UC San Diego

Osteoarthritis (OA) is the most prevalent joint disorder with risk factors that include aging and joint injury. OA is characterized as the degeneration of articular cartilage, but invariably affects other joint tissues, including subchondral bone, menisci, synovium, ligaments, tendons, and muscles. Of these tissues, the meniscus, in particular, plays a critical role in the knee joint, providing load bearing and transmission, shock absorption, smooth articulation, and joint stability. These biomechanical functions are dependent upon the hierarchical structure and composition of the meniscus at the tissue level, as well as homeostatic mechanisms maintained at the cell and molecular level. The importance of the meniscus is emphasized by the fact that meniscal degeneration and injuries as well as partial/total meniscectomy contribute to the development and/or progression of OA. However, the precise relationship between meniscus degeneration and aging, injury, and OA is poorly understood. Previous studies have examined the macroscopic and microscopic meniscus structure, composition, and biomechanical properties independently, but do not provide a global understanding of meniscus degeneration. This dissertation investigates the structure-function relationship of the meniscus in humans and mice during aging, injury, and OA using multidisciplinary biological and engineering tools and techniques across multiple scales, from tissue to molecular level. Age-dependent changes in the nanobiomechanical properties of the extracellular matrix of human meniscus were characterized by atomic force microscopy (AFM), which revealed distinct nanobiomechanical profiles of healthy, aged, degenerated, and OA tissue. A semi-quantitative histopathological grading system was developed to assess degenerative changes in the structure and composition of menisci from mice models of normal aging, injury, and OA. This histopathological grading system was applied to understand changes in and the function of autophagy in mice menisci during aging and injury. Lastly, qualitative and quantitative ultrashort echotime (UTE) magnetic resonance imaging (MRI) was used to assess morphological and functional properties in menisci as well as determine the potential for identifying early biomarkers of meniscus degeneration and progression. This multiscale study of the structure--function relationship in the meniscus provides insight into diagnostics and treatment of meniscus injuries and degeneration for the prevention or slowing of the progression of OA.