Biomaterial and Cell Based Cartilage Repair

Abstract

Injuries to human native cartilage tissue are particularly troublesome because cartilage has little ability to heal or regenerate itself. The reconstruction, repair, and regeneration of cartilage tissue continue to be one of the greatest clinical challenges, especially in orthopaedic and plastic surgery. A large body of literature exists on the generation of cartilage through tissue engineering, most of which are in vitro studies. The development of cell/scaffold-based therapies continues to be an area of intensive research. This dissertation is a synthesis of much that has been learned, and it focused on generating functional new cartilage using cells, articular, auricular, and mesenchymal stem cells (MSCs), and the manipulation of hydrogels to act as cell carrier devices for cartilage repair and regeneration. The goal was to move beyond in vitro assessment and perform these studies in vivo in order to move tissue engineering strategies closer to clinical application. The studies presented in this dissertation could provide a sound basis for further translation of cell/scaffold therapies in patients needing cartilage repair. Based on the clinical results that have been reported thus far, autologous chondrocytes continue to be the favored cell type for cartilage repair and regeneration. In this dissertation, the knowledge gained from cartilage generation using juvenile animal cells was translated into similar results using human cells combined with a hydrogel system. The results have demonstrated that cells from middle-aged, or even older, people have the capacity to generate cartilage ECM that is comparable to that observed by cells from juvenile animals—which has been the focus of most reported experimental cartilage engineering studies. Evaluating these parameters will help in developing strategies to apply tissue engineering clinically. Due to the limitations caused by donor site morbidity and loss of phenotype during in vitro expansion when using chondrocytes, mesenchymal stem cells are a promising alternative cell source that needs to be explored. In this dissertation, experiments have shown that chondrocyte-conditioned medium (CCM) was effective in inducing chondrogenic differentiation of BMSCs resulting in new cartilage ECM. Specifically, CCM had a stronger influence on chondrogenesis than supplementation of the standard culture medium with TGF-β3 without inducing calcification. Undoubtedly, the elucidation of these molecules and their mechanism of action will provide an appropriate strategy for improving chondrogenic cell therapies from MSCs. Among the numerous scaffolds, hydrogels could be ideal cell carriers for cartilage tissue engineering. In this dissertation, results have shown that the photochemically crosslinked hydrogels and the combination of nondegradable/degradable hydrogel composites have great potential to exceed the traditional natural hydrogels to be better scaffolds for cell-based cartilage repair and regeneration. The interpretation of these studies provides strong evidence for performing large animal experiments and clinical trials using tissue engineering techniques. Cell/hydrogel implantation applying the strategies demonstrated in this dissertation into immunocompetent animal models and long-term outcomes will be tested in the near future.