Investigations into treatment strategies for post-traumatic osteoarthritis and end stage osteoarthritis

Osteoarthritis (OA) is a chronic and progressively degenerative disease which affects not only the articular cartilage and subjacent bone of a joint, but also the synovium, ligaments, and muscles. OA progression has been classified microscopically by the loss of proteoglycans and collagen, both of which lead to the disruption of the extracellular matrix (ECM) and subsequent impairment of the biomechanical attributes of the joint. OA resulting from an injury to the joint, whether it be an intra-articular fracture (IAF), sprain, or damage to the cartilage, account for 12% of cases, and are classified as post-traumatic osteoarthritis (PTOA). Current management options for OA and PTOA are mainly focused on managing pain, improving joint functionality, and giving patients a better quality of life. For these reasons, there is a need to find procedures which can prevent or impede PTOA by halting the progression of the articular cartilage damage and be applied as standalone treatments or in conjunction with standard procedures. Since OA is a disease which typically only affects the cells within the joint space, it is a good candidate for treatment using intra-articular injection since this provides local delivery and decreases the chances of systemic adverse effects. One strategy that has shown promise for mitigating the deleterious effects of PTOA is the use of amobarbital, a mitochondrial electron transport chain (mETC) member complex I inhibitor. This treatment has been shown to be efficacious at preserving the composition and structure of the articular cartilage for up to six months after an IAF. In contrast, the untreated control animals grew lesions. In this dissertation, amobarbital was incorporated into a hyaluronic acid (HA) hydrogel depot style delivery vehicle and the stability of the drug was significantly improved compared to the free drug solution. In previous research, amobarbital injection was found to be less effective 12 months after an IAF, and for this reason, gene therapy was considered to further improve PTOA outcomes. The purpose of gene therapy was to shield the cartilage from further injury by targeting PTOA related decreased lubricin, or proteoglycan 4 (PRG4), production. In order to avoid the adverse systemic effects associated with viral gene delivery, a non-viral gene delivery system using the polymers poly(lactic-co-glycolic) acid (PLGA) and polyethyleneimine (PEI) was fabricated to be a safer alternative to adeno-associated virus (AAV) vectors. Of all the formulations tested, the PLGA/PEI-PRG4-EGFP formulation, fabricated as a proof-of-principle gene delivery system, had the greatest potential for future animal studies after demonstrating significantly higher in vitro transfection efficiency in rabbit synovial fibroblasts compared to all other formulations tested. Once PTOA reaches the point where nonoperative intervention is unsuccessful at alleviating pain, doctors will typically recommend joint replacement surgery. Hip and knee joint replacement surgeries are the most common procedures in the U.S. and have a high rate of success. Unfortunately, aseptic prosthetic loosening has been shown to occur in up to 20% of cases within 25 years of implantation causing implant failure. Implant failure can be the result of one or more contributing factors such as inadequate qualitative or quantitative bone stock, age, gender, implant insertion trauma, or poor osseointegration. Osseointegration is the process by which the implant surface forms a direct bond with the surrounding bone tissue. Coating the implant surface with osteoconductive therapeutics such as bisphosphonates is one example of a method to improve osseointegration. Zoledronic acid (ZA) is a bisphosphonate compound found to improve bone implant osseointegration. In this dissertation, ZA and/or the fluorescently labeled version of ZA (AF647-ZOL) were complexed with calcium and coated in a lipid to form hydrophobic composites using the reverse microemulsion method. These composites were then combined with PLGA dissolved in chloroform to create coating solutions able to deposit the drug(s) and polymer onto model titanium screws. Drug deposition was quantified using fluorescence imaging and the ZA/PLGA coating solution was used to dip-coat titanium screws which were subsequently implanted into rats. The animals implanted with the ZA/PLGA coated screws showed bone growth in the medullary cavity of the tibia adjacent to the implant site which was not seen in the uncoated or PLGA only coated implant groups. This work provides promising preliminary data in support of testing this coating solution using a more precise coating method to achieve complete osseointegration, characterized by bone growth between the screw threads.