| One of the most difficult challenges facing orthopedic surgeons is treating patients suffering from focal articular cartilage injuries, which are debilitating and have been shown to progress to arthritis. The capacity of cartilage to repair itself is minimal with the availability of endogenous cartilage as a repair material limited. Repair of localized cartilage defects would have significant health benefits, but no current clinical treatment option available is applicable to a wide patient population, while demonstrating long term restoration of normal function and pain relief. This dissertation describes the design of an acellular biomaterial that possesses the criteria required for a successful cartilage repair strategy. This biomaterial is designed to fill the wound site with a mechanically sound material from the outset, for intended long term in vivo survival. In order to meet the requirements for repair of focal cartilage injuries, novel tyramine-based hyaluronan hydrogels (TB-HA) were developed, through chemical crosslinking of hyaluronan (HA), a normal component of articular cartilage. The TB-HA biomaterials are made in a two step process in which the HA is first substituted with tyramine, and then crosslinked through formation of dityramine bridges by xvi the enzymatic action of peroxidase and hydrogen peroxide to provide a very stable, non-hydrolysable material. Design verification of established delivery, mechanical and biological response criteria was performed. The TB-HA hydrogels were produced using simple techniques and were easily sterilized, characterized and quality controlled using routine methods. Mechanical characterization showed that a 100 mg/ml TB-HA hydrogel exhibited values of aggregate modulus, Young's modulus and Poisson's ratio, which were in the range of those previously reported for articular cartilage. A minimal inflammatory response and potential for long term longevity was shown in a rat implantation model. The TB-HA biomaterial repair strategy was implemented and validated successfully in an in vivo rabbit model for the repair of a focal defect for up to one month, with potential for longer duration. Thus, the TB-HA hydrogels offer potential as permanent or bridging treatment of small contained focal articular cartilage defects. The feasibility of TB-HA in more complex repair situations will be explored in further investigations. |
