Skip to main content

Advertisement

SpringerLink
Log in

Sicherheit des Einsatzes von Stammzellen zur Behandlung von Arthrose und Knorpeldefekten im Kniegelenk

Ein systematisches Review

Safety of stem cells for treatment of cartilage defects and osteoarthritis of the knee

A systematic review

  • Leitthema
  • Published:
Knie Journal Aims and scope

Zusammenfassung

Hintergrund

Mesenchymale Stammzellen (MSC) stellen eine attraktive Zellquelle für die potenzielle Heilung und Regeneration geschädigten Gewebes dar. Diese systematische Übersichtsarbeit wurde initiiert, um die Sicherheit und mögliche Komplikationen des therapeutischen Einsatzes von MSC zur Behandlung von Arthrose und Knorpeldefekten im Kniegelenk zu eruieren.

Methoden

Das Review basiert auf einer systematischen Literaturrecherche in MEDLINE. Alle Berichte über klinische Ergebnisse von Patienten mit Arthrose oder Knorpeldefekten des Knies, die einer Therapie mit expandierten oder nichtexpandierten Stammzellen unterzogen worden sind, wurden hinsichtlich der Sicherheit des Verfahrens analysiert.

Ergebnisse

Es konnten 89 Studien (2992 Patienten), die über die Sicherheit der Therapie mit MSC berichteten, identifiziert werden. Davon lieferten 43 Studien detaillierte Informationen über Komplikationen. 36 dieser 43 Studien (83,72 %) berichteten über mindestens je einen Fall von Gelenkschwellung, Gelenkerguss oder Schmerzen nach der Applikation. Der häufigste Grund für die Notwendigkeit einer erneuten Operation war die Arthrofibrose, über die in 6 Studien (229 Patienten) berichtet wurde, wobei sie bei 10 (4,37 %) Patienten auftrat. In allen Fällen trat die Arthrofibrose nach der Applikation der MSC über eine (Mini‑)Arthrotomie auf. Es wurden keine Berichte über eine Tumorentstehung im Bereich der Implantation/Injektion gefunden.

Schlussfolgerung

Der therapeutische Einsatz expandierter oder nichtexpandierter Stammzellen aus Knochenmark, Fett, Nabelschnur, Synovia oder Plazenta zur Behandlung degenerativer Knorpelerkrankungen des Kniegelenks ist sicher und nicht mit einem höheren Komplikationsrisiko verbunden als vergleichbare Therapien.

Abstract

Purpose

Mesenchymal stem cells (MSC) are an attractive cell source for potential healing and regeneration of damaged tissue. This systematic review was initiated to detect safety and potential complications of the therapeutic use of MSCs for the treatment of osteoarthritis and cartilage defects of the knee joint.

Methods

The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. All reports on clinical outcomes of patients with osteoarthritis or cartilage defects of the knee treated with expanded or non-expanded stem cells were analyzed for safety.

Results

A total of 89 studies (2992 patients) reporting on safety were identified, whereby 43 provided detailed information about complications. Of those 43 studies, 36 (83.72%) reported on at least one case each with joint swelling/effusion or post-injectional pain. The most common reason for the need of reintervention was arthrofibrosis reported in 6 studies (229 patients), which developed in 10 (4.37%) patients. In all cases the arthrofibrosis occurred after administration of MSC via (mini-)arthrotomy. No reports on tumor formation in the region of implantation/injection were found.

Conclusion

Therapeutic use of expanded or non-expanded stem cells from bone marrow, fat, umbilical cord, synovia or placenta for the treatment of degenerative cartilage diseases of the knee joint is safe and not associated with a higher risk of complications as comparable therapies.

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

Abb. 1

Literatur

  1. Afizah H, Hui JHP (2016) Mesenchymal stem cell therapy for osteoarthritis. J Clin Orthop Trauma 7:177–182. https://doi.org/10.1016/j.jcot.2016.06.006

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ajani UA, Ford ES, Mokdad AH (2004) Prevalence of high C‑reactive protein in persons with serum lipid concentrations within recommended values https://doi.org/10.1373/clinchem.2004.036004

    Book  Google Scholar 

  3. Akgun I, Unlu MC, Erdal OA et al (2015) Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Arch Orthop Trauma Surg 135:251–263. https://doi.org/10.1007/s00402-014-2136-z

    Article  PubMed  Google Scholar 

  4. Altman R, Hackel J, Niazi F et al (2018) Efficacy and safety of repeated courses of hyaluronic acid injections for knee osteoarthritis: A systematic review. Semin Arthritis Rheum 48:168–175. https://doi.org/10.1016/j.semarthrit.2018.01.009

    Article  CAS  PubMed  Google Scholar 

  5. Awad ME, Hussein KA, Helwa I et al (2019) Meta-analysis and evidence base for the efficacy of autologous bone marrow mesenchymal stem cells in knee cartilage repair: Methodological guidelines and quality assessment. Stem Cells Int 2019:3826054. https://doi.org/10.1155/2019/3826054

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bannuru RR, Osani M, Vaysbrot EE, McAlindon TE (2016) Comparative safety profile of hyaluronic acid products for knee osteoarthritis: a systematic review and network meta-analysis. Osteoarthr Cartil 24:2022–2041. https://doi.org/10.1016/j.joca .2016.07.010

    Article  CAS  Google Scholar 

  7. Bansal A, Lamplot JD, VandenBerg J, Brophy RH (2018) Meta-analysis of the risk of infections after anterior cruciate ligament reconstruction by graft type. Am J Sports Med 46:1500–1508. https://doi.org/10.1177/0363546517714450

    Article  PubMed  Google Scholar 

  8. Barkholt L, Flory E, Jekerle V et al (2013) Risk of tumorigenicity in mesenchymal stromal cell-based therapies—bridging scientific observations and regulatory viewpoints. Cytotherapy 15:753–759. https://doi.org/10.1016/J.JCYT.2013.03.005

    Article  PubMed  Google Scholar 

  9. Bellagamba BCB et al (2016) Human mesenchymal stem cells are resistant to cytotoxic and genotoxic effects of cisplatin in vitro. Genet Mol Biol 39:129–134. https://doi.org/10.1590/1678-4685-GMB-2015-0057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Caplan AI (2017) Mesenchymal stem cells: Time to change the name! Stem Cells Transl Med 6:1445–1451. https://doi.org/10.1002/sctm.17-0051

    Article  PubMed  PubMed Central  Google Scholar 

  11. Caplan AI, Correa D (2011) The MSC: An injury drugstore. Cell Stem Cell 9:11–15. https://doi.org/10.1016/j.stem.2011.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Direkze NC, Hodivala-Dilke K, Jeffery R et al (2004) Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 64:8492–8495. https://doi.org/10.1158/0008-5472.CAN-04-1708

    Article  CAS  PubMed  Google Scholar 

  13. 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  PubMed  Google Scholar 

  14. Ekhtiari S, Horner NS, de Sa D et al (2017) Arthrofibrosis after ACL reconstruction is best treated in a step-wise approach with early recognition and intervention: a systematic review. Knee Surg Sport Traumatol Arthrosc 25:3929–3937. https://doi.org/10.1007/s00167-017-4482-1

    Article  Google Scholar 

  15. Freitag J, Shah K, Wickham J et al (2017) The effect of autologous adipose derived mesenchymal stem cell therapy in the treatment of a large osteochondral defect of the knee following unsuccessful surgical intervention of osteochondritis dissecans—A case study. BMC Musculoskelet Disord 18:298. https://doi.org/10.1186/s12891-017-1658-2

    Article  PubMed  PubMed Central  Google Scholar 

  16. Garza JR, Campbell RE, Tjoumakaris FP et al (2020) Clinical efficacy of intra-articular mesenchymal stromal cells for the treatment of knee osteoarthritis: a double-blinded prospective randomized controlled clinical trial. Am J Sports Med 48:588–598. https://doi.org/10.1177/0363546519899923

    Article  PubMed  Google Scholar 

  17. Gobbi A, Whyte GP (2016) One-stage cartilage repair using a hyaluronic acid-based scaffold with activated bone marrow-derived mesenchymal stem cells compared with microfracture. Am J Sports Med 44:2846–2854. https://doi.org/10.1177/0363546516656179

    Article  PubMed  Google Scholar 

  18. Gobbi A, Chaurasia S, Karnatzikos G, Nakamura N (2015) Matrix-induced autologous chondrocyte implantation versus multipotent stem cells for the treatment of large patellofemoral chondral lesions: a Nonrandomized prospective trial. CARTILAGE 6:82–97. https://doi.org/10.1177/1947603514563597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gupta PK, Chullikana A, Rengasamy M et al (2016) Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): Preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther 18:1–18. https://doi.org/10.1186/s13075-016-1195-7

    Article  CAS  Google Scholar 

  20. Harris JD, Siston RA, Brophy RH et al (2011) Failures, re-operations, and complications after autologous chondrocyte implantation—a systematic review. Osteoarthr Cartil 19:779–791. https://doi.org/10.1016/j.joca .2011.02.010

    Article  CAS  Google Scholar 

  21. Hernigou P, Auregan JC, Dubory A et al (2018) Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee. Int Orthop 42:2563–2571. https://doi.org/10.1007/s00264-018-3916-9

    Article  PubMed  Google Scholar 

  22. Khalifeh Soltani S, Forogh B, Ahmadbeigi N et al (2019) Safety and efficacy of allogenic placental mesenchymal stem cells for treating knee osteoarthritis: a pilot study. Cytotherapy 21:54–63. https://doi.org/10.1016/j.jcyt.2018.11.003

    Article  PubMed  Google Scholar 

  23. Kovács B, Vajda E, Nagy EE (2019) Molecular sciences regulatory effects and interactions of the Wnt and OPG-Rankl-rank signaling at the Bone-cartilage interface in osteoarthritis. Int J Mol Sci. https://doi.org/10.3390/ijms20184653

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kuah D, Sivell S, Longworth T et al (2018) Safety, tolerability and efficacy of intra-articular Progenza in knee osteoarthritis: A randomized double-blind placebo-controlled single ascending dose study. J Transl Med 16:1–13. https://doi.org/10.1186/s12967-018-1420-z

    Article  CAS  Google Scholar 

  25. Lamo-Espinosa JM, Mora G, Blanco JF 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. https://doi.org/10.1186/s12967-016-0998-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu L, Dai C, Zhang Z et al (2019) Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: A prospective, randomized, double-blind, active-controlled, phase IIb clinical trial. Stem Cell Res Ther 10:1–10. https://doi.org/10.1186/s13287-019-1248-3

    Article  CAS  Google Scholar 

  27. Lu L, Dai C, Du H et al (2020) Intra-articular injections of allogeneic human adipose-derived mesenchymal progenitor cells in patients with symptomatic bilateral knee osteoarthritis: A phase i pilot study. Regen Med 15:1625–1636. https://doi.org/10.2217/rme-2019-0106

    Article  CAS  PubMed  Google Scholar 

  28. Martinčič D, Leban J, Filardo G et al (2021) Autologous chondrocytes versus filtered bone marrow mesenchymal stem/stromal cells for knee cartilage repair—a prospective study. Int Orthop 45:931–939. https://doi.org/10.1007/s00264-020-04727-2

    Article  PubMed  Google Scholar 

  29. 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. https://doi.org/10.1177/0363546517735844

    Article  PubMed  Google Scholar 

  30. Niemeyer P, Kornacker M, Mehlhorn A et al (2007) Comparison of immunological properties of bone marrow stromal cells and adipose tissue-derived stem cells before and after osteogenic differentiation in vitro. Tissue Eng. https://doi.org/10.1089/ten.2006.0114

    Article  PubMed  Google Scholar 

  31. Oldershaw RA (2012) Cell sources for the regeneration of articular cartilage: The past, the horizon and the future. Int J Exp Pathol 93:389–400. https://doi.org/10.1111/j.1365-2613.2012.00837.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pers Y‑M, Rackwitz L, Ferreira R et al (2016) Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med 5:847–856. https://doi.org/10.5966/sctm.2015-0245

    Article  PubMed  PubMed Central  Google Scholar 

  33. Pestka JM, Luu NH, Südkamp NP et al (2018) Revision surgery after cartilage repair: data from the German cartilage registry (Knorpelregister DGOU). Orthop J Sport Med 6:1–8. https://doi.org/10.1177/2325967117752623

    Article  Google Scholar 

  34. Ries C, Egea V, Karow M et al (2007) MMP‑2, MT1-MMP, and TIMP‑2 are essential for the invasive capacity of human mesenchymal stem cells: Differential regulation by inflammatory cytokines. Blood 109:4055–4063. https://doi.org/10.1182/blood-2006-10-051060

    Article  CAS  PubMed  Google Scholar 

  35. Roato I, Belisario DC, Compagno M et al (2019) Concentrated adipose tissue infusion for the treatment of knee osteoarthritis: clinical and histological observations. Int Orthop 43:15–23. https://doi.org/10.1007/s00264-018-4192-4

    Article  PubMed  Google Scholar 

  36. Røsland GV, Svendsen A, Torsvik A et al (2009) Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res 69:5331–5339. https://doi.org/10.1158/0008-5472.CAN-08-4630

    Article  CAS  PubMed  Google Scholar 

  37. Ryu DJ, Jeon YS, Park JS et al (2020) Comparison of bone marrow aspirate concentrate and allogenic human umbilical cord blood derived mesenchymal stem cell implantation on chondral defect of knee: assessment of clinical and magnetic resonance imaging outcomes at 2‑year follow-up. Cell Transplant 29:963689720943581. https://doi.org/10.1177/0963689720943581

    Article  PubMed  Google Scholar 

  38. Saeedi P, Halabian R, Imani Fooladi AA (2019) A revealing review of mesenchymal stem cells therapy, clinical perspectives and modification strategies. Stem Cell Investig 6:34–34. https://doi.org/10.21037/sci.2019.08.11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sekiya I, Muneta T, Horie M, Koga H (2015) Arthroscopic transplantation of synovial stem cells improves clinical outcomes in knees with cartilage defects. Clin Orthop Relat Res 473:2316–2326. https://doi.org/10.1007/s11999-015-4324-8

    Article  PubMed  PubMed Central  Google Scholar 

  40. Suzuki K, Sun R, Origuchi M et al (2011) Mesenchymal stromal cells promote tumor growth through the enhancement of neovascularization. Mol Med 17:579–587. https://doi.org/10.2119/MOLMED.2010.00157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tan SHS, Kwan YT, Neo WJ et al (2021) Intra-articular injections of mesenchymal stem cells without adjuvant therapies for knee osteoarthritis: a systematic review and meta-analysis. Am J Sports Med. https://doi.org/10.1177/0363546520981704

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tibbo ME, Limberg AK, Salib CG et al (2019) Acquired idiopathic stiffness after total knee arthroplasty: a systematic review and meta-analysis. J Bone Joint Surg Am 101:1320–1330. https://doi.org/10.2106/JBJS.18.01217

    Article  PubMed  Google Scholar 

  43. Tolar J, Nauta AJ, Osborn MJ et al (2007) Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 25:371–379. https://doi.org/10.1634/STEMCELLS.2005-0620

    Article  CAS  PubMed  Google Scholar 

  44. Veber M, Vogler J, Knežević M et al (2020) Combination of filtered bone marrow aspirate and biomimetic scaffold for the treatment of knee osteochondral lesions: cellular and early clinical results of a single centre case series. Tissue Eng Regen Med 17:375–386. https://doi.org/10.1007/s13770-020-00253-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 99:1681–1690. https://doi.org/10.1097/TP.0000000000000678

    Article  CAS  PubMed  Google Scholar 

  46. Wannemuehler TJ, Manukyan MC, Brewster BD et al (2012) Advances in mesenchymal stem cell research in sepsis. J Surg Res 173:113–126. https://doi.org/10.1016/J.JSS.2011.09.053

    Article  PubMed  Google Scholar 

  47. de Windt TS, Vonk LA, Slaper-Cortenbach ICM et al (2017) Allogeneic MSCs and recycled autologous chondrons mixed in a one-stage cartilage cell transplantion: a first-in-man trial in 35 patients. Stem Cells 35:1984–1993. https://doi.org/10.1002/stem.2657

    Article  CAS  PubMed  Google Scholar 

  48. Wylie JD, Hartley MK, Kapron AL et al (2016) Failures and reoperations after matrix-assisted cartilage repair of the knee: a systematic. Arthroscopy 32:386–392. https://doi.org/10.1016/j.arthro.2015.07.025

    Article  PubMed  Google Scholar 

  49. Yang HY, Song EK, Kang SJ et al (2021) Allogenic umbilical cord blood-derived mesenchymal stromal cell implantation was superior to bone marrow aspirate concentrate augmentation for cartilage regeneration despite similar clinical outcomes. Knee Surg Sport Traumatol Arthrosc. https://doi.org/10.1007/s00167-021-06450-w

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. OCM | Orthopädische Chirurgie München, Steinerstr. 6, 81369, München, Deutschland

    Svea Faber & Philipp Niemeyer

  2. Universitätsklinikum Regensburg, Regensburg, Deutschland

    Peter Angele

  3. Sporthopaedicum, Regensburg, Deutschland

    Peter Angele & Johannes Zellner

  4. Klinik für Unfall‑, Hand- und Wiederherstellungschirurgie, Universitätsklinikum Münster, Münster, Deutschland

    Felix Dyrna

  5. Kantonsspital Baselland, Bruderholz, Schweiz

    Michael T. Hirschmann

  6. Zentrum für Regenerative Medizin, Universität für Weiterbildung Krems, Krems, Österreich

    Stefan Nehrer

  7. Crossklinik, Basel, Schweiz

    Amir Steinitz

  8. Praxis Cartilage Care, Bern, Schweiz

    Bernhard Waibl

  9. Klinik für Orthopädie und Unfallchirurgie, Universitätsklinikum Freiburg, Freiburg, Deutschland

    Philipp Niemeyer

Authors
  1. Svea Faber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Angele
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Felix Dyrna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael T. Hirschmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stefan Nehrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amir Steinitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernhard Waibl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Johannes Zellner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Philipp Niemeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Svea Faber.

Ethics declarations

Interessenkonflikt

S. Faber, P. Angele, F. Dyrna, M.T. Hirschmann, S. Nehrer, A. Steinitz, B. Waibl, J. Zellner und P. Niemeyer geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Redaktion

Philipp Niemeyer, München

figure qr

Zusatzmaterial online – bitte QR-Code scannen

Supplementary Information

Tab. 1 Studien, in denen ausführlich über Nebenwirkungen/Komplikationen berichtet wurde

43205_2023_232_MOESM2_ESM.pdf

Tab. 2 Studien, die entweder über keine Komplikationen/AEs, keine auf der Injektionsseite oder keine schwerwiegenden Komplikationen berichten, ohne auf die nicht schwerwiegenden AEs einzugehen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Faber, S., Angele, P., Dyrna, F. et al. Sicherheit des Einsatzes von Stammzellen zur Behandlung von Arthrose und Knorpeldefekten im Kniegelenk. Knie J. 5, 164–170 (2023). https://doi.org/10.1007/s43205-023-00232-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43205-023-00232-9

Schlüsselwörter

Keywords

Search

Navigation