Skip to main content
SpringerLink
Log in

Intra-articular injection of culture-expanded mesenchymal stem cells with or without addition of platelet-rich plasma is effective in decreasing pain and symptoms in knee osteoarthritis: a controlled, double-blind clinical trial

  • KNEE
  • Published:
Knee Surgery, Sports Traumatology, Arthroscopy Aims and scope

Abstract

Purpose

To compare the clinical and laboratory outcomes of intra-articular injections of culture-expanded bone-derived mesenchymal stem cells (MSCs) with or without platelet-rich plasma (PRP) to intra-articular corticosteroid injections for the treatment of knee osteoarthritis (OA).

Methods

Forty-seven patients with radiographic and symptomatic knee OA were randomized into three groups for intra-articular injections: autologous bone marrow-derived culture-expanded MSCs (n = 16); autologous bone marrow-derived culture-expanded MSCs + PRP (n = 14); and corticosteroid (n = 17). The outcomes were assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS) and range of motion (ROM) at baseline, 1, 2, 3, 6, 9 and 12 months and intra-articular cytokines analysis at baseline, 6 and 12 months postoperatively.

Results

The three groups showed significant improvement in most KOOS domains and global score at 1st month and all domains and global score at 12-month follow-up (p < 0.05). At the 1st month, only the MSCs group showed significant differences in KOOS symptoms domain (p = 0.003). The MSCs and MSCs + PRP groups showed the highest percentage of improvement in most KOOS domains and global score compared to the corticosteroid group. All three groups showed a significant reduction in intra-articular levels of human interleukin-10 cytokine, from baseline to 12 months (p < 0.05).

Conclusion

An intra-articular injection of bone marrow-derived culture-expanded MSCs with or without the addiction of PRP is effective in improving the function and decreasing symptoms caused by knee OA at 12-month follow-up.

Level of evidence

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.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Agung M, Ochi M, Yanada S, Adachi N, Izuta Y, Yamasaki T et al (2006) Mobilization of bone marrow-derived mesenchymal stem cells into the injured tissues after intraarticular injection and their contribution to tissue regeneration. Knee Surg Sports Traumatol Arthrosc 14:1307–1314

    Article  PubMed  Google Scholar 

  2. Amable PR, Carias RB, Teixeira MV, da Cruz Pacheco I, do Amaral RJ, Granjeiro JM et al (2013) Platelet-rich plasma preparation for regenerative medicine: optimization and quantification of cytokines and growth factors. Stem Cell Res Ther 4:67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Arroll B, Goodyear-Smith F (2004) Corticosteroid injections for osteoarthritis of the knee: meta-analysis. BMJ 328:869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Askari A, Naghizadeh MM, Homayounfar R, Shahi A, Afsarian MH, Paknahad A et al (2016) Increased serum levels of IL-17A and IL-23 are associated with decreased vitamin D3 and increased pain in osteoarthritis. PLoS One 11:e0164757

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Bastos R, Mathias M, Andrade R, Bastos R, Balduino A, Schott V et al (2018) Intra-articular injections of expanded mesenchymal stem cells with and without addition of platelet-rich plasma are safe and effective for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc 26:3342–3350

    Article  PubMed  Google Scholar 

  6. Bendinelli P, Matteucci E, Dogliotti G, Corsi MM, Banfi G, Maroni P et al (2010) Molecular basis of anti-inflammatory action of platelet-rich plasma on human chondrocytes: mechanisms of NF-kappaB inhibition via HGF. J Cell Physiol 225:757–766

    Article  CAS  PubMed  Google Scholar 

  7. Campbell KA, Saltzman BM, Mascarenhas R, Khair MM, Verma NN, Bach BR Jr et al (2015) Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? A systematic review of overlapping meta-analyses. Arthroscopy 31:2213–2221

    Article  PubMed  Google Scholar 

  8. Cole BJ, Karas V, Hussey K, Pilz K, Fortier LA (2017) Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med 45:339–346

    Article  PubMed  Google Scholar 

  9. Cordeiro-Spinetti E, de Mello W, Trindade LS, Taub DD, Taichman RS, Balduino A (2014) Human bone marrow mesenchymal progenitors: perspectives on an optimized in vitro manipulation. Front Cell Dev Biol 2:7

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dai WL, Zhou AG, Zhang H, Zhang J (2017) Efficacy of platelet-rich plasma in the treatment of knee osteoarthritis: a meta-analysis of randomized controlled trials. Arthroscopy 33:659–670.e651

    Article  PubMed  Google Scholar 

  11. Devji T, Guyatt GH, Lytvyn L, Brignardello-Petersen R, Foroutan F, Sadeghirad B et al (2017) Application of minimal important differences in degenerative knee disease outcomes: a systematic review and case study to inform BMJ rapid recommendations. BMJ Open 7:e015587

    Article  PubMed  PubMed Central  Google Scholar 

  12. Di Martino A, Di Matteo B, Papio T, Tentoni F, Selleri F, Cenacchi A et al (2019) Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med 47:347–354

    Article  PubMed  Google Scholar 

  13. Di Y, Han C, Zhao L, Ren Y (2018) Is local platelet-rich plasma injection clinically superior to hyaluronic acid for treatment of knee osteoarthritis? A systematic review of randomized controlled trials. Arthritis Res Ther 20:128

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Goncalves R, Cabri J, Pinheiro J, Ferreira P, Gil J (2010) Reliability, validity and responsiveness of the Portuguese version of the Knee Injury and Osteoarthritis Outcome Score-physical function short-form (KOOS-PS). Osteoarthr Cartil 18:372–376

    Article  CAS  Google Scholar 

  15. Ha C-W, Park Y-B, Kim SH, Lee H-J (2019) Intra-articular mesenchymal stem cells in osteoarthritis of the knee: a systematic review of clinical outcomes and evidence of cartilage repair. Arthroscopy 35:277–288.e272

    Article  PubMed  Google Scholar 

  16. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC et al (2005) Clarification of the nomenclature for MSC: the international society for cellular therapy position statement. Cytotherapy 7:393–395

    Article  CAS  PubMed  Google Scholar 

  17. Huang Y, Liu X, Xu X, Liu J (2019) Intra-articular injections of platelet-rich plasma, hyaluronic acid or corticosteroids for knee osteoarthritis: a prospective randomized controlled study. Orthopade 48:239–247

    Article  PubMed  Google Scholar 

  18. Hurley ET, Yasui Y, Gianakos AL, Seow D, Shimozono Y, Kerkhoffs G et al (2018) Limited evidence for adipose-derived stem cell therapy on the treatment of osteoarthritis. Knee Surg Sports Traumatol Arthrosc 26:3499–3507

    Article  PubMed  Google Scholar 

  19. Iannone F, De Bari C, Dell’Accio F, Covelli M, Cantatore FP, Patella V et al (2001) Interleukin-10 and interleukin-10 receptor in human osteoarthritic and healthy chondrocytes. Clin Exp Rheumatol 19:139–145

    CAS  PubMed  Google Scholar 

  20. Imamura M, Ezquerro F, Marcon Alfieri F, Vilas Boas L, Tozetto-Mendoza TR, Chen J et al (2015) Serum levels of proinflammatory cytokines in painful knee osteoarthritis and sensitization. Int J Inflamm 2015:329792–329792

    Article  CAS  Google Scholar 

  21. Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC et al (2014) Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells 32:1254–1266

    Article  CAS  PubMed  Google Scholar 

  22. Johnstone B, Hering TM, Caplan AI, Goldberg VM, Yoo JU (1998) In vitrochondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res 238:265–272

    Article  CAS  PubMed  Google Scholar 

  23. Joshi Jubert N, Rodriguez L, Reverte-Vinaixa MM, Navarro A (2017) Platelet-rich plasma injections for advanced knee osteoarthritis: a prospective, randomized, double-blinded clinical trial. Orthop J Sports Med 5:2325967116689386

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jüni P, Hari R, Rutjes AW, Fischer R, Silletta MG, Reichenbach S et al (2015) Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD005328.pub3

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H (2011) Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 7:33–42

    Article  CAS  PubMed  Google Scholar 

  26. Khatab S, van Buul GM, Kops N, Bastiaansen-Jenniskens YM, Bos PK, Verhaar JA et al (2018) Intra-articular injections of platelet-rich plasma releasate reduce pain and synovial inflammation in a mouse model of osteoarthritis. Am J Sports Med 46:977–986

    Article  PubMed  Google Scholar 

  27. Kim M, Rhee J-K, Choi H, Kwon A, Kim J, Lee GD et al (2017) Passage-dependent accumulation of somatic mutations in mesenchymal stromal cells during in vitro culture revealed by whole genome sequencing. Sci Rep 7:14508

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Kim YS, Koh YG (2018) Comparative matched-pair analysis of open-wedge high tibial osteotomy with versus without an injection of adipose-derived mesenchymal stem cells for varus knee osteoarthritis: clinical and second-look arthroscopic results. Am J Sports Med 46:2669–2677

    Article  PubMed  Google Scholar 

  29. Koh Y-G, Choi Y-J (2012) Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee 19:902–907

    Article  PubMed  Google Scholar 

  30. Koh Y-G, Kwon O-R, Kim Y-S, Choi Y-J (2014) Comparative outcomes of open-wedge high tibial osteotomy with platelet-rich plasma alone or in combination with mesenchymal stem cell treatment: a prospective study. Arthroscopy 30:1453–1460

    Article  PubMed  Google Scholar 

  31. Lamo-Espinosa JM, Mora G, Blanco JF, Granero-Moltó F, Nuñez-Córdoba JM, Sánchez-Echenique C et al (2016) Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med 14:246

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Laver L, Marom N, Dnyanesh L, Mei-Dan O, Espregueira-Mendes J, Gobbi A (2017) PRP for degenerative cartilage disease: a systematic review of clinical studies. Cartilage 8:341–364

    Article  CAS  PubMed  Google Scholar 

  33. Lin KY, Yang CC, Hsu CJ, Yeh ML, Renn JH (2019) Intra-articular injection of platelet-rich plasma is superior to hyaluronic acid or saline solution in the treatment of mild to moderate knee osteoarthritis: a randomized, double-blind, triple-parallel, placebo-controlled clinical trial. Arthroscopy 35:106–117

    Article  PubMed  Google Scholar 

  34. Liu Y, Peng H, Meng Z, Wei M (2015) Correlation of IL-17 level in synovia and severity of knee osteoarthritis. Med Sci Monit 21:1732–1736

    Article  PubMed  PubMed Central  Google Scholar 

  35. Martin CL, Browne JA (2018) Intra-articular corticosteroid injections for symptomatic knee osteoarthritis: what the orthopaedic provider needs to know. J Am Acad Orthop Surg. https://doi.org/10.5435/jaaos-d-18-00106

    Article  PubMed  Google Scholar 

  36. McIntyre JA, Jones IA, Han B, Vangsness CT (2018) Intra-articular mesenchymal stem cell therapy for the human joint: a systematic review. Am J Sports Med 46:3550–3563

    Article  PubMed  Google Scholar 

  37. Meheux CJ, McCulloch PC, Lintner DM, Varner KE, Harris JD (2016) Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: a systematic review. Arthroscopy 32:495–505

    Article  PubMed  Google Scholar 

  38. Ogura T, Ackermann J, Barbieri Mestriner A, Merkely G, Gomoll AH (2018) Minimal clinically important differences and substantial clinical benefit in patient-reported outcome measures after autologous chondrocyte implantation. Cartilage. https://doi.org/10.1177/19476035187998391947603518799839

    Article  PubMed  PubMed Central  Google Scholar 

  39. Pas HI, Winters M, Haisma HJ, Koenis MJJ, Tol JL, Moen MH (2017) Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br J Sports Med 51:1125–1133

    Article  PubMed  Google Scholar 

  40. Pers YM, Ruiz M, Noël D, Jorgensen C (2015) Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives. Osteoarthr Cartil 23:2027–2035

    Article  Google Scholar 

  41. Phinney DG, Pittenger MF (2017) Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells 35:851–858

    Article  CAS  PubMed  Google Scholar 

  42. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    Article  CAS  PubMed  Google Scholar 

  43. Robinson PG, Murray IR, West CC, Goudie EB, Yong LY, White TO et al (2018) Reporting of mesenchymal stem cell preparation protocols and composition: a systematic review of the clinical orthopaedic literature. Am J Sports Med 47:991–1000

    Article  PubMed  Google Scholar 

  44. van Buul GM, Koevoet WLM, Kops N, Bos PK, Verhaar JAN, Weinans H et al (2011) Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. Am J Sports Med 39:2362–2370

    Article  PubMed  Google Scholar 

  45. Wang Y, Zhang Z, Chi Y, Zhang Q, Xu F, Yang Z et al (2013) Long-term cultured mesenchymal stem cells frequently develop genomic mutations but do not undergo malignant transformation. Cell Death Dis 4:e950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang Z, Zheng C, Zhong Y, He J, Cao X, Xia H et al (2017) Interleukin-17 can induce osteoarthritis in rabbit knee joints similar to Hulth’s method. Biomed Res Int 2017:2091325

    PubMed  PubMed Central  Google Scholar 

  47. Wojdasiewicz P, Poniatowski LA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat Inflamm 2014:561459

    Article  CAS  Google Scholar 

  48. Wong KL, Lee KBL, Tai BC, Law P, Lee EH, Hui JHP (2013) Injectable cultured bone marrow–derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy 29:2020–2028

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to sincerely acknowledge ESHO Empresa de Serviços Hospitalares S.A and Keila Mara Cassiano.

Funding

The authors report no financial funding.

Author information

Authors and Affiliations

  1. Clínica do Dragão, Espregueira-Mendes Sports Centre - FIFA Medical Centre of Excellence, Porto, Portugal

    Ricardo Bastos, Renato Andrade & João Espregueira-Mendes

  2. Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil

    Ricardo Bastos, Marcelo Mathias & Vinicius Schott

  3. Dom Henrique Research Centre, Porto, Portugal

    Ricardo Bastos, Renato Andrade & João Espregueira-Mendes

  4. 3B’s Research Group–Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco, 4805-017, Guimarães, Portugal

    Ricardo Bastos, J. Miguel Oliveira & Rui L. Reis

  5. ICVS/3B’s–PT Government Associate Laboratory, Braga/Guimarães, Portugal

    Ricardo Bastos, J. Miguel Oliveira, Rui L. Reis & João Espregueira-Mendes

  6. Faculty of Sports, University of Porto, Porto, Portugal

    Renato Andrade

  7. Kearney Lab, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin 2, Ireland

    Ronaldo J. F. C. Amaral

  8. Tissue Engineering Research Group, Department of Anatomy, RCSI, Dublin 2, Ireland

    Ronaldo J. F. C. Amaral

  9. Centre for Research in Medical Devices (CURAM), National University of Ireland Galway, Galway, Ireland

    Ronaldo J. F. C. Amaral

  10. Excellion, Nireói, Rio de Janeiro, Brazil

    Alex Balduino

  11. Hospital Lusíadas, Porto, Portugal

    Raquel Bastos

  12. The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Avepark, Barco, 4805-017, Guimarães, Portugal

    J. Miguel Oliveira & Rui L. Reis

  13. Sports Medicine and Shoulder Surgery, Hospital for Special Surgery, New York, NY, USA

    Scott Rodeo

  14. Orthopaedics Department of Minho University, Braga, Portugal

    João Espregueira-Mendes

  15. The Biomechanics Group, Department of Mechanical Engineering, Imperial College London, London, England

    Ricardo Bastos

Authors
  1. Ricardo Bastos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcelo Mathias
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Renato Andrade
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ronaldo J. F. C. Amaral
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vinicius Schott
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alex Balduino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Raquel Bastos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Miguel Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rui L. Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Scott Rodeo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. João Espregueira-Mendes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RB, RB, MM, SR: conceptualized and designed the work; participated in the patient’s follow-up, acquisition, analysis, interpretation of data. RB, RA: drafted the work. VS, RFA, SR, JEM: revising it critically for important intellectual content; analyzed and interpreted the data. RFA, AB: biologists involved in platelet-rich plasma preparation protocol and procedures, and the culture-expanded MSCs procedures. RB: anesthesiologist physician involved in surgical procedures. RLR, JMO: senior biologists responsible for interpretation of the results and translation interpretation to clinical applications. All author approved the final version to be published.

Corresponding author

Correspondence to João Espregueira-Mendes.

Ethics declarations

Conflict of interest

No financial or non-financial competing interest exists for this manuscript. The manuscript was not influenced by personal or financial relationship with other people or organizations.

Ethical approval

Comissão Nacional de Ética em Pesquisa (Brazilian National Ethics in Research Committee)–CONEP, under number 14878813.4.0000.5533.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 19 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bastos, R., Mathias, M., Andrade, R. et al. Intra-articular injection of culture-expanded mesenchymal stem cells with or without addition of platelet-rich plasma is effective in decreasing pain and symptoms in knee osteoarthritis: a controlled, double-blind clinical trial. Knee Surg Sports Traumatol Arthrosc 28, 1989–1999 (2020). https://doi.org/10.1007/s00167-019-05732-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00167-019-05732-8

Keywords

Search

Navigation