Investigation of molecular parameters on cartilage regeneration in experimental models of cartilage defects and osteoarthritis

by Eleftherios Makris

Institution: University of Thessaly (UTH); Πανεπιστήμιο Θεσσαλίας
Year: 2014
Keywords: Οστεοαρθρίτιδα; Αναγέννηση αρθρικού χόνδρου; Διασταυρούμενοι δεσμοί κολλαγόνου; Υποξία; Osteoarthritis; Artiuclar cartilage regeneration; Cartilage tissue engineering; Collagen Crosslinks; Hypoxia
Record ID: 1154049
Full text PDF: http://hdl.handle.net/10442/hedi/34775


Articular cartilage and fibrocartilage have limited abilities to self-repair following disease- or injury-induced degradation. Given the critical role of these tissues to protect the osseous features of the knee and other joints in the human body, and ensure smooth, stable joint articulation, it is necessary to develop treatments that promote regeneration and/or repair of these tissues. Tissue engineering holds tremendous potential as a future means to treat damaged or diseased cartilaginous tissues. While much progress has been recently made toward developing functional neocartilage constructs with compressive properties on par with native tissue values, their tensile properties remain far behind. It is, therefore, critical that novel treatments be established to generate robust neotissue to address the approximately 46.4 million individuals affected by arthritis in the United States alone.Motivated by the progress that has been achieved in cartilage tissue engineering the past decade, this thesis had three global objectives: 1) to investigate novel molecular pathways toward regenerating articular cartilage in in vitro and in vivo experimental models of cartilage defects and osteoarthritis, 2) to develop and optimize treatment modalities toward engineering neocartilage of clinical applicability, and 3) to promote neotissue maturation and foster integration between self-assembled neocartilage and native tissue. Toward achieving these goals, this thesis sought to tailor the use of exogenous agents to promote native articular cartilage and fibrocartilage organization in engineered tissues. To begin, a treatment regimen consisting of copper and hydroxylysine, two important mediators of the physiologic collagen crosslinking process, was utilized to enhance the collagen crosslink content of self-assembled neocartilage constructs. A hypoxia treatment regimen was also investigated with the similar goal of enhancing the crosslink content and, therefore, the functional properties of native and engineered musculoskeletal tissues. Given the well-described correlation between increased collagen crosslink content and neotissue tensile properties, a more direct approach to increase these crosslinks was established via application of the exogenous agent lysyl oxidase (LOX) to further enhance neotissue functional properties. Other studies in this thesis focused on developing approaches for enhancing the collagen content and organization of the engineered tissues that, when combined with the novel collagen crosslinking approaches, would potentially result in mature engineered tissues capable of repairing cartilage defects in experimental (animal) models. Specifically, two agents known to modulate intracellular Ca2+ signaling (digoxin and adenosine triphosphate) were investigated as an alternative means to improve matrix content and biomechanical properties of neocartilage through promoting both collagen enhancement and collagen crosslinking. In addition, similar studies were focused on optimizing a treatment regimen consisting of the…