The tissue-engineering of functional osteochondral constructs for cartilage repair

Articular cartilage is a specialized connective tissue that bears load and reduces friction across moving joints. When damaged, articular cartilage does not heal, but often degenerates further, leading to pain and loss of function. This dissertation focuses on the engineering of anatomically-shaped osteochondral replacement tissue that may in the future be used to replace entire articular surfaces destroyed by traumatic injury or degenerative disease. Guiding this effort toward a biologic arthroplasty system are questions inherent to the paradigm of functional tissue-engineering: (1) How closely can we reproduce the native properties of cartilage in engineered tissue? (2) How important is it to reproduce these properties and what level of construct development is necessary prior to implantation? (3) How can we effectively transition from efforts in the lab to evaluation in a clinically-relevant in vivo model?;Within the context of these overriding questions, the research in this dissertation shows that with an appropriate cell source, scaffold material and mechano-chemical culture environment, engineered chondral tissue can be produced to match or exceed the equilibrium Young's modulus and the proteoglycan content of native cartilage from which the chondrocyte cells were isolated. The dynamic modulus and the collagen content however remain currently at sub-native values. Furthermore, the functional tissue properties are sensitive to chemical perturbation and will deteriorate if exposed prematurely in culture to inflammatory cytokines that are common within a damaged or diseased joint. A period of in vitro cultivation therefore appears necessary to promote the chondrocyte-mediated elaboration of an extracellular matrix that will afford biomechanical and chemical protection from the in vivo joint loading environment.;When increasing the complexity of engineered chondral constructs to more clinically-relevant osteochondral constructs, the choice of underlying substrate is dependent on its ability to sustain successful chondral tissue development in culture as well as its clinical appropriateness upon in vivo implantation. Devitalized trabecular bone is shown in this doctoral dissertation to be inhibitive towards chondral development and a promising synthetic alternative is identified and successfully used in a hybrid (biologic-synthetic) implant.;The first steps are taken towards the culture and implantation of a complete biological arthroplasty in the form of a canine patella and challenges are identified. These include: nutrient limitations due to increased diffusional distances when increasing construct size, challenges associated with the installation and fixation of large constructs, and mechanical failure of the chondral region of implanted constructs due to insufficient mechanical strength and problems in the patellar base design.;The research in this dissertation has spanned a breadth of work from the generation of a functional engineered tissue in the lab to making the first steps in the translation to clinical application by implantation and evaluation in a large animal model. The complexity of the tissue was increased from small chondral-only cylinders to bilayered osteochondral tissues with underlying base substrates and finally to large anatomically-shaped osteochondral constructs in the form of human and canine patellae. It is anticipated that these findings will aid and improve the functional tissue engineering of articular cartilage and advance the field towards the goal of creating a viable clinical treatment for osteoarthritis.