Currently, there are no lasting treatments to restore degenerated articular cartilage in people with osteoarthritis. Many treatment strategies for osteoarthritis attempt to restore the extracellular matrix (ECM) to its native stiffness, but these approaches have not been successful. Instead, this project focuses on the ability for healthy cartilage to swell, which in conjunction with the stiffness of the ECM, helps support load and lower friction. The ability for cartilage to swell, or its osmotic pressure, is derived from the negatively charged sidechains of proteoglycans (aggrecan). These negatively charged groups (glycosaminoglycans) are lost in osteoarthritis. To restore the osmotic pressure, often measured as the fixed charge density, we propose developing synthetic aggrecan mimics made from polystyrene sulfonate. In conjunction with this treatment, we will develop a platform capable of resolving cartilage swelling in situ, which will help determine our treatment efficacy, while also contributing to a timeline of mechanical changes in the cartilage. To facilitate physiological relevance, our platform will evaluate swelling on full-stack equine explants. This project will first establish how typical OA-like processes, like enzymatic digestion, impact the in situ swelling in our cartilage explants. Then, we will test how more physiologically relevant OA precursors, such as mechanical injury or inflammation, lead to aberrant swelling behavior. Due to the orthogonal nature of swelling measurements to standard mechanical testing, we will be able to decouple mechanical changes derived by the osmotic pressure of the cartilage from those resulting from matrix damage. Finally, after synthesis of our polymer aggrecan mimics, we will test if our intervention can revert the swelling behavior of damaged cartilage into the swelling behavior seen in native cartilage. The impact of this work is a new treatment strategy based on the swelling behavior of cartilage: while swelling is equally important to the mechanical function of cartilage, it has not seen a similar level of research as an intervention target. We hypothesize that without restoring the swelling behavior, current OA treatment strategies are unlikely to be successful in the long term.