Meniscus tissue engineering with nanofibrous scaffolds

The fibrocartilaginous menisci dwell between the articular surfaces of the knee and play a central role in joint function. Damage through trauma or degenerative changes is a common orthopaedic injury, disrupts the meniscus mechanical function, and leads to the precocious development of osteoarthritis. The current standard of treatment is removal of the damaged tissue, a procedure that does not re-establish normal knee mechanics. Given the frequency of meniscal injury, a restorative repair strategy remains a major unmet need in orthopaedic medicine. With the goal of replacing damaged meniscus with engineered biologic tissue that can restore meniscal function, this work focuses on scaffolds composed of aligned biocompatible and biodegradable nanofibers that mimic the length-scale and organization of fibrous tissues. The highly ordered extracellular matrix of the meniscus is primarily composed of co-aligned collagen fibers, enabling the tissue to bear the high tensile loads seen with normal joint loading. To explore the use of nanofibrous scaffolds for engineering fibrocartilage, the effect of nanofiber alignment on the organization of cells and cell-deposited collagen was investigated. Cells seeded on randomly organized nanofibers produced disorganized collagen, but on co-aligned nanofibers, collagen deposition was observed to occur parallel to the nanofiber direction. With the ability to generate organized collagenous tissues via nanofiber alignment, the remainder of this work focused on optimizing the combination of scaffold, relevant cell type, and inducers of tissue formation. Towards improving the functionality of aligned nanofibrous scaffolds, composites of multiple polymer fibers were investigated. Additionally, the tissue forming potential of cells isolated from human sources was examined in a nanofibrous context. Finally, the effect of modulating the mechanical environment on tissue formation was examined through cyclic tensile loading of nanofiber-based tissues. Overall, this thesis establishes a novel approach to engineering meniscal fibrocartilage. Using a multi-pronged approach, the formation of fibrocartilage was optimized through scaffold design, cell source selection, and modulation of the mechanical environment. This work represents a significant advance in meniscus tissue engineering, and has bearing on other fibrous, anisotropic tissues such as the temporomandibular fibrocartilage, annulus fibrosus of the intervertebral disc, as well as tendon and ligament