7:1–23. doi: 10.1002/adtp.202300425.

43. Wu J, Wu J, Liu Z, et al. Mesenchymal stem cell–derived extracellular vesicles in joint diseases: therapeutic effects and underlying mechanisms. J Orthop Translat 2024;48:53–69. doi: 10.1016/j.jot.2024.07.005.

44. Yang J, Liu Y, Wang M, et al. Repair effect of umbilical cord mesenchymal stem cells embedded in hydrogel on mouse insulinoma 6 cells injured by streptozotocin. Polymers (Basel) 2024;16:1845. doi: 10.3390/polym16131845.

45. Song S, Li C, Xiao Y, Ye Z, Rong M, Zeng J. Beyond conventional therapies: mscs in the battle against nerve injury. Regen Ther 2025;28:280–91. doi: 10.1016/j.reth.2024.12.017.

46. Natarajan RN, Andersson GBJ. Lumbar disc degeneration is an equally important risk factor as lumbar fusion for causing adjacent segment disc disease. J Orthop Res 2017;35:123–30. doi: 10.1002/jor.23283.

47. Huang H, Liu X, Wang J, et al. Umbilical cord mesenchymal stem cells for regenerative treatment of intervertebral disc degeneration. Front Cell Dev Biol 2023;11:1–11. doi: 10.3389/fcell.2023.1215698.

48. Ohnishi T, Homan K, Fukushima A, Ukeba D, Iwasaki N, Sudo H. A review: methodologies to promote the differentiation of mesenchymal stem cells for the regeneration of intervertebral disc cells following intervertebral disc degeneration. Cells 2023;12:2161. doi : 10.3390/cells12172161.

49. Kim Y hoon, Kim K won, Rhyu K won, et al. Bone fusion materials : past , present , and future. Asian Spine J 2025;1–10. doi: 10.31616/asj.2024.0520.

50. Keshavarz S, Alavi CE, Aghayan H, Jafari-Shakib R, Vojoudi E. Advancements in degenerative disc disease treatment: a regenerative medicine approach. Stem Cell Rev Rep 2025;21:1252-82. doi: 10.1007/s12015-025-10882-z.

51. Munda M, Velnar T. Stem cell therapy for degenerative disc disease: Bridging the gap between preclinical promise and clinical potential. Biomol Biomed 2024;24:210–8. doi: 10.17305/bb.2023.9518.

52. Tian R, Zhou Y, Ren Y, Zhang Y, Tang W. Wallerian degeneration: from mechanism to disease to imaging. Heliyon 2025;11:e40729. doi : 10.1016/j.heliyon.2024.e40729.

53. Gu D, Xia Y, Ding Z, et al. Inflammation in the peripheral nervous system after injury. Biomedicines 2024;12:1–15. doi: 10.3390/biomedicines12061256.

54. Sharifi M, Kamalabadi-Farahani M, Salehi M, Ebrahimi-Brough S, Alizadeh M. Recent perspectives on the synergy of mesenchymal stem cells with micro/nano strategies in peripheral nerve regeneration-a review. Front Bioeng Biotechnol 2024;12:1–21. doi: 10.3389/fbioe.2024.1401512.

55. Mushtaq M, Zineldeen DH, Mateen MA, Haider KH. mesenchymal stem cells’ “garbage bags” at work: treating radial nerve injury with mesenchymal stem cell-derived exosomes. World J Stem Cells 2024;16:467–78. doi: 10.4252/wjsc.v16.i5.467.

56. Li Q, Zhang F, Fu X, Han N. Therapeutic potential of mesenchymal stem cell-derived exosomes as nanomedicine for peripheral nerve injury. Int J Mol Sci 2024;25:7882. doi: 10.3390/ijms25147882.

57. Felici N, Alban A. Timing of surgery in peripheral nerve injury of the upper extremity. J Hand Surg Eur 2024;49:712–20. doi: 10.1177/17531934241240867.

58. Widodo W, Aprilya D, Satria O. Regenerative medicine : a new horizon in peripheral nerve injury and repair. Orthop Rev (Pavia) 2025;17:1–9. doi: 10.52965/001c.133572.

59. Aldali F, Deng C, Nie M, Chen H. Advances in therapies using mesenchymal stem cells and their exosomes for treatment of peripheral nerve injury: state of the art and future perspectives. Neural Regen Res 2025;20:3151–71. doi: 10.4103/NRR.NRR-D-24-00235.

60. Zhou H, He Y, Xiong W, et al. MSC based gene delivery methods and strategies improve the therapeutic efficacy of neurological diseases. Bioact Mater 2023;23:409–37. doi: 10.1016/j.bioactmat.2022.11.007.

61. Hammam IA, Winters R, Hong Z. Advancements in the application of biomaterials in neural tissue engineering: a review. Biomed Eng Adv 2024;8:100132. doi: 10.1016/j.bea.2024.100132.

62. Iwai T, Ikeguchi R, Aoyama T, et al. Nerve regeneration using a Bio 3D conduit derived from umbilical cord–derived mesenchymal stem cells in a rat sciatic nerve defect model. PLoS One 2024;19:1–17. doi: 10.1371/journal.pone.0310711.

63. Moghassemi S, Nikanfar S, Dadashzadeh A, et al. The revolutionary role of placental derivatives in biomedical research. Bioact Mater 2025;49:456–85. doi : 10.1016/j.bioactmat.2025.03.011.

64. Da Silva K, Kumar P, Choonara YE. The paradigm of stem cell secretome in tissue repair and regeneration: present and future perspectives. Wound Repair Regen 2025;33:1–32. doi: 10.1111/wrr.13251.

65. Namini MS, Daneshimehr F, Beheshtizadeh N, et al. Cell-free therapy based on extracellular vesicles: a promising therapeutic strategy for peripheral nerve injury. Stem Cell Res Ther 2023;14:1–18. doi: 10.1186/s13287-023-03467-5.

66. Nevado-Sánchez E, Rodríguez-Díaz M, Núñez-Rodríguez S, et al. Effectiveness of stem cell secretomes in the regeneration and functional recovery of severed nerves in patients with nerve injuries: a systematic review. Cells 2025;14:1–18. doi : 10.3390/cells14070492.

67. Wu S, Sun S, Fu W, Yang Z, Yao H, Zhang Z. The role and prospects of mesenchymal stem cells in skin repair and regeneration. Biomedicines 2024;12:743. doi : 10.3390/biomedicines12040743.

68. Han Y, Yang J, Fang J, et al. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther 2022;7:1–19. doi : 10.1038/s41392-022-00932-0.

69. Kumar MA, Baba SK, Sadida HQ, et al. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct Target Ther 2024;9. doi : 10.1038/s41392-024-01735-1.

70. Bhol NK, Bhanjadeo MM, Singh AK, et al. The interplay between cytokines, inflammation, and antioxidants: mechanistic insights and therapeutic potentials of various antioxidants and anti-cytokine compounds. Biomed Pharmacother 2024;178:117177. doi: 10.1016/j.biopha.2024.117177.

71. Everts PA, Lana JF, Onishi K, et al. Angiogenesis and tissue repair depend on platelet dosing and bioformulation strategies following orthobiological platelet-rich plasma procedures: a narrative review. Biomedicines 2023;11:1922. doi : 10.3390/biomedicines11071922.

72. Wechsler ME, Rao V V., Borelli AN, Anseth KS. Engineering the msc secretome: a hydrogel focused approach. Adv Health Mater 2021;10:1–17. doi: 10.1002/adhm.202001948.

73. Pacilio S, Lombardi S, Costa R, et al. Role of perinatal stem cell secretome as potential therapy for muscular dystrophies. Biomedicines 2025;13:1–17. doi: 10.3390/biomedicines13020458.

74. Miron RJ, Estrin NE, Sculean A, Zhang Y. Understanding exosomes: part 2—emerging leaders in regenerative medicine. Periodontol 2000 2024;94:257–414. doi : 10.1111/prd.12561.

75. Wu SH, Zhou ZS, Li Y, Jiang J. Advancements in diabetic foot ulcer research: focus on mesenchymal stem cells and their exosomes. Heliyon 2024;10:e37031. doi: 10.1016/j.heliyon.2024.e37031.

76. Bina V, Brancato AM, Caliogna L, et al. Mesenchymal stem cells and secretome as a new possible approach to treat cartilage damage: an in vitro study. Biomolecules 2024;14:1068. doi: 10.3390/biom14091068.

77. Yang X, Tian S, Fan L, et al. Integrated regulation of chondrogenic differentiation in mesenchymal stem cells and differentiation of cancer cells. Cancer Cell Int 2022;22:1–13. doi: 10.1186/s12935-022-02598-8.

78. Yari H, Mikhailova M V, Mardasi M, et al. Emerging role of mesenchymal stromal cells (MSCs)-derived exosome in neurodegeneration-associated conditions: a groundbreaking cell-free approach. Stem Cell Res Ther 2022;13:1–23. doi: 10.1186/s13287-022-03122-5.

79. Izhiman Y, Esfandiari L. Emerging role of extracellular vesicles and exogenous stimuli in molecular mechanisms of peripheral nerve regeneration. Front Cell Neurosci 2024;18:1–21. doi: 10.3389/fncel.2024.1368630.

80. Lyamina S, Baranovskii D, Kozhevnikova E, et al. mesenchymal stromal cells as a driver of inflammaging. Int J Mol Sci 2023;24:6372. doi: 10.3390/ijms24076372.

81. Beheshtizadeh N, Gharibshahian M, Bayati M, et al. Vascular endothelial growth factor (VEGF) delivery approaches in regenerative medicine. Biomed Pharmacother 2023;166:115301. doi: 10.1016/j.biopha.2023.115301.

82. Huang Y, Wu L, Zhao Y, et al. Schwann cell promotes macrophage recruitment through il-17b/il-17rb pathway in injured peripheral nerves. Cell Rep 2024;43:113753. doi: 10.1016/j.celrep.2024.113753.

83. Torizal FG, Kerans FFA, Khumaira A. Production of mesenchymal stem cell derived-secretome as cell-free regenerative therapy and immunomodulation: a biomanufacturing perspective. Biocell. 2022;46:1885–91. doi: 10.32604/biocell.2022.019591.

84. Yamaguchi N, Horio E, Sonoda J, et al. Immortalization of mesenchymal stem cells for application in regenerative medicine and their potential risks of tumorigenesis. Int J Mol Sci 2024;25:1–26. doi: 10.3390/ijms252413562.

85. Chouaib B, Haack-Sørensen M, Chaubron F, Cuisinier F, Collart-Dutilleul PY. Towards the standardization of mesenchymal stem cell secretome-derived product manufacturing for tissue regeneration. Int J Mol Sci 2023;24:12594. doi: 10.3390/ijms241612594.

86. Lu P, Ruan D, Huang M, et al. Harnessing the potential of hydrogels for advanced therapeutic applications: current achievements and future directions. Signal Transduct Target Ther 2024;9:166. doi: 10.1038/s41392-024-01852-x.

87. Kaur H, Gogoi B, Sharma I, et al. Hydrogels as a potential biomaterial for multimodal therapeutic applications. Mol Pharm 2024;21:4827–48. doi: 10.1021/acs.molpharmaceut.4c00595.

88. Chen H, Xu J, Sun J, et al. Recent advances on thermosensitive hydrogels-mediated precision therapy. Asian J Pharm Sci 2024;19:100911. doi: 10.1016/j.ajps.2024.100911.

89. Pablos JL, Lozano D, Manzano M, Vallet-Regí M. Regenerative medicine: hydrogels and mesoporous silica nanoparticles. Mater Today Bio 2024;29:101342. doi: 10.1016/j.mtbio.2024.101342.

90. Li F, Zhang J, Yi K, et al. Delivery of stem cell secretome for therapeutic applications. ACS Appl Bio Mater 2022;5:2009–30. doi: 10.1021/acsabm.1c01312.

91. Raspa A, Gelain F. mimicking extracellular matrix via engineered nanostructured biomaterials for neural repair. Curr Neuropharmacol 2020;19:2110–24. doi: 10.2174/1570159X18666201111111102.

92. Liang J, Liu P, Yang X, et al. Biomaterial-based scaffolds in promotion of cartilage regeneration: recent advances and emerging applications. J Orthop Translat 2023;41:54–62. doi: 10.1016/j.jot.2023.08.006.

93. Krishani M, Shin WY, Suhaimi H, Sambudi NS. Development of scaffolds from bio-based natural materials for tissue regeneration applications: a review. Gels 2023;9:100. doi: 10.3390/gels9020100.

94. Aoki K, Ideta H, Komatsu Y, et al. Bone-regeneration therapy using biodegradable scaffolds: calcium phosphate bioceramics and biodegradable polymers. Bioengineering 2024;11:180. doi: 10.3390/bioengineering11020180.

95. Wang M, Xu Y, Cao L, et al. Mechanical and biological properties of 3d printed bone tissue engineering scaffolds. Front Bioeng Biotechnol 2025;13:1–23. doi: 10.3389/fbioe.2025.1545693.

96. Baptista CJM, Rocha SCM. Biochemical properties of amniotic membrane. In: Mamede AC, Carvalho MJ, Abrantes A, Laranjo M, Maia C, Botelho MF, editors. Amniotic membrane : origin, characterization, and medical application. Dodrecht: Springer Science+Business Media; 2015; pp. 19–40. doi: 10.1007/978-94-017-9975-1_2.

97. Zhou T, Yuan Z, Weng J, et al. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol 2021;14:1–24. doi: 10.1186/s13045-021-01037-x.

98. Gerdfaramarzi MS, Bazmi S, Kiani M, Afshar L, Fadavi M, Enjoo SA. Ethical challenges of cord blood banks: a scoping review. J Med Life 2022;15:735-41. doi: 10.25122/jml-2021-0162.

99. Rebelatto CLK, Boldrini-Leite LM, Daga DR, et al. Quality control optimization for minimizing security risks associated with mesenchymal stromal cell-based product development. Int J Mol Sci 2023;24: 12955. doi: 10.3390/ijms241612955.

100. Capelli C, Cuofano C, Pavoni C, et al. Potency assays and biomarkers for cell-based advanced therapy medicinal products. Front Immunol 2023;14:1–18. doi: 10.3389/fimmu.2023.1186224.

101. Partan RU, Putra KM, Kusuma NF, et al. Umbilical cord mesenchymal stem cell secretome improves clinical outcomes and changes biomarkers in knee osteoarthritis. J Clin Med 2023;12:7138. doi: 10.3390/jcm12227138.

102. Lubis AMT, Aprianto P, Pawitan JA, Priosoeryanto BP, Dewi TIT, Kamal AF. Intra-articular injection of secretome, derived from umbilical cord mesenchymal stem cell, enhances the regeneration process of cartilage in early-stage osteo-arthritis: an animal study. Acta Orthop 2023;94:300-6. doi: 10.2340/17453674.2023.12359.

103. Li S, Rong Q, Zhou Y, Che Y, Ye Z, Liu J, Wang J, Zhou M. Osteogenically committed hUCMSCs-derived exosomes promote the recovery of critical-sized bone defects with enhanced osteogenic properties. APL Bioeng 2024;8:016107. doi: 10.1063/5.0159740.

104. Jia S, Yang T, Gao S, Bai L, et al. Exosomes from umbilical cord mesenchymal stem cells ameliorate intervertebral disc degeneration via repairing mitochondrial dysfunction. J Orthop Translat 2024;46:103-15. doi: 10.1016/j.jot.2023.10.004.