Joint surface restoration of deep osteochondral defects represents a significant unmet clinical need. Moreover, untreated lesions lead to a high rate of osteoarthritis. The current strategies to repair deep osteochondral defects such as osteochondral grafting or sandwich strategies combining bone autografts with ACI/MACI fail to generate long-lasting osteochondral interfaces. Herein, we investigated the capacity of juvenile Osteochondral Grafts (OCGs) to repair osteochondral defects in skeletally mature animals. With this regenerative model in view, we set up a new biological, bilayered, and scaffold-free Tissue Engineered (TE) construct for the repair of the osteochondral unit of the knee.

Skeletally immature (5 weeks old) and mature (11 weeks old) Lewis rats were used. Cylindrical OCGs were excised from the intercondylar groove of the knee of skeletally immature rats and transplanted into osteochondral defects created in skeletally mature rats. To create bilayered TE constructs, micromasses of human periosteum-derived progenitor cells (hPDCs) and human articular chondrocytes (hACs) were produced in vitro using chemically defined medium formulations. These constructs were subsequently implanted orthotopically in vivo in nude rats. At 4 and 16 weeks after surgery, the knees were collected and processed for subsequent 3D imaging analysis and histological evaluation. Micro-computed tomography (µCT), H&E and Safranin O staining were used to evaluate the degree of tissue repair.

Our results showed that the osteochondral unit of the knee in 5 weeks old rats exhibit an immature phenotype, displaying active subchondral bone formation through endochondral ossification, the absence of a tidemark, and articular chondrocytes oriented parallel to the articular surface. When transplanted into skeletally mature animals, the immature OCGs resumed their maturation process, i.e., formed new subchondral bone, partially established the tidemark, and maintained their Safranin O-positive hyaline cartilage at 16 weeks after transplantation. The bilayered TE constructs (hPDCs + hACs) could partially recapitulate the cascade of events as seen with the immature OCGs, i.e., the regeneration of the subchondral bone and the formation of the typical joint surface architecture, ranging from non-mineralized hyaline cartilage in the superficial layers to a progressively mineralized matrix at the interface with a new subchondral bone plate.

Cell-based TE constructs displaying a hierarchically organized structure comprising of different tissue forming units seem an attractive new strategy to treat osteochondral defects of the knee.

Purpose: Long-term follow-up was to determine clinical benefit of ChondroCelect (CC) in the repair of full-thickness femoral cartilage lesions as compared to microfracture (MF).

Methods: In a randomized controlled clinical trial CC (n=57) was compared to MF (n=61) in patients aged 18 to 50 years with single ICRS grade III/IV symptomatic cartilage defects of the femoral condyles. Clinical improvement was measured up to 36 months using the KOOS (Knee injury and Osteoarthritis Outcome Score). Safety was monitored throughout the study.

Results: At baseline, KOOS was comparable between treatment groups (Mean ± SD: CC, 56.30 ± 13.61 and MF, 59.53 ± 14.95). Improvement from baseline in adjusted mean ± SE for the Overall KOOS was 21.25 ± 3.60 for the CC group vs. 15.83 ± 3.48 for the MF group at 36 months. When using the mixed linear model analysis at 36 months, statistically significantly greater improvements were demonstrated in the CC group vs. the MF group in change from baseline for the overall KOOS (D 7.60%, P = 0.018), as well as in 4 of 5 KOOS domains (activities of daily living, pain, symptoms/stiffness, and quality of life). Percentages of treatment responders were 83% (n = 34/41) vs. 62% (n = 31/50) based on the KOOS for CC and MF groups, respectively. Two (3.9%) patients in the CC group and 7 (11.5%) patients in the MF group underwent a re-intervention and were therefore considered treatment failures. Both treatments were well tolerated and the proportion of patients reporting AEs diminished over time, indicating stabilization of the patients’ condition.

Conclusions: Implantation of ChondroCelect in the treatment of articular cartilage defects of the femoral condyles shows superior clinical benefit at 36 months vs. microfracture. Structural superiority in favour of the ChondroCelect group was previously demonstrated at 1 year follow up.

Purpose: A three-year evaluation of long-term clinical efficacy of Characterized Chondrocyte Implantation (CCI) compared to microfracture (MF), in the repair of symptomatic cartilage defects of the femoral condyles at 36 months post-surgery.

Materials and Methods: In a prospective, randomized, controlled, multicenter trial, CCI was compared to MF in patients aged 18–50 years with a single symptomatic ICRS grade III–IV lesion of the knee. Clinical outcome was measured 36 months after surgery by means of the KOOS, VAS for pain and ARS, with a non-inferiority margin preset at 9 % points for KOOS and VAS. Furthermore, response to treatment and progression of knee symptoms were assessed. Treatment failure was monitored throughout the study.

Results: Improvement from baseline was higher in the CCI group (N = 41) compared to the MF group (N = 49) for all clinical outcome parameters. Mean improvement from baseline for Overall KOOS was 22.14 vs. 14.48, respectively, with VAS and ARS scores revealing a similar trend. Responder analysis showed 83% of the patients treated with CCI improving vs. 61% after MF. Additionally, we observed a shift in the proportion of knee symptoms over time (52% vs. 35% of asymptomatic knees at 36 months compared to 2% vs. 8% at baseline in the CCI and MF group respectively). At 36 months, failure rates were low in both groups (n=2 in CCI vs. n=7 in MF).

Conclusions: Previous data have described a superior structural repair after CCI compared to MF at 1 year post-surgery. Continued clinical improvement as well as a favorable responder analysis was demonstrated for CCI compared to MF at 36 months.