UC San Diego

Articular cartilage exhibits limited intrinsic healing, and when defects are left untreated, they can increase in size and cartilage degeneration may progress to end-stage joint failure. Osteochondral allografting has been widely used in the clinic to treat large or multiple focal defects, or as a salvage procedure to avoid total joint replacement, and aims to restore mature, hyaline cartilage in a biologically, structurally, and functionally appropriate manner. Repair outcomes may be influenced by the presence of viable chondrocytes within graft cartilage and the integration of the graft bone to surrounding host tissue. Thus, the overall motivation of this dissertation work was to develop an integrative and multi-scale approach to cartilage defect repair analysis by osteochondral allografts in order to expand the current understanding of in vivo cartilage and bone remodeling. A novel approach for analyzing in vivo cartilage defect repair by osteochondral allografts was developed using interdisciplinary and multi-scale analysis methods in the goat model. Maintenance of cartilage load-bearing function in allografts in vivo was associated with zonal maintenance of cartilage cellularity and matrix content. Reduced cellularity at the articular surface, resulting from 4°C storage, was associated with variable long-term outcomes, while allograft failure was accompanied with cartilage softening, loss of cells/matrix, and/or graft subsidence. Production of the lubricant, proteoglycan-4 (PRG4), from allografts was a useful marker of biological performance. 37°C storage supports long-term chondrocyte viability, especially at the vulnerable articular surface. Bone structure in allografts was altered in vivo compared to non-operated bone, with allografts displaying bone cysts, and bone surface channels with or without roughening at the bone-cartilage interface. This work has further elucidated the interrelationship between biological and structural aspects of cartilage and bone remodeling in vivo after osteochondral allografting. Such analysis has established the inferiority of 4°C stored allografts versus fresh allografts, identified potential biomarkers of allograft performance and alternative storage protocols, and provided insight into the pathogenesis of subchondral bone cysts during cartilage defect repair. Analyzing cartilage and bone biology, structure, and function in an integrative manner identified properties of the osteochondral tissue that are critical to repair efficacy and potential mechanisms of graft success/failure