Heparin-Conjugated Fibrin Hydrogel with Chondroinductive Growth Factors and Human Synovium-Derived Mesenchymal Stem Cells for the Treatment of Articular Cartilage Defects: Evaluation of Clinical Safety

T. Toktarov, B. Saginov, Ye. Raimagambetov, B. Balbossynov, G. Korganbekova, M. Urazayev, A. Issabekova, G. Zhubanova, G. Kaukabayeva, A. Sekenova, G. Kudaibergen, Zh. Akhmetkarimova, S. Eskendirova, Ye. Ramankulov, O. Bekarissov, A. Batpen, V. Ogay

International Journal of Biomedicine. 2022;12(4):539-547.
DOI: 10.21103/Article12(4)_OA3
Originally published December 5, 2022


The purpose of this study was to evaluate the safety of an injectable heparin-conjugated fibrin (HCF) hydrogel containing human synovium-derived mesenchymal stem cells (SDMSCs), TGF-β1, and BMP-4 after implantation into articular cartilage defect in patients with osteoarthritis (OA). The study included 15 OA patients with a mean age of 44.2±18.0 years. The median articular cartilage defect size was 4.9±2.0 cm. HCF hydrogel, containing SDMSCs and growth factors (TGF-β1 and BMP-4), was implanted into the cartilage defect using DUPLOJECT two-syringe device connected with the DUPLOTIP dual lumen cannula. Clinical and radiological outcomes were evaluated with VAS, WOMAC, KOOS, and MOCART. The clinical study results showed that implantation of HCF hydrogel with autologous SDMSCs, TGF-β1, and BMP-4 appeared to be safe and did not show severe adverse events in OA patients. The assessment of clinical outcomes after 6 months showed improvement in VAS, WOMAC, and KOOS scores in all patients. The MOCART evaluation demonstrated an enhancement of cartilage tissue repair in 73.3% of OA patients at 6 months after surgery. Thus, implantation of HCF hydrogel with SDMSCs, TGF-β1, and BMP-4 was safe and demonstrated signs of improvement in articular cartilage repair. The evaluation of the long-term safety and therapeutic efficacy of HCF hydrogel is required in a further clinical study using a larger number of OA patients.

mesenchymal stem cells • fibrin hydrogel • growth factors • cartilage defect • clinical safety
  1. Hiligsmann M, Reginster JY. The economic weight of osteoarthritis in Europe. J Medicographia. 2013;35:197–202.
  2. Klug A, Gramlich Y, Rudert M, Drees P, Hoffmann R, Weißenberger M, Kutzner KP. The projected volume of primary and revision total knee arthroplasty will place an immense burden on future health care systems over the next 30 years. Knee Surg Sports Traumatol Arthrosc. 2021 Oct;29(10):3287-3298. doi: 10.1007/s00167-020-06154-7. 
  3. Safiri S, Kolahi AA, Smith E, Hill C, Bettampadi D, Mansournia MA, et al. Global, regional and national burden of osteoarthritis 1990-2017: a systematic analysis of the Global Burden of Disease Study 2017. Ann Rheum Dis. 2020 Jun;79(6):819-828. doi: 10.1136/annrheumdis-2019-216515.
  4. Evenbratt H, Andreasson L, Bicknell V, Brittberg M, Mobini R, Simonsson S. Insights into the present and future of cartilage regeneration and joint repair. Cell Regen. 2022 Feb 2;11(1):3. doi: 10.1186/s13619-021-00104-5. 
  5. Steinert AF, Ghivizzani SC, Rethwilm A, Tuan RS, Evans CH, Nöth U. Major biological obstacles for persistent cell-based regeneration of articular cartilage. Arthritis Res Ther. 2007;9(3):213. doi: 10.1186/ar2195.
  6. Huang K, Li Q, Li Y, Yao Z, Luo D, Rao P, Xiao J. Cartilage Tissue Regeneration: The Roles of Cells, Stimulating Factors and Scaffolds. Curr Stem Cell Res Ther. 2018;13(7):547-567. doi: 10.2174/1574888X12666170608080722. 
  7. Vinatier C, Mrugala D, Jorgensen C, Guicheux J, Noël D. Cartilage engineering: a crucial combination of cells, biomaterials and biofactors. Trends Biotechnol. 2009 May;27(5):307-14. doi: 10.1016/j.tibtech.2009.02.005..
  8. Huselstein C, Li Y, He X. Mesenchymal stem cells for cartilage engineering. Biomed Mater Eng. 2012;22(1-3):69-80. doi: 10.3233/BME-2012-0691. 
  9. Salgado AJ, Oliveira JT, Pedro AJ, Reis RL. Adult stem cells in bone and cartilage tissue engineering. Curr Stem Cell Res Ther. 2006 Sep;1(3):345-64. doi: 10.2174/157488806778226803. 
  10. Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant. 2011;20(1):5-14. doi: 10.3727/096368910X. 
  11. Fan J, Varshney RR, Ren L, Cai D, Wang DA. Synovium-derived mesenchymal stem cells: a new cell source for musculoskeletal regeneration. Tissue Eng Part B Rev. 2009 Mar;15(1):75-86. doi: 10.1089/ten.teb.2008.0586. 
  12. Sasaki A, Mizuno M, Ozeki N, Katano H, Otabe K, Tsuji K, Koga H, Mochizuki M, Sekiya I. Canine mesenchymal stem cells from synovium have a higher chondrogenic potential than those from infrapatellar fat pad, adipose tissue, and bone marrow. PLoS One. 2018 Aug 23;13(8):e0202922. doi: 10.1371/journal.pone.0202922.
  13. Jones BA, Pei M. Synovium-derived stem cells: a tissue-specific stem cell for cartilage engineering and regeneration. Tissue Eng Part B Rev. 2012 Aug;18(4):301-11. doi: 10.1089/ten.TEB.2012.0002. 
  14. Koga H, Muneta T, Ju YJ, Nagase T, Nimura A, Mochizuki T, Ichinose S, von der Mark K, Sekiya I. Synovial stem cells are regionally specified according to local microenvironments after implantation for cartilage regeneration. Stem Cells. 2007 Mar;25(3):689-96. doi: 10.1634/stemcells.2006-0281. 
  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. Koga H, Muneta T, Nagase T, Nimura A, Ju YJ, Mochizuki T, Sekiya I. Comparison of mesenchymal tissues-derived stem cells for in vivo chondrogenesis: suitable conditions for cell therapy of cartilage defects in rabbit. Cell Tissue Res. 2008 Aug;333(2):207-15. doi: 10.1007/s00441-008-0633-5. 
  17. Magne D, Vinatier C, Julien M, Weiss P, Guicheux J. Mesenchymal stem cell therapy to rebuild cartilage. Trends Mol Med. 2005 Nov;11(11):519-26. doi: 10.1016/j.molmed.2005.09.002.
  18. 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. 
  19. Wagenbrenner M, Mayer-Wagner S, Rudert M, Holzapfel BM, Weissenberger M. Combinations of Hydrogels and Mesenchymal Stromal Cells (MSCs) for Cartilage Tissue Engineering-A Review of the Literature. Gels. 2021 Nov 16;7(4):217. doi: 10.3390/gels7040217. 
  20. Gugjoo MB, Amarpal, Abdelbaset-Ismail A, Aithal HP, Kinjavdekar P, Pawde AM, Kumar GS, Sharma GT. Mesenchymal stem cells with IGF-1 and TGF- β1 in laminin gel for osteochondral defects in rabbits. Biomed Pharmacother. 2017 Sep;93:1165-1174. doi: 10.1016/j.biopha.2017.07.032. 
  21. Huang H, Hu X, Zhang X, Duan X, Zhang J, Fu X, Dai L, Yuan L, Zhou C, Ao Y. Codelivery of Synovium-Derived Mesenchymal Stem Cells and TGF-β by a Hybrid Scaffold for Cartilage Regeneration. ACS Biomater Sci Eng. 2019 Feb 11;5(2):805-816. doi: 10.1021/acsbiomaterials.8b00483. 
  22. Vayas R, Reyes R, Arnau MR, Évora C, Delgado A. Injectable Scaffold for Bone Marrow Stem Cells and Bone Morphogenetic Protein-2 to Repair Cartilage. Cartilage. 2021 Jul;12(3):293-306. doi: 10.1177/1947603519841682. 
  23. Ogay VB, Isabekova AS, Sarsenova MA, Ramankulov EM. Patent of the Republic of Kazakhstan. A method for obtaining an injectable biocomposite hydrogel to stimulate the regeneration of bone and cartilage tissue. 2019;33784:29.
  24. Sarsenova M, Raymagambetov Y, Issabekova A, Karzhauov M, Kudaibergen G,  Akhmetkarimova Zh, Batpen, A, Ramankulov Y, Ogay V. Regeneration of Osteochondral Defects by Combined Delivery of Synovium-Derived Mesenchymal Stem Cells, TGF-β1 and BMP-4 in Heparin-Conjugated Fibrin Hydrogel. Polymers. 2022 (under review).
  25. Yang HS, La WG, Bhang SH, Jeon JY, Lee JH, Kim BS. Heparin-conjugated fibrin as an injectable system for sustained delivery of bone morphogenetic protein-2. Tissue Eng Part A. 2010 Apr;16(4):1225-33. doi: 10.1089/ten.TEA.2009.0390.
  26. Haleem AM, Singergy AA, Sabry D, Atta HM, Rashed LA, Chu CR, et al. The Clinical Use of Human Culture-Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects: A Pilot Study and Preliminary Results. Cartilage. 2010 Oct;1(4):253-261. doi: 10.1177/1947603510366027. 
  27. Kim YS, Choi YJ, Suh DS, Heo DB, Kim YI, Ryu JS, Koh YG. Mesenchymal stem cell implantation in osteoarthritic knees: is fibrin glue effective as a scaffold? Am J Sports Med. 2015 Jan;43(1):176-85. doi: 10.1177/0363546514554190.
  28. Ren X, Zhao M, Lash B, Martino MM, Julier Z. Growth Factor Engineering Strategies for Regenerative Medicine Applications. Front Bioeng Biotechnol. 2020 Jan 21;7:469. doi: 10.3389/fbioe.2019.00469.
  29. Joung YK, Bae JW, Park KD. Controlled release of heparin-binding growth factors using heparin-containing particulate systems for tissue regeneration. Expert Opin Drug Deliv. 2008 Nov;5(11):1173-84. doi: 10.1517/17425240802431811. 
  30. Wei W, Ma Y, Yao X, Zhou W, Wang X, Li C, Lin J, He Q, Leptihn S, Ouyang H. Advanced hydrogels for the repair of cartilage defects and regeneration. Bioact Mater. 2020 Oct 10;6(4):998-1011. doi: 10.1016/j.bioactmat.2020.09.030.
  31. Liu M, Zeng X, Ma C, Yi H, Ali Z, Mou X, Li S, Deng Y, He N. Injectable hydrogels for cartilage and bone tissue engineering. Bone Res. 2017 May 30;5:17014. doi: 10.1038/boneres.2017.14.
  32. Palladino MA, Morris RE, Starnes HF, Levinson AD. The transforming growth factor-betas. A new family of immunoregulatory molecules. Ann N Y Acad Sci. 1990;593:181-7. doi: 10.1111/j.1749-6632.1990.tb16110.x. 
  33. McCaffrey TA, Falcone DJ, Du B. Transforming growth factor-beta 1 is a heparin-binding protein: identification of putative heparin-binding regions and isolation of heparins with varying affinity for TGF-beta 1. J Cell Physiol. 1992 Aug;152(2):430-40. doi: 10.1002/jcp.1041520226. 

Download Article
Received September 30, 2022.
Accepted November 2, 2022.
©2022 International Medical Research and Development Corporation.