Use of Environmental and Physical Stimuli in Cartilage Tissue Engineering Engineering

__Abstract__ Articular cartilage enables friction-free, and thus painless, joint movement, while also functioning as a shock absorber. Although articular cartilage is made up of only few main components, natural healing fails to re-establish the native organization of the extracellular matrix and surgical intervention has only limited success in long term follow up. The relatively simple composition of articular cartilage, combined with a high prevalence of damage, make it an attractive target for the development of cell based therapies for tissue repair. Unfortunately, the avascularity of the tissue, combined with its unique architecture, pose significant challenges for such therapies. The challenging combination of mechanical stress and a hypoxic/acidic in-vivo environment, makes the use of external physical stimulation especially interesting for articular chondrocytes. In this thesis various aspects of the use of external stimuli to study and manipulate chondrocytes in vitro are explored. The effects of mechanical stimulation, hypoxia, pH and osmolarity in (chondrocyte) cell culture are investigated for their effect on extracellular matrix production and relevant signalling pathways. Novel bioreactor technology is presented to accurately control the total culture environment and also investigate interdependencies of culture parameters. From the work presented in this thesis we can acknowledge that environmental stimulation can play a significant role in both experimentation, to understand (patho)physiological processes, and production of cell therapies, to maximize therapeutic potential