Autologous tissue transplantations for osteochondral repair

Abstract

Articular cartilage forms the articulating surface of synovial joints. Along with the synovial fluid it facilitates near frictionless movement in healthy joints. Injuries to articular cartilage in the knee are frequent and can lead to severe osteoarthritis, which is expected to affect 25% of the adult population by 2030. Hyaline cartilage does not regenerate spontaneously when injured and the current clinical treatment methods suffer from high cost and relatively high failure rates. This calls for new treatment methods to be developed. The backbone of developing new treatment methods for cartilage injuries is a reliable, cost-effective, clinically relevant large animal model. Study 1 aimed at developing such a model. We hypothesized that in the Göttingen minipig, the repair response of a selection of treatment methods would be similar to what is found in a clinical setting, and that two defects per knee, rather than one, could be applied without affecting the repair outcome. We found that the outcomes of the applied treatments were consistent with the outcomes in clinical studies. Furthermore, the use of two defects per knee did not have any significant effect on the repair response. The Göttingen minipig model was easy to handle, cost-effective, and provided a predictable repair response. Based on this study the use of two defects per knee in male Göttingen minipigs is recommended. The model has been implemented as the standard animal model for cartilage research at the Orthopedic Research Laboratory, Aarhus University Hospital. Synthetic osteochondral scaffolds represent an off-the-shelf, one-step treatment method, and preliminary clinical results have been promising. However, MRI investigations have shown issues related to subchondral healing. In study 2 we aimed at evaluating the osteochondral repair in 10 patients treated with the MaioRegen synthetic scaffold. Of the ten patients, two patients were re-operated due to treatment failure. CT imaging revealed that none of the eight remaining patients had complete regeneration of the subchondral bone. At 2.5 years, 6/8 patients had no or very limited (< 10%) bone formation in the defects and 2/8 had 50-75% bone formation in the treated defect. MRI showed no improvement at either one or 2.5 years compared with baseline. Clinical outcome scores were improved at 2.5 years. These results raise serious concerns about the biological repair potential of the MaioRegen scaffold. The use of the MaioRegen scaffold has been discontinued in Denmark as a result of this study. An alternative treatment approach for osteochondral lesions is combined transplantation of autologous bone graft and cartilage fragments, embedded in fibrin glue. In study 3 we investigated the early biological and clinical outcome of autologous dual-tissue transplantation (ADTT). ADTT is a combined autologous bone and cartilage chips transplantation for treatment of osteochondral injuries. It is easily applicable and bypasses the need for costly cell culturing or synthetic materials. After one year, all eight patients had significant improvements on MRI, CT and all clinical outcome scores. This study establishes ADTT as a promising, low-cost, treatment option for osteochondral injuries in the knee. To investigate the role of the implanted cartilage chips, we tested the isolated effect of the chips in the newly developed Göttingen minipig model. In study 4 we compared ADTT with autologous bone graft alone. The hypothesis was that the presence of cartilage chips would improve the quality of the repair tissue. Twelve Göttingen minipigs were included, and follow-up time was six and 12 months. Follow-up consisted of histomorphometry, immunohistochemistry, semi-quantitative scoring and CT. There was significantly more hyaline cartilage in the ADTT group compared with the autologous bone graft group at both six and 12 months. At both six and 12 months there were significantly more fibrocartilage in the ADTT group compared with the ABG group. The presence of cartilage chips in an osteochondral defect facilitated the formation of fibrocartilage as opposed to fibrous tissue at both six and 12 months. This study substantiates the chondrogenic role of cartilage chips in osteochondral defects, but questions the widely accepted repair mechanism involved in cartilage chip treatment methods. Further studies on the repair mechanism(s) involved are needed to improve the clinical application of autologous cartilage chips.