Abstract Every year, millions of people suffer from arthritis such as osteoarthritis, a disease associated with extreme joint pain and inflammation. Despite the strong effect of opioids for pain treatment, the drug causes serious problems of drug abuse and addiction. Alternatively, other analgesics including NSAIDs (non-opiate and non-steroid anti- inflammation drugs) and glucocorticoids have been traditionally prescribed to alleviate OA pain without the concern of opioid addiction. These drugs also have limitations, which are largely due to the routes of administration. Oral tables struggle with the first-pass metabolism, thus requiring a large amount of drugs and easily leading to severe systemic side effects. For example, NSAID drugs often have low bioavailability and are prescribed with a large oral dose of 300-1000 mg/day, which causes significant GI problems (e.g. stomach bleeding, and stomach ulcers), retinal disfunction, cardiovascular diseases etc. Glucocorticoid tablets, when used with a large quantity, also exhibit side effects of lower resistance to infection, higher risk of osteoporosis etc.12. Besides oral delivery, intra-articular (IA) injections of pain medicines, especially for glucocorticoids such as Dexamethasone (Dex)13, 14, have shown the efficacy to treat OA pain. However, the injections need to be repeated multiple times to sustain the analgesic effect, posing significant problems of complexity, cost, and inconvenience, leading to low patient compliance/adherence. The invasiveness of repeated IA injections could also cause more cartilage damages. In this regard, transdermal microneedles (MNs) have appeared as a powerful system to penetrate the SC, facilitating the intra-skin delivery of various drugs. Tiny MNs avoid touching the nerve endings to tremendously reduce pain and can be even self-administered by non-professionals, significantly increasing patient compliance. Here, we propose a novel (trans)dermal biodegradable MN system which can be fully embedded into the skin at a single-time to perform a well-controlled sustained release of non-opioid analgesics over a long period for the treatment of chronic musculoskeletal pains. Our objective in this R21 is to develop a single-time skin administration MN patch to perform a long-term delivery of a common non-opioid glucocorticoid, Dexamethasone or Dex (as a drug model). These MNs will be the first transdermal system to provide a separate control over the release dose and the release period, which can be easily extended over a long period to treat chronic OA pain. Our overarching hypothesis is that patients with OA/arthritis pains would be able to self-apply such a MN patch on the skin even at home (similar to a wound bandage) at just a single time to obtain a long-term pain relief, similar to the analgesic effect obtained from the repeated IA injections. We design our project with two specific aims; Aim 1 is to characterize the release kinetics of the core-shell MNs and engi...