International Journal of Biomedicine. 2022;12(4):548-553.
Originally published December 5, 2022
Regeneration of damaged articular cartilage remains one of the most complex and unresolved problems in traumatology and orthopedics. In this study, we investigated whether intra-articular injection of synovium-derived mesenchymal stem cells (SD-MSCs) with low molecular weight hyaluronic acid (LMWHA) could promote the regeneration of damaged cartilage in rabbits. To answer this question, rabbits' SD-MSCs were harvested, expanded in culture, and characterized by CFU assay and a multilineage differentiation test. For in vivo study, we created a defect within the cartilage layer without destroying subchondral bone. Two weeks after the cartilage defect, SD-MSCs (2×106 cells) were suspended in 0.5% LMWHA and injected into the left knee, and hyaluronic acid (HA) solution alone was placed into the right knee. Cartilage regeneration in experimental and control groups was evaluated macroscopically and histologically at Days 30, 60, and 90. The results of the study showed an early process of cartilage regeneration in the defect area on Day 30 after intra-articular MSCs-HA injection. Histological studies revealed that cartilage defect was covered by a thin layer of spindle-shaped undifferentiated cells and proliferated chondroblasts, in contrast to a single HA injection, which did not induce cartilage regeneration. On Day 60, we observed that the size of the cartilage defect after MSCs-HA injection significantly decreased, compared to one after HA injection. On Day 90, the cartilage defect in a knee treated with MSCs-HA was fully regenerated and was similar to intact cartilage. Thus, the combined application of the MSCs, HA, and chondroinductive proteins have a high therapeutic effect on cartilage defect regeneration in rabbits.
1. Marlovits S, Kutscha-Lissberg F, Aldrian S, Resinger C, Singer P, Zeller P, Vécsei V. [Autologous chondrocyte transplantation for the treatment of articular cartilage defects in the knee joint. Techniques and results]. Radiologe. 2004 Aug;44(8):763-72. doi: 10.1007/s00117-004-1082-0. [Article in German].
2. Caldwell KL, Wang J. Cell-based articular cartilage repair: the link between development and regeneration. Osteoarthritis Cartilage. 2015 Mar;23(3):351-62. doi: 10.1016/j.joca.2014.11.004.
3. Kan HS, Chan PK, Chiu KY, Yan CH, Yeung SS, Ng YL, Shiu KW, Ho T. Non-surgical treatment of knee osteoarthritis. Hong Kong Med J. 2019 Apr;25(2):127-133. doi: 10.12809/hkmj187600.
4. Rahmani Del Bakhshayesh A, Babaie S, Tayefi Nasrabadi H, Asadi N, Akbarzadeh A, Abedelahi A. An overview of various treatment strategies, especially tissue engineering for damaged articular cartilage. Artif Cells Nanomed Biotechnol. 2020 Dec;48(1):1089-1104. doi: 10.1080/21691401.2020.1809439.
5. Panseri S, Russo A, Cunha C, Bondi A, Di Martino A, Patella S, Kon E. Osteochondral tissue engineering approaches for articular cartilage and subchondral bone regeneration. Knee Surg Sports Traumatol Arthrosc. 2012 Jun;20(6):1182-91. doi: 10.1007/s00167-011-1655-1.
6. Jiang S, Guo W, Tian G, Luo X, Peng L, Liu S, Sui X, Guo Q, Li X. Clinical Application Status of Articular Cartilage Regeneration Techniques: Tissue-Engineered Cartilage Brings New Hope. Stem Cells Int. 2020 Jun 30;2020:5690252. doi: 10.1155/2020/5690252.
7. Epanomeritakis IE, Lee E, Lu V, Khan W. The Use of Autologous Chondrocyte and Mesenchymal Stem Cell Implants for the Treatment of Focal Chondral Defects in Human Knee Joints-A Systematic Review and Meta-Analysis. Int J Mol Sci. 2022 Apr 6;23(7):4065. doi: 10.3390/ijms23074065.
8. Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal Stem Cells for Regenerative Medicine. Cells. 2019 Aug 13;8(8):886. doi: 10.3390/cells8080886.
9. Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood. 2001 Oct 15;98(8):2396-402. doi: 10.1182/blood.v98.8.2396.
10. Dai R, Yu Y, Yan G, Hou X, Ni Y, Shi G. Intratracheal administration of adipose derived mesenchymal stem cells alleviates chronic asthma in a mouse model. BMC Pulm Med. 2018 Aug 8;18(1):131. doi: 10.1186/s12890-018-0701-x.
11. Voga M, Adamic N, Vengust M, Majdic G. Stem Cells in Veterinary Medicine-Current State and Treatment Options. Front Vet Sci. 2020 May 29;7:278. doi: 10.3389/fvets.2020.00278.
12. Makris EA, Hadidi P, Athanasiou KA. The knee meniscus: structure-function, pathophysiology, current repair techniques, and prospects for regeneration. Biomaterials. 2011 Oct;32(30):7411-31. doi: 10.1016/j.biomaterials.2011.06.037.
13. Zha K, Sun Z, Yang Y, Chen M, Gao C, Fu L, Li H, Sui X, Guo Q, Liu S. Recent Developed Strategies for Enhancing Chondrogenic Differentiation of MSC: Impact on MSC-Based Therapy for Cartilage Regeneration. Stem Cells Int. 2021 Mar 20;2021:8830834. doi: 10.1155/2021/8830834.
14. Bae HC, Park HJ, Wang SY, Yang HR, Lee MC, Han HS. Hypoxic condition enhances chondrogenesis in synovium-derived mesenchymal stem cells. Biomater Res. 2018 Sep 26;22:28. doi: 10.1186/s40824-018-0134-x. Erratum in: Biomater Res. 2019 Mar 4;23:7.
15. Sakaguchi Y, Sekiya I, Yagishita K, Muneta T. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005 Aug;52(8):2521-9. doi: 10.1002/art.21212.
16. Li L, Duan X, Fan Z, Chen L, Xing F, Xu Z, Chen Q, Xiang Z. Mesenchymal Stem Cells in Combination with Hyaluronic Acid for Articular Cartilage Defects. Sci Rep. 2018 Jul 2;8(1):9900. doi: 10.1038/s41598-018-27737-y.
17. Hatsushika D, Muneta T, Horie M, Koga H, Tsuji K, Sekiya I. Intraarticular injection of synovial stem cells promotes meniscal regeneration in a rabbit massive meniscal defect model. J Orthop Res. 2013 Sep;31(9):1354-9. doi: 10.1002/jor.22370.
18. Gale AL, Linardi RL, McClung G, Mammone RM, Ortved KF. Comparison of the Chondrogenic Differentiation Potential of Equine Synovial Membrane-Derived and Bone Marrow-Derived Mesenchymal Stem Cells. Front Vet Sci. 2019 Jun 6;6:178. doi: 10.3389/fvets.2019.00178.
19. Ha CW, Park YB, Chung JY, Park YG. Cartilage Repair Using Composites of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronic Acid Hydrogel in a Minipig Model. Stem Cells Transl Med. 2015 Sep;4(9):1044-51. doi: 10.5966/sctm.2014-0264.
20. Kang SW, Bada LP, Kang CS, Lee JS, Kim CH, Park JH, Kim BS. Articular cartilage regeneration with microfracture and hyaluronic acid. Biotechnol Lett. 2008 Mar;30(3):435-9. doi: 10.1007/s10529-007-9576-2.
21. Danišovič L, Varga I, Polák S. Growth factors and chondrogenic differentiation of mesenchymal stem cells. Tissue Cell. 2012 Apr;44(2):69-73. doi: 10.1016/j.tice.2011.11.005.
22. Blaney Davidson EN, van der Kraan PM, van den Berg WB. TGF-beta and osteoarthritis. Osteoarthritis Cartilage. 2007 Jun;15(6):597-604. doi: 10.1016/j.joca.2007.02.005.
23. Miljkovic ND, Cooper GM, Marra KG. Chondrogenesis, bone morphogenetic protein-4 and mesenchymal stem cells. Osteoarthritis Cartilage. 2008 Oct;16(10):1121-30. doi: 10.1016/j.joca.2008.03.003.
Received October 31, 2022.
Accepted November 30, 2022.
©2022 International Medical Research and Development Corporation.