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Safety and efficacy of matrix-associated autologous chondrocyte implantation with spheroid technology is independent of spheroid dose after 4 years

  • Philipp NiemeyerEmail author
  • Volker Laute
  • Wolfgang Zinser
  • Thilo John
  • Christoph Becher
  • Peter Diehl
  • Thomas Kolombe
  • Jakob Fay
  • Rainer Siebold
  • Stefan Fickert
KNEE
  • 42 Downloads

Abstract

Purpose

The aim of this study was to investigate the effect of product dose in autologous chondrocyte implantation (ACI) for the treatment of full-thickness cartilage defects of the knee and to assess its influence on clinical and morphological mid-term outcome.

Methods

Seventy-five patients were included in this single-blind, randomised, prospective, controlled clinical trial. Patients were assigned randomly to three different dose groups [low (3–7 spheroids/cm2), medium (10–30 spheroids/cm2), or high (40–70 spheroids/cm2)] and assessed using standardised clinical and morphological scoring systems (KOOS, IKDC, MOCART) for 4 years following the intervention.

Results

The analysis population comprised 75 patients (22 women, 53 men) aged 34 ± 9 years. Defect sizes ranged from 2 to 10 cm2 following intraoperative debridement. The assessment of the primary variable ‘overall KOOS’ showed a statistically significant improvement, compared with baseline, for each dose group, i.e., at baseline the mean ‘overall KOOS’ scores were 60.4 ± 13.6, 59.6 ± 15.4, and 51.1 ± 15.4 for the low-, medium-, and high-dose groups, respectively, and 57.0 ± 15.2 for ‘all patients’. After 48 months those values improved to 80.0 ± 14.7, 84.0 ± 14.9, and 66.9 ± 21.5 in the respective dose groups and 77.1 ± 18.6 for ‘all patients’. Pairwise comparisons of these dose groups did not reveal any statistically significant differences. Likewise, assessment of the subjective IKDC score revealed no statistically significant differences between the three dose groups up to the 48-month visit. However, between 12 and 48 months there was a low, but steady, improvement in the low-dose group and a substantial amelioration in the medium-dose group. The mean MOCART total scores 3 months after treatment were 59.8 ± 10.9, 64.5 ± 10.3, and 64.7 ± 9.4 for the low-, medium-, and high-dose groups, and 62.9 ± 10.3 for ‘all patients’; 48 months after treatment these were 73.9 ± 13.1, 78.0 ± 12.4, and 74.3 ± 14.0 for the respective dose groups and 75.5 ± 13.1 for ‘all patients’.

Conclusions

Results of this study confirm the efficacy and safety of the applied “advanced therapy medicinal product”; no dose dependence was found either for the incidence or for the severity of any adverse reactions. All doses applied in the present study led to significant clinical improvement over time and can therefore be regarded as effective doses. The influence of product doses in the range investigated seems to be low and can be neglected. Thus, the authorised dose range of 10–70 spheroids/cm2 confirmed by this clinical trial offers a broad therapeutic window for the surgeon applying the product, thereby reducing the risk of over- or underdosing.

Level of evidence

I.

Keywords

Autologous chondrocyte implantation Cartilage lesion Knee surgery Patella Randomised clinical trial 

Notes

Funding

The present study was funded by the company CO.DON AG, Teltow, Germany.

Compliance with ethical standards

Conflict of interest

The present study has been financed by the company Co.don (Teltow, Germany) has been part of the approval process for european market authorization by the European Medicinal Agency (EMA). All authors received grants for limited educational purposes and financial support for conducting the present study.

Ethical approval

All procedures performed in this studies were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. Ethical approval for this study was obtained from Heidelberg University (2009-016466-82).

References

  1. 1.
    Ahlback S, Bauer GC, Bohne WH (1968) Spontaneous osteonecrosis of the knee. Arthritis Rheum 11:705–733PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Anderer U, Libera J (2002) In vitro engineering of human autogenous cartilage. J Bone Miner Res 17:1420–1429PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Basad E, Ishaque B, Bachmann G, Sturz H, Steinmeyer J (2010) Matrix-induced autologous chondrocyte implantation versus microfracture in the treatment of cartilage defects of the knee: a 2-year randomised study. Knee Surg Sports Traumatol Arthrosc 18:519–527PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Becher C, Laute V, Fickert S, Zinser W, Niemeyer P, John T et al (2017) Safety of three different product doses in autologous chondrocyte implantation: results of a prospective, randomised, controlled trial. J Orthop Surg Res 12:71PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Bekkers JE, de Windt TS, Raijmakers NJ, Dhert WJ, Saris DB (2009) Validation of the Knee Injury and Osteoarthritis Outcome Score (KOOS) for the treatment of focal cartilage lesions. Osteoarthritis Cartilage 17:1434–1439PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L (1994) Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889–895PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Brittberg M, Recker D, Ilgenfritz J, Saris DBF, Group SES (2018) Matrix-applied characterized autologous cultured chondrocytes versus microfracture: five-year follow-up of a prospective randomized trial. Am J Sports Med 46:1343–1351CrossRefGoogle Scholar
  8. 8.
    Collins NJ, Misra D, Felson DT, Crossley KM, Roos EM (2011) Measures of knee function: International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, Knee Injury and Osteoarthritis Outcome Score (KOOS), Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS), Knee Outcome Survey Activities of Daily Living Scale (KOS-ADL), Lysholm Knee Scoring Scale, Oxford Knee Score (OKS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Activity Rating Scale (ARS), and Tegner Activity Score (TAS). Arthritis Care Res (Hoboken) 63(Suppl 11):S208–228CrossRefGoogle Scholar
  9. 9.
    Crawford DC, DeBerardino TM, Williams RJ 3rd (2012) NeoCart, an autologous cartilage tissue implant, compared with microfracture for treatment of distal femoral cartilage lesions: an FDA phase-II prospective, randomized clinical trial after two years. J Bone Jt Surg Am 94:979–989CrossRefGoogle Scholar
  10. 10.
    Demange MK, Minas T, von Keudell A, Sodha S, Bryant T, Gomoll AH (2017) Intralesional osteophyte regrowth following autologous chondrocyte implantation after previous treatment with marrow stimulation technique. Cartilage 8:131–138PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    DiBartola AC, Everhart JS, Magnussen RA, Carey JL, Brophy RH, Schmitt LC et al (2016) Correlation between histological outcome and surgical cartilage repair technique in the knee: a meta-analysis. Knee 23:344–349PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Dwivedi G, Chevrier A, Alameh MG, Hoemann CD, Buschmann MD (2018) Quality of cartilage repair from marrow stimulation correlates with cell number, clonogenic, chondrogenic, and matrix production potential of underlying bone marrow stromal cells in a rabbit model. Cartilage. https://doi.org/10.1177/1947603518812555
  13. 13.
    Ebert JR, Fallon M, Zheng MH, Wood DJ, Ackland TR (2012) A randomized trial comparing accelerated and traditional approaches to postoperative weightbearing rehabilitation after matrix-induced autologous chondrocyte implantation: findings at 5 years. Am J Sports Med 40:1527–1537PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Engelhart L, Nelson L, Lewis S, Mordin M, Demuro-Mercon C, Uddin S et al (2012) Validation of the Knee Injury and Osteoarthritis Outcome Score subscales for patients with articular cartilage lesions of the knee. Am J Sports Med 40:2264–2272PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Filardo G, Kon E, Andriolo L, Di Martino A, Zaffagnini S, Marcacci M (2014) Treatment of "patellofemoral" cartilage lesions with matrix-assisted autologous chondrocyte transplantation: a comparison of patellar and trochlear lesions. Am J Sports Med 42:626–634PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Filardo G, Kon E, Andriolo L, Di Matteo B, Balboni F, Marcacci M (2014) Clinical profiling in cartilage regeneration: prognostic factors for midterm results of matrix-assisted autologous chondrocyte transplantation. Am J Sports Med 42:898–905PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Foldager CB, Gomoll AH, Lind M, Spector M (2012) Cell seeding densities in autologous chondrocyte implantation techniques for cartilage repair. Cartilage 3:108–117PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Guillen-Garcia P, Rodriguez-Inigo E, Guillen-Vicente I, Caballero-Santos R, Guillen-Vicente M, Abelow S et al (2014) Increasing the dose of autologous chondrocytes improves articular cartilage repair: histological and molecular study in the sheep animal model. Cartilage 5:114–122PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Hamlett A, Ting N, Hanumara RC, Finman JS (2002) Dose spacing in early dose response clinical trial designs. Drug Inf J 36:855–864CrossRefGoogle Scholar
  20. 20.
    Harris JD, Siston RA, Brophy RH, Lattermann C, Carey JL, Flanigan DC (2011) Failures, re-operations, and complications after autologous chondrocyte implantation—a systematic review. Osteoarthritis Cartilage 19:779–791PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Henderson I, Tuy B, Oakes B (2004) Reoperation after autologous chondrocyte implantation. Indications and findings. J Bone Jt Surg Br 86:205–211CrossRefGoogle Scholar
  22. 22.
    Knutsen G, Drogset JO, Engebretsen L, Grontvedt T, Isaksen V, Ludvigsen TC et al (2007) A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Jt Surg Am 89:2105–2112CrossRefGoogle Scholar
  23. 23.
    Kon E, Filardo G, Berruto M, Benazzo F, Zanon G, Della Villa S et al (2011) Articular cartilage treatment in high-level male soccer players: a prospective comparative study of arthroscopic second-generation autologous chondrocyte implantation versus microfracture. Am J Sports Med 39:2549–2557PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Kreuz PC, Kalkreuth RH, Niemeyer P, Uhl M, Erggelet C (2019) Long-term clinical and MRI results of matrix-assisted autologous chondrocyte implantation for articular cartilage defects of the knee. Cartilage 10:305–313PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Li YY, Cheng HW, Cheung KM, Chan D, Chan BP (2014) Mesenchymal stem cell-collagen microspheres for articular cartilage repair: cell density and differentiation status. Acta Biomater 10:1919–1929PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Madeira C, Santhagunam A, Salgueiro JB, Cabral JM (2015) Advanced cell therapies for articular cartilage regeneration. Trends Biotechnol 33:35–42PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Marlovits S, Singer P, Zeller P, Mandl I, Haller J, Trattnig S (2006) Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: determination of interobserver variability and correlation to clinical outcome after 2 years. Eur J Radiol 57:16–23PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Mesallati T, Buckley CT, Kelly DJ (2014) A comparison of self-assembly and hydrogel encapsulation as a means to engineer functional cartilaginous grafts using culture expanded chondrocytes. Tissue Eng Part C Methods 20:52–63PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Mont MA, Marker DR, Zywiel MG, Carrino JA (2011) Osteonecrosis of the knee and related conditions. J Am Acad Orthop Surg 19:482–494PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Niemeyer P, Laute V, John T, Becher C, Diehl P, Kolombe T et al (2016) The effect of cell dose on the early magnetic resonance morphological outcomes of autologous cell implantation for articular cartilage defects in the knee: a randomized clinical trial. Am J Sports Med 44:2005–2014PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Niemeyer P, Laute V, Zinser W, Becher C, Kolombe T, Fay J et al (2019) A prospective, randomized, open-label, multicenter, phase III noninferiority trial to compare the clinical efficacy of matrix-associated autologous chondrocyte implantation with spheroid technology versus arthroscopic microfracture for cartilage defects of the knee. Orthop J Sports Med 7:2325967119854442PubMedPubMedCentralGoogle Scholar
  32. 32.
    Niemeyer P, Pestka JM, Kreuz PC, Erggelet C, Schmal H, Suedkamp NP et al (2008) Characteristic complications after autologous chondrocyte implantation for cartilage defects of the knee joint. Am J Sports Med 36:2091–2099PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Niemeyer P, Pestka JM, Salzmann GM, Sudkamp NP, Schmal H (2012) Influence of cell quality on clinical outcome after autologous chondrocyte implantation. Am J Sports Med 40:556–561PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Pietschmann MF, Horng A, Niethammer T, Pagenstert I, Sievers B, Jansson V et al (2009) Cell quality affects clinical outcome after MACI procedure for cartilage injury of the knee. Surg Sports Traumatol Arthrosc 17:1305–1311CrossRefGoogle Scholar
  35. 35.
    Riboh JC, Cvetanovich GL, Cole BJ, Yanke AB (2017) Comparative efficacy of cartilage repair procedures in the knee: a network meta-analysis. Knee Surg Sports Traumatol Arthrosc 25:3786–3799PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Roos EM, Engelhart L, Ranstam J, Anderson AF, Irrgang JJ, Marx RG et al (2011) ICRS recommendation document: patient-reported outcome instruments for use in patients with articular cartilage defects. Cartilage 2:122–136PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD (1998) Knee Injury and Osteoarthritis Outcome Score (KOOS)—development of a self-administered outcome measure. J Orthop Sports Phys Ther 28:88–96PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Saris DB, Vanlauwe J, Victor J, Almqvist KF, Verdonk R, Bellemans J et al (2009) Treatment of symptomatic cartilage defects of the knee: characterized chondrocyte implantation results in better clinical outcome at 36 months in a randomized trial compared to microfracture. Am J Sports Med 37(Suppl 1):10S–19SPubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Saris DB, Vanlauwe J, Victor J, Haspl M, Bohnsack M, Fortems Y et al (2008) Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture. Am J Sports Med 36:235–246PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Thanner M, Nagel E (2011) A comprehensive assessment of ATMP. Difficulties and approaches. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 54:843–848PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Vanlauwe J, Saris DB, Victor J, Almqvist KF, Bellemans J, Luyten FP et al (2011) Five-year outcome of characterized chondrocyte implantation versus microfracture for symptomatic cartilage defects of the knee: early treatment matters. Am J Sports Med 39:2566–2574PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Wondrasch B, Risberg MA, Zak L, Marlovits S, Aldrian S (2015) Effect of accelerated weightbearing after matrix-associated autologous chondrocyte implantation on the femoral condyle: a prospective, randomized controlled study presenting MRI-based and clinical outcomes after 5 years. Am J Sports Med 43:146–153PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Wood JJ, Malek MA, Frassica FJ, Polder JA, Mohan AK, Bloom ET et al (2006) Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration. J Bone Jt Surg Am 88:503–507Google Scholar

Copyright information

© European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA) 2020

Authors and Affiliations

  • Philipp Niemeyer
    • 1
    • 2
    Email author
  • Volker Laute
    • 3
  • Wolfgang Zinser
    • 4
  • Thilo John
    • 5
  • Christoph Becher
    • 6
  • Peter Diehl
    • 7
  • Thomas Kolombe
    • 8
  • Jakob Fay
    • 9
  • Rainer Siebold
    • 10
  • Stefan Fickert
    • 11
    • 12
  1. 1.Department of Orthopedic Surgery and TraumatologyFreiburg University HospitalMunichGermany
  2. 2.OCM ClinicMunichGermany
  3. 3.Joint and Spine Centre BerlinBerlinGermany
  4. 4.Department of Orthopedic Surgery and TraumatologySt. Vinzenz-Hospital DinslakenDinslakenGermany
  5. 5.Clinic for Traumatology and Orthopedic SurgeryDRK Hospital Westend BerlinBerlinGermany
  6. 6.Department of Orthopedic SurgeryMedical University Annastift HanoverHanoverGermany
  7. 7.Department of Orthopedic Surgery and TraumatologyOrthopedic Center Munich EastMunichGermany
  8. 8.Traumatology and Reconstructive SurgeryDRK Hospital LuckenwaldeLuckenwaldeGermany
  9. 9.Department of Traumatology and Arthroscopic SurgeryLubinus Clinicum KielKielGermany
  10. 10.Center for Hip, Knee and Foot SurgeryATOS Clinic HeidelbergHeidelbergGermany
  11. 11.Sporthopaedicum StraubingStraubingGermany
  12. 12.Department of Orthopedic Surgery and TraumatologyMannheim University HospitalMannheimGermany

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