UC San Diego

Articular cartilage is a connective tissue covering the ends of long bones and responsible for facilitating normal joint motion. When adult tissue is damaged or diseased, it does not heal adequately, and further breakdown ensues so that replacement tissue or enhanced repair is needed. Strategies for generating engineered tissue or instigating a repair response might be achieved using a biomimetic approach, where the normal in vivo mechanisms of growth and maturation are recapitulated. The objective of this dissertation was to further the understanding of how the chondrocytes within articular cartilage are positioned to contribute to growth and homeostasis, by attaining and maintaining a distinct cell organization and undergoing proliferation. The organization and fates of chondrocytes in cartilage vary with depth from the articular surface and are consistent with an anabolic growth phenotype in immature tissue and a more stable state of homeostasis in mature tissue. From 3-D imaging and analysis of cartilage, the cells in the adult stage are sparse, while cell density is high in growing tissue, especially near the surface, and cells are spread out evenly to maintain a close proximity to the rapidly growing and remodeling tissue. The spatially-varying growth of immature articular cartilage in vitro was analyzed by the displacement of cell nuclei at a surface, revealing that cartilage explants are predisposed to growth occurring primarily near the articular surface. Finally, by analyzing tissue for proliferating cells, it was found that the cell population can be expanded by proliferation during in vivo growth, with the highest capacity for proliferation (in vitro) near the articular surface. The experimental data from these studies combined with a theoretical model describing the dynamics of cartilage cellularity underscores the contribution of cell proliferation to maintenance of high cell density, especially near the articular surface, during cartilage growth. This dissertation highlighted the ability of the cell population to maintain an organization with cells positioned to elicit a highly anabolic state in immature articular cartilage and a more efficient state of homeostasis in adult tissue. The results described herein may allow tissue engineering or repair strategies that more closely mimic in vivo mechanisms, in which growth, maturation, and repair are guided by a population of cells with specific organization and proliferative activity