Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Biomedical Engineering

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

Gillies, Elizabeth R.

2nd Supervisor

Beier, Frank

Co-Supervisor

Abstract

Osteoarthritis (OA) is a degenerative disease of the articular joints that affects over 240 million people globally. Despite its overwhelming prevalence, there is no disease modifying agent currently available to treat the disease, and many treatment options remain palliative in nature. Potentially effective treatments for OA are limited by probable systemic side effects. Intra-articular drug delivery systems present a new opportunity for the treatment of OA; encapsulated therapeutics can be injected directly into the joint, at the area of injury, thereby bypassing systemic administration and diminishing the chance for side effects. This thesis describes the research and development of novel polymeric drug delivery systems for intra-articular administration. Initially, a polymer particle delivery platform using poly(ester amide) (PEA) was developed to encapsulate the non-steroidal anti-inflammatory drug celecoxib. Drug-loaded particles were successfully prepared, and were characterized physicochemically and biologically using in vitro and in vivo techniques. Drug was released in vitro from particles over a period of months, and the particles did not cause significant cellular toxicity. The particles elicit a minimal host response in vivo when tested in an ovine model. The PEA particle delivery platform was further developed to encapsulate and deliver the small molecule, GSK3787, which had been previously implicated as a potential disease modifying agent for OA. The physicochemical properties of the particles were characterized including the measurement of the mechanical properties of individual particles by atomic force microscopy, and it was found that the modulus was in the range of articular cartilage. The drug-loaded and empty particles exhibited low toxicity to mammalian cells. In order to establish an even more prolonged release, and greater control over the system, a hybrid drug delivery system consisting of GSK3787-loaded PEA particles embedded within a thermally-responsive hydrogel was prepared. This system was evaluated to understand the effects of particle and drug incorporation on the gel properties including syneresis, Young’s modulus, degradation, and toxicity. The release of GSK3787 from the hybrid system was slower in vitro than from hydrogel into which drug was directly loaded without particles. The hybrid system is promising for further in vivo evaluation. Overall, this thesis furthered the understanding of polymer drug delivery systems for intra-articular use, and led to the development of three new systems for potential use in treating OA. Furthermore, for the first time, a means to deliver the potential disease modifying agent GSK3787 was developed.

Summary for Lay Audience

Osteoarthritis (OA) is a degenerative disease of the joints that affected over 5 million Canadians in 2019, or 1 in 6 people in the country. The prevalence of the disease is continuing to rise, and it is estimated that 1 in 4 Canadians will be affected by OA in 2035. Despite its prevalence, non-surgical treatment options remain only modestly effective. Drug treatments for the disease are greatly limited by their systemic side effects. Non-steroidal anti-inflammatory drugs for instance, have proven effective at treating the pain associated with the disease, but have well documented gastrointestinal and cardiovascular side effects. While no disease modifying agents are currently used for OA treatment, there are a number of potential agents that cannot be given as traditional oral drugs due to potential negative side effects. In order to reduce these side effects and to open up the potential of using new disease modifying agents, drug delivery systems have been proposed. These systems are made from polymers that are well tolerated in the body, and are designed to encapsulate drug, then to be injected directly into the joint where they will begin to degrade, and slowly release the drug to the affected tissue over time. This thesis describes the research and development of three new drug delivery systems. All of the systems were developed to be injectable, and were tested for their physical, chemical and biological characteristics, to determine if they were suitable systems for the delivery of therapeutics in the treatment of OA. The three drug delivery systems developed in this work have the potential to alter the way that OA is treated, and increase the feasibility of curing the disease.

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