Abstract Millions of Americans suffer from arthritis (e.g., osteoarthritis or OA), a disease associated with inflammation that causes pain and disability, especially in senior population. Current treatments that focus on alleviating pain/inflammation in joints include steroids, non-steroid or non-opioids anti-inflammation drugs, and intra- articular injection. However, these drugs have limitations and many side effects such as causing stomach bleeding/ ulcers when taken orally. In the parent grant, we proposed an approach to use non-opioid analgesic drugs with controlled sustain release obtained from microneedle technique for the treatment of OA pain and inflammation. In this study, we would like to investigate another approach to manage OA pain through intra- articular injection of a novel ionic liquid hydrogel. Hyaluronic acid (HA) intra-articular injection is commonly used to clinically treat joint pain due to its unique ability to suppress anti-inflammation and chondroprotection. Furthermore, when HA synergizes with other pain-relief drugs (e.g., Dexamethasone or DEX), the new combination has a greater pain relief efficacy than HA alone. Recently ionic liquid and deep eutectic solvents have gained a great attention because of their high stability and effectiveness for higher drug loading capacity. The liquid also improves drug tissue penetration and can act as drugs themselves (e.g. lidocaine). Our hypothesis is that hyaluronic acid grafted ionic liquid/ deep eutectic solvents (e.g., Decanoic Acid-Lidocaine) would increase therapeutic effect to treat OA pain and inflammation while preventing join degeneration both in vitro and in vivo. In this supplementary grant, we would have our under-represented graduate student, Tra Vinikoor, research and improve OA therapy by using a HA-grafted ionic liquid or deep eutectic solvent with dual functions of preventing joint degeneration and reducing inflammation. The graduate student will perform the study under the support and supervision of the PI (Dr. Thanh Nguyen) and the co-mentor (Dr. Cato Laurencin). This study will be very important to the student to continue her work on injectable hydrogels for cartilage regeneration/OA treatment and lay a strong foundation for her to achieve her long-term career goals in academia.