Skip to main content

Advertisement

SpringerLink
Log in

Umbilical cord-derived mesenchymal stem cells for treating osteoarthritis of the knee: a single-arm, open-label study

  • Original Article
  • Published:
European Journal of Orthopaedic Surgery & Traumatology Aims and scope Submit manuscript

Abstract

Background

Despite being a common cause of quality-of-life impairment, there are no efficacious therapies that could prevent the progression of knee osteoarthritis (KOA). We conducted an open-label trial of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and hyaluronic acid (HA) for treating KOA.

Methods

This open-label study was conducted from July 2015 to December 2018 at Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Patients diagnosed with KOA were injected three times, comprising of 10 × 106 units of hUC-MSCs in 2-ml secretome implantation and 2-ml hyaluronic acid (HA) injection in the first week, followed with 2-ml HA injection twice in the second and third week.

Results

Twenty-nine subjects (57 knees) were recruited. Seventeen (58.6%) subjects were male, and the mean age was 58.3 ± 9.6 years. Thirty-three (57.9%) knees were classified into Kellgren–Lawrence grade I–II KOA (mild OA). hUC-MSCs significantly decreased pain measured by visual analogue scale in severe KOA from initial to 6th month follow-up [5 ± 2.97 to 3.38 ± 2.44 (p = 0.035)]. The International Knee Documentation Committee score significantly increased at 6th month follow-up (53.26 ± 16.66 to 65.49 ± 13.01, p < 0.001, in subjects with grade I–II and 48.84 ± 18.41 to 61.83 ± 18.83, p = 0.008, in subjects with severe KOA). The Western Ontario and McMaster Universities Osteoarthritis decreased significantly in both groups from initial to 6th month follow-up (from 22.55 ± 15.94 to 13.23 ± 10.29, p = 0.003, and from 27.57 ± 15.99 to 17.92 ± 19.1, p = 0.003, in those with mild and severe KOA, respectively).

Conclusions

hUC-MSCs could be a potentially new regenerative treatment for KOA. The maximum effect of hUC-MSCs was achieved after 6 months of injection.

Level of evidence

Therapeutic level II.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Morille M, Toupet K, Montero-Menei CN et al (2016) PLGA-based microcarriers induce mesenchymal stem cell chondrogenesis and stimulate cartilage repair in osteoarthritis. Biomaterials. https://doi.org/10.1016/j.biomaterials.2016.02.022

    Article  PubMed  Google Scholar 

  2. Zhen G, Wen C, Jia X et al (2013) Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 19:704–712. https://doi.org/10.1038/nm.3143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang Y, Yuan M, Guo Q-Y et al (2015) Mesenchymal stem cells for treating articular cartilage defects and osteoarthritis. Cell Transplant 24:1661–1678. https://doi.org/10.3727/096368914X683485

    Article  PubMed  Google Scholar 

  4. Li G, Yin J, Gao J et al (2013) Subchondral bone in osteoarthritis: insight into risk factors and microstructural changes. Arthritis Res Ther 15:223. https://doi.org/10.1186/ar4405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dulay GS, Cooper C, Dennison EM (2015) Knee pain, knee injury, knee osteoarthritis and work. Best Pract Res Clin Rheumatol 29:454–461. https://doi.org/10.1016/j.berh.2015.05.005

    Article  PubMed  Google Scholar 

  6. Mamidi MK, Das AK, Zakaria Z, Bhonde R (2016) Mesenchymal stromal cells for cartilage repair in osteoarthritis. Osteoarthr Cartil 24:1307–1361. https://doi.org/10.1016/j.joca.2016.03.003

    Article  CAS  PubMed  Google Scholar 

  7. Hussain SM, Neilly DW, Baliga S et al (2016) Knee osteoarthritis: a review of management options. Scott Med J 61:7–16. https://doi.org/10.1177/0036933015619588

    Article  CAS  PubMed  Google Scholar 

  8. Barry F, Murphy M (2013) Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol 9:584–594

    Article  CAS  Google Scholar 

  9. Davatchi F, Sadeghi Abdollahi B, Mohyeddin M, Nikbin B (2016) Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int J Rheum Dis 19:219–225. https://doi.org/10.1111/1756-185X.12670

    Article  PubMed  Google Scholar 

  10. Buckwalter JA (2000) Advancing the science and art of orthopaedics: lessons from history. J Bone Jt Surg Ser A 82-A:1782–1803. https://doi.org/10.2106/00004623-200012000-00012

    Article  Google Scholar 

  11. Kurtz S, Ong K, Lau E et al (2007) Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Jt Surg Ser A 89:780–785. https://doi.org/10.2106/JBJS.F.00222

    Article  Google Scholar 

  12. Derar H, Shahinpoor M (2015) Recent patents and designs on hip replacement prostheses. Open Biomed Eng J. https://doi.org/10.2174/1874120701509010092

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gallo J, Kamínek P, Tichá V et al (2002) Particle disease. A comprehensive theory of periprosthetic osteolysis: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 146:21–28. https://doi.org/10.5507/bp.2002.004

    Article  PubMed  Google Scholar 

  14. Sargeant A, Goswami T (2006) Hip implants: paper V. Mater Des, Physiological Eff. https://doi.org/10.1016/j.matdes.2004.10.028

    Book  Google Scholar 

  15. Srimongkol S (2012) A review of mathematical modeling in total hip replacement. Int Math Forum 7:2561–2569

    Google Scholar 

  16. Lo GH, LaValley M, McAlindon T, Felson DT (2003) Intra-articular hyaluronic acid in treatment of knee osteoarthritis: a meta-analysis. J Am Med Assoc 290:3115–3321. https://doi.org/10.1001/jama.290.23.3115

    Article  CAS  Google Scholar 

  17. Gallagher B, Tjoumakaris FP, Harwood MI et al (2015) Chondroprotection and the prevention of osteoarthritis progression of the knee: a systematic review of treatment agents. Am J Sports Med 43:734–744. https://doi.org/10.1177/0363546514533777

    Article  PubMed  Google Scholar 

  18. Deng M-W, Wei S-J, Yew T-L et al (2015) Cell therapy with G-CSF-mobilized stem cells in a rat osteoarthritis model. Cell Transplant 24:1085–1096. https://doi.org/10.3727/096368914X680091

    Article  PubMed  Google Scholar 

  19. Saw KY, Anz A, Merican S et al (2011) Articular cartilage regeneration with autologous peripheral blood progenitor cells and hyaluronic acid after arthroscopic subchondral drilling: a report of 5 cases with histology. Arthrosc J Arthrosc Relat Surg 27:493–506. https://doi.org/10.1016/j.arthro.2010.11.054

    Article  Google Scholar 

  20. Chiang ER, Ma HL, Wang JP et al (2016) Allogeneic mesenchymal stem cells in combination with hyaluronic acid for the treatment of osteoarthritis in rabbits. PLoS ONE 11:e0149835. https://doi.org/10.1371/journal.pone.0149835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu Q, Niu J, Huang J et al (2015) Knee osteoarthritis and all-cause mortality: the Wuchuan Osteoarthritis Study. Osteoarthr Cartil 23:1154–1157. https://doi.org/10.1016/j.joca.2015.03.021

    Article  CAS  PubMed  Google Scholar 

  22. Gore M, Tai K-S, Sadosky A et al (2011) Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis. J Med Econ 14:497–507. https://doi.org/10.3111/13696998.2011.594347

    Article  PubMed  Google Scholar 

  23. Liu TM, Martina M, Hutmacher DW et al (2006) Identification of common pathways mediating differentiation of bone marrow- and adipose tissue-derived human mesenchymal stem cells into three mesenchymal lineages. Stem Cells 25:750–760. https://doi.org/10.1634/stemcells.2006-0394

    Article  CAS  PubMed  Google Scholar 

  24. Ding D-C, Chang Y-H, Shyu W-C, Lin S-Z (2015) Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy. Cell Transplant 24:339–347. https://doi.org/10.3727/096368915X686841

    Article  PubMed  Google Scholar 

  25. Ding DC, Chou HL, Chang YH et al (2016) Characterization of HLA-G and related immunosuppressive effects in human umbilical cord stroma-derived stem cells. Cell Transplant 25:217–228. https://doi.org/10.3727/096368915X688182

    Article  PubMed  Google Scholar 

  26. Ding DC, Shyu WC, Lin SZ et al (2012) Human umbilical cord mesenchymal stem cells support nontumorigenic expansion of human embryonic stem cells. Cell Transplant 21:1515–1527. https://doi.org/10.3727/096368912X647199

    Article  PubMed  Google Scholar 

  27. Wang H, Yan X, Jiang Y et al (2018) The human umbilical cord stem cells improve the viability of OA degenerated chondrocytes. Mol Med Rep 17:4474–4482. https://doi.org/10.3892/mmr.2018.8413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhu Y, Guan YM, Huang HL, Wang QS (2014) Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits. Acta Pharmacol Sin 35:585–591. https://doi.org/10.1038/aps.2014.9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Min F, Gao F, Li Q, Liu Z (2015) Therapeutic effect of human umbilical cord mesenchymal stem cells modified by angiotensin-converting enzyme 2 gene on bleomycin-induced lung fibrosis injury. Mol Med Rep 11:2387–2396. https://doi.org/10.3892/mmr.2014.3025

    Article  CAS  PubMed  Google Scholar 

  30. Amable PR, Teixeira MVT, Carias RBV et al (2014) Protein synthesis and secretion in human mesenchymal cells derived from bone marrow, adipose tissue and Wharton’s jelly. Stem Cell Res Ther 5:53. https://doi.org/10.1186/scrt442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen J, Liu Z, Hong MM et al (2014) Proangiogenic compositions of microvesicles derived from human umbilical cord mesenchymal stem cells. PLoS ONE 16:e115316. https://doi.org/10.1371/journal.pone.0115316

    Article  CAS  Google Scholar 

  32. Centeno CJ, Busse D, Kisiday J et al (2008) Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells, platelet lysate and dexamethasone. Am J Case Rep 11:343–353

    Google Scholar 

  33. Centeno CJ, Busse D, Kisiday J et al (2008) Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Med Hypotheses 71:900–908. https://doi.org/10.1016/j.mehy.2008.06.042

    Article  CAS  PubMed  Google Scholar 

  34. Emadedin M, Aghdami N, Taghiyar L et al (2012) Intra-articular injection of autologous mesenchymal stem cells in six patients with knee Osteoarthritis. Arch Iran Med 15:422–428

    PubMed  Google Scholar 

  35. Kellgren JH, Lawrence JS (1957) Radiological assessment of osteo-arthrosis. Ann Rheum Dis 16:494–502

    Article  CAS  Google Scholar 

  36. Murphy JM, Fink DJ, Hunziker EB, Barry FP (2003) Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum 48:3464–3474. https://doi.org/10.1002/art.11365

    Article  PubMed  Google Scholar 

  37. Pawitan JA, Liem IK, Budiyanti E et al (2014) Umbilical cord derived stem cell culture: multiple-harvest explant method. Int J PharmTech Res 6:1202–1208

    Google Scholar 

  38. Dilogo IH, Primaputra MRA, Pawitan JA, Liem IK (2017) Modified Masquelet technique using allogeneic umbilical cord-derived mesenchymal stem cells for infected non-union femoral shaft fracture with a 12 cm bone defect: a case report. Int J Surg Case Rep 34:11–16. https://doi.org/10.1016/j.ijscr.2017.03.002

    Article  PubMed  PubMed Central  Google Scholar 

  39. Litwic A, Edwards MH, Dennison EM, Cooper C (2013) Epidemiology and burden of osteoarthritis. Br Med Bull 105:185–199. https://doi.org/10.1093/bmb/lds038

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kong L, Zheng LZ, Qin L, Ho KKW (2017) Role of mesenchymal stem cells in osteoarthritis treatment. J Orthop Transl 9:89–103. https://doi.org/10.1016/j.jot.2017.03.006

    Article  Google Scholar 

  41. Brittberg M, Lindahl A, Nilsson A et al (1994) Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889–895. https://doi.org/10.1056/NEJM199410063311401

    Article  CAS  PubMed  Google Scholar 

  42. Martel-Pelletier J, Wildi LM, Pelletier JP (2012) Future therapeutics for osteoarthritis. Bone 51:297–311. https://doi.org/10.1016/j.bone.2011.10.008

    Article  CAS  PubMed  Google Scholar 

  43. Alhadlaq A, Mao JJ (2004) Mesenchymal stem cells: isolation and therapeutics. Stem Cells Dev 13:436–448. https://doi.org/10.1089/scd.2004.13.436

    Article  CAS  PubMed  Google Scholar 

  44. Bruder SP, Fink DJ, Caplan AI (1994) Mesenchymal stem cells in bone development, bone repair, and skeletal regenaration therapy. J Cell Biochem 56:283–294. https://doi.org/10.1002/jcb.240560303

    Article  CAS  PubMed  Google Scholar 

  45. Cha J, Falanga V (2007) Stem cells in cutaneous wound healing. Clin Dermatol 25:73–78. https://doi.org/10.1016/j.clindermatol.2006.10.002

    Article  PubMed  Google Scholar 

  46. Gangji V, Toungouz M, Hauzeur J-P (2005) Stem cell therapy for osteonecrosis of the femoral head. Expert Opin Biol Ther. https://doi.org/10.1517/14712598.5.4.437

    Article  PubMed  Google Scholar 

  47. Centeno CJ (2014) Clinical challenges and opportunities of mesenchymal stem cells in musculoskeletal medicine. PM&R 6:70–77. https://doi.org/10.1016/j.pmrj.2013.08.612

    Article  Google Scholar 

  48. Kim S-W, Han H, Chae G-T et al (2006) Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger’s disease and ischemic limb disease animal model. Stem Cells 24:1620–1626. https://doi.org/10.1634/stemcells.2005-0365

    Article  PubMed  Google Scholar 

  49. Baker CD, Abman SH (2013) Umbilical cord stem cell therapy for bronchopulmonary dysplasia: ready for prime time? Thorax 68:402–404. https://doi.org/10.1136/thoraxjnl-2012-202661

    Article  PubMed  Google Scholar 

  50. Gu Z, Akiyama K, Ma X et al (2010) Transplantation of umbilical cord mesenchymal stem cells alleviates lupus nephritis in MRL/lpr mice. Lupus 19:1502–1514. https://doi.org/10.1177/0961203310373782

    Article  CAS  PubMed  Google Scholar 

  51. Li X, Duan L, Liang Y et al (2016) Human umbilical cord blood-derived mesenchymal stem cells contribute to chondrogenesis in coculture with chondrocytes. Biomed Res Int 2016:3827057. https://doi.org/10.1155/2016/3827057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Deng H, Liao L, Wu J et al (2017) Clinical efficacy of intravesical electrical stimulation on detrusor underactivity: 8 years of experience from a single center. Med (United States) 96:e8020. https://doi.org/10.1097/MD.0000000000008020

    Article  Google Scholar 

  53. Zheng P, Ju L, Jiang B et al (2013) Chondrogenic differentiation of human umbilical cord blood-derived mesenchymal stem cells by co-culture with rabbit chondrocytes. Mol Med Rep 8:1169–1182. https://doi.org/10.3892/mmr.2013.1637

    Article  CAS  PubMed  Google Scholar 

  54. Mennan C, Wright K, Bhattacharjee A et al (2013) Isolation and characterisation of mesenchymal stem cells from different regions of the human umbilical cord. Biomed Res Int 2013:916136. https://doi.org/10.1155/2013/916136

    Article  PubMed  PubMed Central  Google Scholar 

  55. Maumus M, Jorgensen C, Noël D (2013) Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. Biochimie 95:2229–2234. https://doi.org/10.1016/j.biochi.2013.04.017

    Article  CAS  PubMed  Google Scholar 

  56. Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 8:315–317. https://doi.org/10.1080/14653240600855905

    Article  CAS  Google Scholar 

  57. Ding DC, Shyu WC, Chiang MF et al (2007) Enhancement of neuroplasticity through upregulation of β1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis 27:339–353. https://doi.org/10.1016/j.nbd.2007.06.010

    Article  CAS  PubMed  Google Scholar 

  58. Wang D, Chen K, Du WT et al (2010) CD14 + monocytes promote the immunosuppressive effect of human umbilical cord matrix stem cells. Exp Cell Res 316:2414–2423. https://doi.org/10.1016/j.yexcr.2010.04.018

    Article  CAS  PubMed  Google Scholar 

  59. Xu S, Liu H, Xie Y et al (2015) Effect of mesenchymal stromal cells for articular cartilage degeneration treatment: a meta-analysis. Cytotherapy 17:1342–1352. https://doi.org/10.1016/j.jcyt.2015.05.005

    Article  CAS  PubMed  Google Scholar 

  60. Vega A, Martín-Ferrero MA, Del Canto F et al (2015) Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation 17:1342–1352. https://doi.org/10.1097/TP.0000000000000678

    Article  CAS  Google Scholar 

  61. Gupta PK, Das AK, Chullikana A, Majumdar AS (2012) Mesenchymal stem cells for cartilage repair in osteoarthritis. Stem Cell Res Ther 3:25. https://doi.org/10.1186/scrt116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. van Lent PLEM, van den Berg WB (2013) Mesenchymal stem cell therapy in osteoarthritis: advanced tissue repair or intervention with smouldering synovial activation? Arthritis Res Ther 15:112. https://doi.org/10.1186/ar4190

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zhang B, Wang M, Gong A et al (2015) HucMSc-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells 33:2158–2168. https://doi.org/10.1002/stem.1771

    Article  CAS  PubMed  Google Scholar 

  64. Feng C, Luo X, He N et al (2018) Efficacy and persistence of allogeneic adipose-derived mesenchymal stem cells combined with hyaluronic acid in osteoarthritis after intra-articular injection in a sheep model. Tissue Eng Part A 24:219–233. https://doi.org/10.1089/ten.tea.2017.0039

    Article  CAS  PubMed  Google Scholar 

  65. Matas J, Orrego M, Amenabar D et al (2019) Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial. Stem Cells Transl Med 8:215–224. https://doi.org/10.1002/sctm.18-0053

    Article  CAS  PubMed  Google Scholar 

  66. O’Hanlon CE, Newberry SJ, Booth M et al (2016) Hyaluronic acid injection therapy for osteoarthritis of the knee: concordant efficacy and conflicting serious adverse events in two systematic reviews. Syst Rev 5:186. https://doi.org/10.1186/s13643-016-0363-9

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Boenyamin Setiawan, PhD and National Innovation System Research Incentive Program (INSINAS) for funding our research, as well as Tri Kurniawati, BSc for her assistance throughout the grant administration process.

Author information

Authors and Affiliations

  1. Department of Orthopaedics and Traumatology, Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

    Ismail Hadisoebroto Dilogo, Anissa Feby Canintika & Alberto Lastiko Hanitya

  2. Stem Cell Medical Technology Integrated Medical Service Unit, Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

    Ismail Hadisoebroto Dilogo, Jeanne Adiwinata Pawitan & Isabella Kurnia Liem

  3. Stem Cell and Tissue Engineering Research Center, IMERI, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

    Ismail Hadisoebroto Dilogo, Jeanne Adiwinata Pawitan & Isabella Kurnia Liem

  4. Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

    Jeanne Adiwinata Pawitan

  5. Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

    Isabella Kurnia Liem

  6. Department of Radiology, Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

    Jacub Pandelaki

Authors
  1. Ismail Hadisoebroto Dilogo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anissa Feby Canintika
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberto Lastiko Hanitya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeanne Adiwinata Pawitan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isabella Kurnia Liem
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jacub Pandelaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ismail Hadisoebroto Dilogo.

Ethics declarations

Conflict of interest

Ismail Hadisoebroto Dilogo, Anissa Feby Canintika, Alberto Lastiko Hanitya, Jeanne Adiwinata Pawitan, Isabella Kurnia Liem and Jacub Pandelaki declare that they have no conflict of interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dilogo, I.H., Canintika, A.F., Hanitya, A.L. et al. Umbilical cord-derived mesenchymal stem cells for treating osteoarthritis of the knee: a single-arm, open-label study. Eur J Orthop Surg Traumatol 30, 799–807 (2020). https://doi.org/10.1007/s00590-020-02630-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00590-020-02630-5

Keywords

Search

Navigation