Introduction

Introducation: Matrix-associated autologous chondrocyte implantation (ACI) and microfracture (MF) are well-established treatments for full-thickness cartilage defects of the knee. However, clinical studies of high-level evidence comparing matrix-associated ACI to MF are still limited. Additionally, since different products and principles of ACI vary significantly, there is a specific need for clinical evidence in terms of efficiency and safety for every individual approach. With regard to this, the present prospective randomized clinical trial was initiated to investigate confirm the non-inferiority and investigate the superiority of a pure autologous spheroid based ACI (SPHEROX ^TM) compared with microfracture by a statistical hierarchical approach for focal and isolated cartilage defects of the knee op to a defect size of 2 cm^2.

Content

Methods: Patients with focal cartilage defects of the knee between 1 and 4 cm² were randomized to be treated by ACI or microfracture. No concomitant procedures were included. Both procedures followed standard protocols. In short, at time of screening arthroscopy the availability of the patients for the present study was confirmed and the patient was randomizend in either the ACI group or the microfracture group. While microfracturing was performed immediately in this group, for the ACI group cell harvesting was performed during index arthroscopy followed by the expansion period of approximately 8 weeks. In the ACI group, the transplantation was performed as a second surgery in a mini-open approach. For the ACI 10–70 spheroids/cm² were administered. Rehabilitation was similar in both group. In short, partial weight bearing was recommended for a period of 8 weeks and limited range of motion was recommended in preference of the individual surgeon. CPM was used routinely. The primary outcome measure was the Knee Injury and Osteoarthritis Outcome Score (KOOS) at the time of surgery and 6,12, 24 and 36 months following index surgery. This report presents results for 24 and 36 months after treatment.

Results: Both ACI and microfracture led to a significant improvement treated over the three-year observation period. For the overall KOOS, the statistical hypothesis of non-inferiority (the intended primary goal of the study) was formally confirmed; additionally, for the three subscores “Quality of Life”, “Activities of daily living” and “Sport and Recreation”, superiority of the ACI over MF was shown at different timepoints during the follow-up period. Occurrence of adverse events were not different between both treatments (ACI 77%; MF 74%). Concerning patient's safety, 9 Serious adverse events were reported for ACI and 10 for MF. However, none of the SAE was considered treatment related in the ACI group, while in the MF group 5 were possible treatment related.

Conclusion: Patients treated with matrix-associated ACI with spheroid technology showed substantial improvement in various clinical outcomes after 36 months. The advantage of ACI compared with microfracture was underlined by the clear, formal demonstration of its statistical non-inferiority, approaching superiority, and by (descriptive) superiority in the KOOS subscores ‘Activities of daily living’ and ‘Sport/Recreation’. Age and defect size showed no significant effect on clinical outcome, indicating that the treatment of limited focal defects – i.e., smaller than currently recommended by national and international orthopedic societies – should be considered.

Introduction

Current repair strategies for articular cartilage lesions, including treatments based on autologous articular chondrocytes implantation, cannot yet offer predictable, reproducible and durable restoration of cartilage structure and function. Nasal chondrocytes (NC) have a larger, more reproducible and less age-dependent capacity to generate cartilaginous tissues than articular chondrocytes. A first-in-human study previously demonstrated safety and feasibility of engineered NC-based grafts for articular cartilage focal lesions, as well as promising clinical and radiological results¹. We thus aimed at assessing efficacy of the grafts in a phase 2 clinical trial. In particular, we tested whether the clinical and radiological outcomes are associated with the degree of maturation of the implanted engineered tissues.

Content

Methods: A prospective, randomized, multicenter clinical trial is currently ongoing in 5 centers in 4 countries (University Hospital Basel, Switzerland; University Hospital Svethi Duh Zagreb, Croatia; Medical Center University of Freiburg and Medical Center König-Ludwig-Haus, Germany; and Istituto Ortopedico Galeazzi Milan, Italy), including a total of 108 patients with symptomatic cartilage lesions of the knee randomized to two treatment groups: N-TEC (mature tissue engineered cartilage grafts based on NC; 2 weeks pre-culture) or N-CAM (immature grafts based on NC associated with a matrix; 3 days pre-culture). An autologous nasal cartilage biopsy and blood are harvested and sent to Fraunhofer Institute (Würzburg, Germany) for graft manufacturing. After implantation into the knee cartilage defect via mini-arthrotomy, patients are followed-up for 24 months. Primary outcome is the difference in KOOS (Knee Injury and Osteoarthritis Outcome Score, questionnaire for symptoms and function) at 24 months between treatment groups. Secondary clinical outcomes are safety (number of SAR/SUSAR) until 24 months, KOOS at 12 months, EQ-5d (quality of life) at 12 and 24 months. Secondary radiological outcomes are the MOCART (“Magnetic Resonance Observation of Cartilage Repair Tissue”) scores at 3, 12, 24 months to assess morphology of the repair tissue, and content of cartilage specific proteins (Glycosaminoglycans) by “delayed Gadolinium Enhanced MRI of Cartilage” (dGEMRIC).

Results: Up to May 2019, 67 patients have been treated. 22 patients (11 N-TEC and 11 N-CAM) completed 12 months follow-up. For all 67 patients, no Serious Adverse Reactions (SAR) or Suspected Unexpected Serious Adverse Reactions (SUSAR) have been recorded so far. Mean overall KOOS improved significantly (p<0.05) and with clinical relevance for both N-TEC and N-CAM (from 55.5 and 60.7 at baseline to 88.6 and 83.9 at 12 months). The EQ-5d scores also significantly improved (p<0.05; from 0.57 and 0.60 at baseline to 0.81 and 0.83 at 12 months). The MOCART scores indicated good defect filling and integration, with a slight increase from 3 (N-TEC 52.5, N-CAM 55.5) to 12 months (N-TEC 66.7, N-CAM 60.9). The dGEMRIC analysis indicated hyaline-like repair tissue for both treatment groups at 12 months (ΔR1 values: N-TEC 1.34, N-CAM 1.29).

Discussion & Conclusion: The interim analysis of this ongoing phase 2 clinical trial confirmed safety of the procedure and suggests that NC-based grafts can lead to structural restoration of focal cartilage defects with hyaline-like cartilage tissue, significant clinical improvement and high patient satisfaction. Clinical outcomes in this so far small cohort of patients does not differ significantly between the two implantation groups. Treatment and analysis of the remainder of patients is ongoing to consolidate this assessment, with the perspective of extending indications to more advanced degenerative changes as seen in osteoarthritis.

References

¹ Mumme M, Barbero A et al. (2016) Lancet 388:1985-94.

Acknowledgments

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 681103, BIO-CHIP (). Ivan Martin & Marcus Mumme are submitting the abstract on behalf of the whole BIO-CHIP Consortium