Osteoarthritis (OA) is a joint degenerative disease that affects over 30.8 million adults in the U.S. OA progression is a complex process involving different pathological mechanisms in the articular cartilage, the synovial membrane and the subchondral bone. Treatment at early stages is limited to systemic pain management using analgesics and non-steroidal anti-inflammatory drugs (NSAID). Later, when the symptoms are more severe, OA is treated with intra-articular injections of corticosteroids and visco-supplements such as hyaluronic acid (HA). However, these therapies only offer short term pain relief because they act as anti-inflammatory and lubricating agents respectively and do not mitigate OA progression. Additionally, these compounds are subjected to rapid clearance from the joint space. Finally, at late stages of OA patients often require total joint replacement.

Currently, there are no FDA-approved drugs able to mitigate or halt OA progression. Recent research has led to the discovery of multiple disease modifying drugs that have shown promising results in pre-clinical models of OA. Despite these efforts, the translation of these molecules to the clinic has been challenging in part because of the scarcity of appropriate drug delivery vehicles and the lack of understanding of drug effects on different intra-articular tissues involved on the progression of the disease.

Therefore, the objective of this project was to design an improved intra-articular (IA) drug delivery vehicle using peptide-functionalized poly(ethylene glycol) (PEG) microgels targeting different tissues within the joint to address problems related to intra-articular retention and tissue-specific drug delivery. In studies presented in Chapter 3, I used a microfluidic device to synthesize PEG microgels containing poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) loaded with a model drug such as Rhodamine B. This delivery vehicle with nano-composite design allowed for loading and sustained release of small molecules. In Chapter 4 it is demonstrated that functionalization of PEG microgels with targeting peptides led to specific binding of these delivery devices to bovine articular cartilage sections and synoviocytes in vitro. Finally, in Chapter 5 the IA retention of the engineered drug delivery system and their effect on the joint health in a rat model of OA was evaluated. PEG microgels did not negatively impact joint health and OA progression and were retained in the intra-articular space for at least 3 weeks. Also, synoviocyte-targeting PEG microgels were shown to be retained within the synovial membrane.

Overall, this work provides an intra-articular drug delivery vehicle that in addition to controlling the release of small molecule drugs, allows for improved intraarticular retention and specific binding to tissues involved in OA progression such as articular cartilage and synovium. Also, considering that PEG microgels are tunable systems that could also be used for the encapsulation of biologics and cells, this work may provide a better tool to study the effects of a combination of therapeutic strategies (small molecules, proteins, nucleic acids and cells) on specific joint tissues. This work is expected to contribute to the screening of therapy strategies and the development of tissue-specific treatments to prevent OA progression.