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

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Knee Surgery, Sports Traumatology, Arthroscopy Aims and scope

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.

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Funding

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

Author information

Authors and Affiliations

  1. Department of Orthopedic Surgery and Traumatology, Freiburg University Hospital, Munich, Germany

    Philipp Niemeyer

  2. OCM Clinic, Munich, Germany

    Philipp Niemeyer

  3. Joint and Spine Centre Berlin, Berlin, Germany

    Volker Laute

  4. Department of Orthopedic Surgery and Traumatology, St. Vinzenz-Hospital Dinslaken, Dinslaken, Germany

    Wolfgang Zinser

  5. Clinic for Traumatology and Orthopedic Surgery, DRK Hospital Westend Berlin, Berlin, Germany

    Thilo John

  6. Department of Orthopedic Surgery, Medical University Annastift Hanover, Hanover, Germany

    Christoph Becher

  7. Department of Orthopedic Surgery and Traumatology, Orthopedic Center Munich East, Munich, Germany

    Peter Diehl

  8. Traumatology and Reconstructive Surgery, DRK Hospital Luckenwalde, Luckenwalde, Germany

    Thomas Kolombe

  9. Department of Traumatology and Arthroscopic Surgery, Lubinus Clinicum Kiel, Kiel, Germany

    Jakob Fay

  10. Center for Hip, Knee and Foot Surgery, ATOS Clinic Heidelberg, Heidelberg, Germany

    Rainer Siebold

  11. Sporthopaedicum Straubing, Straubing, Germany

    Stefan Fickert

  12. Department of Orthopedic Surgery and Traumatology, Mannheim University Hospital, Mannheim, Germany

    Stefan Fickert

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  1. Philipp Niemeyer
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  10. Stefan Fickert
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Corresponding author

Correspondence to Philipp Niemeyer.

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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).

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Niemeyer, P., Laute, V., Zinser, W. et al. Safety and efficacy of matrix-associated autologous chondrocyte implantation with spheroid technology is independent of spheroid dose after 4 years. Knee Surg Sports Traumatol Arthrosc 28, 1130–1143 (2020). https://doi.org/10.1007/s00167-019-05786-8

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  • DOI: https://doi.org/10.1007/s00167-019-05786-8

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