Degradation of articular cartilage results in poor joint movement and afflicts millions of patients each year. Since this tissue is incapable of self-repair, developing new approaches to treat injured cartilage would be a tremendous boon to patient quality of life, as well as have important economic ramifications. To address this debilitating condition, this thesis investigated the biomechanical nature of single chondrocytes and studied their emergent biophysical environment.

Detailed insight into the role of intracellular structures on chondrocyte mechanical characteristics is a vital first step in understanding the etiology of cartilage degradation and identifying potential treatments. This thesis demonstrated that actin, intermediate filaments, and microtubules each play a unique function in cellular compressive stiffness, Poisson's ratio and its strain dependence, as well as recovery behavior in response to a range of applied strains. The in situ stiffness of the nucleus was found to be minimally greater than that of the cytoplasm, countering current theories in chondrocyte biomechanics and identifying a potential new avenue for mechanotransduction. A videocapture method was also developed to examine the response of single chondrocytes to direct shear, whose results were further correlated with alterations in actin and focal adhesions.

This thesis then examined the effect of two key components of cartilage regenerative processes, phenotypic modulation and growth factors, on cellular mechanics. A 'mechanical range' was observed for single cells along a chondrogenic lineage and a subpopulation of differentiated stem cells was identified with similar characteristics as chondrocytes. Moreover, growth factors were found to induce changes in chondrocyte stiffness and volumetric properties.

The second major component of this thesis examined the developing biophysical milieu of chondrocytes. Through a novel 'self-assembly' tissue engineering approach, the evolving matrix composition and mechanical properties of cartilage neotissue were examined. Moreover, several notable similarities were identified between tissue maturation in self-assembled cartilage and known developmental processes for native tissue.

This thesis sheds light on how chondrocytes respond to physicochemical stimuli, the role of biophysical factors in the maintenance of the cellular phenotype, and the composition of the emergent chondrocyte environment. This work can greatly aid researchers toward developing effective treatments for deteriorated cartilage.