Skip to main content
SpringerLink
Log in

Ethical and Practical Considerations for Integrating Cellular (“Stem Cell”) Therapy into Clinical Practice

  • Stem Cells in Orthopaedic Surgery (J Dragoo and KJ Jones, Section Editors)
  • Published:
Current Reviews in Musculoskeletal Medicine Aims and scope Submit manuscript

Abstract

Purpose of Review

Cellular therapies, also known as “stem cell” interventions (SCI), have undergone a rapid popularization in the USA and worldwide. The current review aimed at outlining (1) the ethical challenges facing the implementation of SCI; (2) the applicability of the currently available SCI; and (3) recommendations to achieve ethical, well-regulated incorporation of SCI in the clinical setting.

Recent Findings

Concerns regarding the inadequate characterization, poor adverse effects disclosure, and unorthodox, often inappropriate, market practices have engendered a genuine concern regarding the SCI compliance with ethical standards. Six instances of litigation on the basis of misrepresentation or inappropriate informed consent were recorded between 2012 and 2018. Such concerns have been furthered by the loopholes in the regulatory aspect governing the use of SCI coupled with the unclear literature-reported efficacy and diverse spectrum of profess indications. Similarly, the application of SCI in the clinical field is yet to prove its value. The uncertain efficacy, coupled with obscure true-costs of utilization, impedes a value-based assessment.

Summary

A multidisciplinary approach involving legislative and medical professional societies should continue to advance regulations that govern SCI. A well-regulated system that allows for the ethical integration of SCI with appositely evidenced-based described benefits and risks should be sought.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bauer TW. Stem cell therapy for knee pain—what exactly are we injecting, and why? J Bone Jt Surg. 2016;98(18):1509–10. https://doi.org/10.2106/JBJS.16.00872.

    Article  Google Scholar 

  2. Piuzzi NS, Ng M, Chughtai M, Khlopas A, Ng K, Mont M, et al. The stem-cell market for the treatment of knee osteoarthritis: a patient perspective. J Knee Surg. 2018;31(6):551–6. https://doi.org/10.1055/s-0037-1604443.

    Article  PubMed  Google Scholar 

  3. • Ng M, Song S, Piuzzi NS, et al. Stem cell industry update: 2012 to 2016 reveals accelerated investment, but market capitalization and earnings lag. Cytotherapy. 2017;19(10):1131–9. https://doi.org/10.1016/j.jcyt.2017.07.006Outlines the rising trends within the stem cell market.

  4. Nho SJ, Kymes SM, Callaghan JJ, Felson DT. The burden of hip osteoarthritis in the United States: epidemiologic and economic considerations. J Am Acad Orthop Surg. 2013;21(suppl):S1–6. https://doi.org/10.5435/JAAOS-21-07-S1.

    Article  PubMed  Google Scholar 

  5. Bitton R. The economic burden of osteoarthritis. Am J Manag Care. 2009;15(8 Suppl):S230–5.

    PubMed  Google Scholar 

  6. Maumus M, Guérit D, Toupet K, Jorgensen C, Noël D. Mesenchymal stem cell-based therapies in regenerative medicine: applications in rheumatology. Stem Cell Res Ther. 2011;2(2):1–6. https://doi.org/10.1186/scrt55.

    Article  Google Scholar 

  7. Syed BA, Evans JB. Stem cell therapy market. Nat Rev Drug Discov. 2013;12(3):185–6. https://doi.org/10.1038/nrd3953.

    Article  CAS  PubMed  Google Scholar 

  8. • Ng MK, Mont MA, Piuzzi NS. Analysis of readability, quality, and content of online information available for “stem cell” injections for knee osteoarthritis. J Arthroplasty. 2020;35(3):647–651.e2. https://doi.org/10.1016/j.arth.2019.10.013Highlights the poor characterization of the marketed stem cell interventions on digital platforms.

    Article  PubMed  Google Scholar 

  9. Pas HI, Winters M, Haisma HJ, Koenis MJ, Tol JL, Moen MH. Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br J Sports Med. 2017;51(15):1125–33. https://doi.org/10.1136/bjsports-2016-096793.

    Article  PubMed  Google Scholar 

  10. Jevotovsky DS, Alfonso AR, Einhorn TA, Chiu ES. Osteoarthritis and stem cell therapy in humans: a systematic review. Osteoarthr Cartil. 2018;26(6):711–29. https://doi.org/10.1016/j.joca.2018.02.906.

    Article  CAS  PubMed  Google Scholar 

  11. Papakostidis C, Tosounidis TH, Jones E, Giannoudis PV. The role of “cell therapy” in osteonecrosis of the femoral head. Acta Orthop. 2016;87(1):72–8. https://doi.org/10.3109/17453674.2015.1077418.

    Article  PubMed  Google Scholar 

  12. Chahla J, Piuzzi NS, Mitchell JJ, Dean CS, Pascual-Garrido C, LaPrade RF, et al. Intra-articular cellular therapy for osteoarthritis and focal cartilage defects of the knee: a systematic review of the literature and study quality analysis. J Bone Jt Surg - Am. 2016;98(18):1511–21. https://doi.org/10.2106/JBJS.15.01495.

    Article  Google Scholar 

  13. Murray IR, Chahla J, Frank RM, Piuzzi NS, Mandelbaum BR, Dragoo JL, et al. Rogue stem cell clinics. Bone Joint J. 2020;102-B(2):148–54. https://doi.org/10.1302/0301-620X.102B2.BJJ-2019-1104.R1.

    Article  PubMed  PubMed Central  Google Scholar 

  14. •• Piuzzi NS, Dominici M, Long M, et al. Proceedings of the signature series symposium “cellular therapies for orthopaedics and musculoskeletal disease proven and unproven therapies-promise, facts and fantasy,” international society for cellular therapies, montreal, canada, may 2, 2018. Cytotherapy. 2018;20(11):1381–400. https://doi.org/10.1016/j.jcyt.2018.09.001Provides guidelines and recommendations that aid in the identification of proven vs. unproven stem cell therapies.

    Article  PubMed  Google Scholar 

  15. •• Chu CR, Rodeo S, Bhutani N, et al. Optimizing clinical use of biologics in orthopaedic surgery: consensus recommendations from the 2018 AAOS/NIH U-13 conference. J Am Acad Orthop Surg. 2019;27(2):e50–63. https://doi.org/10.5435/JAAOS-D-18-00305Provides guidelines elucidating the proper use designation of stem cell therapies in orthopaedics.

    Article  PubMed  Google Scholar 

  16. Ellison B. Stem cell research and social justice : aligning scientific progress with social need. Curr Stem Cell Reports. 2016;2:328–35. https://doi.org/10.1007/s40778-016-0063-3.

    Article  Google Scholar 

  17. Nherera LM, Trueman P, Horner A, Johnstone AJ, Watson TJ, Fatoye FA. Comparing the costs and outcomes of an integrated twin compression screw (ITCS) nail with standard of care using a single lag screw or a single helical blade cephalomedullary nail in patients with intertrochanteric hip fractures. J Orthop Surg Res. 2018;13(1):1–8. https://doi.org/10.1186/s13018-018-0923-x.

    Article  Google Scholar 

  18. •• Murray IR, Chahla J, Frank RM, Piuzzi NS, Mandelbaum BR, Dragoo JL. Rogue stem cell clinics. Bone Joint J. 2020;102-B(2):148–54. https://doi.org/10.1302/0301-620X.102B2.BJJ-2019-1104.R1Outlines the magnitude of the direct-to-consumer marketing practices and provides recommendations for sufficient regulation.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Frow EK, Brafman DA, Muldoon A, Krum L, Williams P, Becker B, et al. Characterizing direct-to-consumer stem cell businesses in the Southwest United States. Stem Cell Reports. 2019;13(2):247–53. https://doi.org/10.1016/j.stemcr.2019.07.001.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Piuzzi NS, Chahla J, Jiandong H, Chughtai M, LaPrade RF, Mont MA, et al. Analysis of cell therapies used in clinical trials for the treatment of osteonecrosis of the femoral head: a systematic review of the literature. J Arthroplast. 2017;32(8):2612–8. https://doi.org/10.1016/j.arth.2017.02.075.

    Article  Google Scholar 

  21. Marcucio RS, Nauth A, Giannoudis PV, Bahney C, Piuzzi NS, Muschler G, et al. Stem cell therapies in orthopaedic trauma. J Orthop Trauma. 2015;29(Suppl 12):S24–7. https://doi.org/10.1097/BOT.0000000000000459.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Vakharia RM, Roche MW, Alcerro JC, Lavernia CJ. The current status of cell- based therapies for primary knee osteoarthritis. Orthop Clin NA. 2019;50(4):415–23. https://doi.org/10.1016/j.ocl.2019.06.001.

    Article  Google Scholar 

  23. Shakouri-Motlagh A, Khanabdali R, Heath DE, Kalionis B. The application of decellularized human term fetal membranes in tissue engineering and regenerative medicine (TERM). Placenta. 2017;59:124–30. https://doi.org/10.1016/j.placenta.2017.07.002.

    Article  CAS  PubMed  Google Scholar 

  24. Pogozhykh O, Prokopyuk V, Figueiredo C, Pogozhykh D. Review article placenta and placental derivatives in regenerative therapies : experimental studies. Hist Prospects. 2018;2018.

  25. Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014;32(5):1254–66. https://doi.org/10.1002/stem.1634.

    Article  CAS  PubMed  Google Scholar 

  26. Wyles CC, Houdek MT, Behfar A, Sierra RJ. Mesenchymal stem cell therapy for osteoarthritis: current perspectives. Stem Cells Cloning Adv Appl. 2015;8:117–24. https://doi.org/10.2147/SCCAA.S68073.

    Article  Google Scholar 

  27. Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. 2012;19(6):902–7. https://doi.org/10.1016/j.knee.2012.04.001.

    Article  PubMed  Google Scholar 

  28. Lamo-Espinosa JM, Mora G, Blanco JF, Granero-Moltó F, Nuñez-Córdoba JM, Sánchez-Echenique C, et al. 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. 2016;14(1):1–9. https://doi.org/10.1186/s12967-016-0998-2.

    Article  CAS  Google Scholar 

  29. Hurley ET, Yasui Y, Gianakos AL, Seow D, Shimozono Y, Kerkhoffs GMMJ, et al. Limited evidence for adipose-derived stem cell therapy on the treatment of osteoarthritis. Knee Surgery, Sport Traumatol Arthrosc. 2018;26(11):3499–507. https://doi.org/10.1007/s00167-018-4955-x.

    Article  Google Scholar 

  30. Peeters CMM, Leijs MJC, Reijman M, van Osch GJVM, Bos PK. Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review. Osteoarthr Cartil. 2013;21(10):1465–73. https://doi.org/10.1016/j.joca.2013.06.025.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008;67(12):1716–23. https://doi.org/10.1136/ard.2008.092015.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang W. The powerful placebo effect in osteoarthritis. Clin Exp Rheumatol. 2019;37(5):118–23.

    PubMed  Google Scholar 

  33. Bauer G, Elsallab M, Abou-El-Enein M. Concise review: a comprehensive analysis of reported adverse events in patients receiving unproven stem cell-based interventions. Stem Cells Transl Med. 2018;7(9):676–85. https://doi.org/10.1002/sctm.17-0282.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Turner L. The US Direct-to-consumer marketplace for autologous stem cell interventions. Perspect Biol Med. 2018;61(1):7–24. https://doi.org/10.1353/pbm.2018.0024.

    Article  PubMed  Google Scholar 

  35. Knoepfler PS. The stem cell hard sell: report from a clinic’s patient recruitment seminar. Stem Cells Transl Med. 2017;6(1):14–6. https://doi.org/10.5966/sctm.2016-0208.

    Article  PubMed  Google Scholar 

  36. Caulfield T, Sipp D, Murry CE, Daley GQ, Kimmelman J, SCIENTIFIC COMMUNITY. Confronting stem cell hype. Science. 2016;352(6287):776–7. https://doi.org/10.1126/science.aaf4620.

    Article  CAS  PubMed  Google Scholar 

  37. Im G-I. Clinical use of stem cells in orthopaedics. Eur Cell Mater. 2017;33:183–96. https://doi.org/10.22203/eCM.v033a14.

    Article  PubMed  Google Scholar 

  38. Palsis JA, Brehmer TS, Pellegrini VD, Drew JM, Sachs BL. The cost of joint replacement: comparing two approaches to evaluating costs of total hip and knee arthroplasty. J Bone Joint Surg Am. 2018;100(4):326–33. https://doi.org/10.2106/JBJS.17.00161.

    Article  PubMed  Google Scholar 

  39. Piuzzi NS, Mantripragada VP, Sumski A, Selvam S, Boehm C, Muschler GF. Bone marrow-derived cellular therapies in orthopaedics: part I: recommendations for bone marrow aspiration technique and safety. JBJS Rev. 2018;6(11):e4. https://doi.org/10.2106/JBJS.RVW.18.00007.

    Article  PubMed  Google Scholar 

  40. Horner C, Tenenbaum E, Sipp D, Master Z. Can civil lawsuits stem the tide of direct-to-consumer marketing of unproven stem cell interventions. NPJ Regen Med. 2018;3(1):1–4. https://doi.org/10.1038/s41536-018-0043-6.

    Article  Google Scholar 

  41. Turner L. Direct-to-consumer marketing of stem cell interventions by Canadian businesses. Regen Med. 2018;13(6):643–58. https://doi.org/10.2217/rme-2018-0033.

    Article  CAS  PubMed  Google Scholar 

  42. Jones IA, Togashi R, Wilson ML, Heckmann N, Vangsness CT. Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol. 2019;15(2):77–90. https://doi.org/10.1038/s41584-018-0123-4.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Sipp D. The malignant niche: safe spaces for toxic stem cell marketing. NPJ Regen Med. 2017;2(1). https://doi.org/10.1038/s41536-017-0036-x.

  44. Browne JA, Nho SJ, Goodman SB, Della Valle CJ. American association of hip and knee surgeons, hip society, and knee society position statement on biologics for advanced hip and knee arthritis. J Arthroplast. 2019;34(6):1051–2. https://doi.org/10.1016/j.arth.2019.03.068.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, OH, USA

    Nicolas S. Piuzzi & Ahmed Emara

  2. Department of Orthopaedic Surgery, Division of Sports Medicine, Rush University Medical Center, Chicago, IL, USA

    Jorge Chahla

  3. Department of Orthopaedic Surgery, Cedars Sinai Kerlan Jobe Institute, Santa Monica, CA, USA

    Bert R. Mandelbaum

Authors
  1. Nicolas S. Piuzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmed Emara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jorge Chahla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bert R. Mandelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicolas S. Piuzzi.

Ethics declarations

Institutional Review Board approval was not required for the current study.

Conflict of Interest

Nicolas S. Piuzzi has the following declarations: ISCT: board or committee member; Journal of Hip Surgery: editorial or governing board; Journal of Knee Surgery: editorial or governing board; Orthopaedic Research Society: board or committee member; RegenLab: research support; Zimmer: research support. Ahmed K. Emara has no conflict of interest. Jorge Chahla has the following declarations: Arthrex, Inc.: unpaid consultant; CONMED Linvatec: unpaid consultant; Smith & Nephew: unpaid consultant. Bert R. Mandelbaum has the following declarations: AJSM, cartilage: editorial or governing board; Arthrex, Inc.: IP royalties; paid consultant; Chairman CONCACAF Medical Committee: board or committee member; DePuy, A Johnson & Johnson Company: paid consultant; Exactech, Inc.: PAID consultant; Kerlan Jobe Institute: board or committee member.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

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

This article is part of the Topical Collection on Stem Cells in Orthopaedic Surgery

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Piuzzi, N.S., Emara, A., Chahla, J. et al. Ethical and Practical Considerations for Integrating Cellular (“Stem Cell”) Therapy into Clinical Practice. Curr Rev Musculoskelet Med 13, 525–529 (2020). https://doi.org/10.1007/s12178-020-09647-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12178-020-09647-7

Keywords

Search

Navigation