This study was designed to determine if the maturation stage of engineered cartilage implanted in a goat model of cartilage injury infl uences the repair outcome. Goat engineered cartilage was generated from autologous chondrocytes cultured in hyaluronic acid scaffolds using 2 d, 2 weeks or 6 weeks of pre-culture and implanted above hydroxyapatite/hyaluronic acid sponges into osteochondral defects. Control defects were left untreated or treated with cell-free scaffolds. The quality of repair tissues was assessed 8 weeks or 8 months post implantation by histological staining, modifi ed O'Driscoll scoring and biochemical analyses. Increasing pre-culture time resulted in progressive maturation of the grafts in vitro. After 8 weeks in vivo, the quality of the repair was not improved by any treatment. After 8 months, O'Driscoll histology scores indicated poor cartilage architecture for untreated (29.7 ± 1.6) and cell-free treated groups (24.3 ± 5.8). The histology score was improved when cellular grafts were implanted, with best scores observed for grafts pre-cultured for 2 weeks (16.3 ± 5.8). As compared to shorter pre-culture times, grafts cultured for 6 weeks (histology score: 22.3 ± 6.4) displayed highest type II/I collagen ratios but also inferior architecture of the surface and within the defect, as well as lower integration with native cartilage. Thus, pre-culture of engineered cartilage for 2 weeks achieved a suitable compromise between tissue maturity and structural/integrative properties of the repair tissue. The data demonstrate that the stage of development of engineered cartilage is an important parameter to be considered in designing cartilage repair strategies.
Objectives
Bioreactor‐based production systems have the potential to overcome limitations associated with conventional tissue engineering manufacturing methods, facilitating regulatory compliant and cost‐effective production of engineered grafts for widespread clinical use. In this work, we established a bioreactor‐based manufacturing system for the production of cartilage grafts.
Materials & Methods
All bioprocesses, from cartilage biopsy digestion through the generation of engineered grafts, were performed in our bioreactor‐based manufacturing system. All bioreactor technologies and cartilage tissue engineering bioprocesses were transferred to an independent GMP facility, where engineered grafts were manufactured for two large animal studies.
Results
The results of these studies demonstrate the safety and feasibility of the bioreactor‐based manufacturing approach. Moreover, grafts produced in the manufacturing system were first shown to accelerate the repair of acute osteochondral defects, compared to cell‐free scaffold implants. We then demonstrated that grafts produced in the system also facilitated faster repair in a more clinically relevant chronic defect model. Our data also suggested that bioreactor‐manufactured grafts may result in a more robust repair in the longer term.
Conclusion
By demonstrating the safety and efficacy of bioreactor‐generated grafts in two large animal models, this work represents a pivotal step towards implementing the bioreactor‐based manufacturing system for the production of human cartilage grafts for clinical applications.
Read the Editorial for this article on doi:10.1111/cpr.12625
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