Project Summary: Arthritis is a significant economic and health burden in the United States which is estimated to exceed $394 billion in healthcare costs by 2030. Osteoarthritis (OA) is the most common type of arthritis, affecting over 32 million adults in the United States and represents over 25% of medical office visits according to the Centers for Disease Control and Prevention and the National Institutes of Health. Over 40% of individuals over 65 have symptomatic OA and reduced mobility due to the disease. OA pain is often mitigated with conservative treatment approaches such as water therapy, walking, cycling, and pharmaceuticals. Regular use of NSAIDs can have adverse side effects on cardiovascular, gastrointestinal and renal systems. As such, topical NSAIDs and intra- articular corticosteroids are often used to provide localized pain relief for patients. However, neither of these therapeutic approaches provide pain relief without risks including skin irritation, infection and accelerated loss of cartilage. Long-duration ultrasound has been used to reduce pain and improve joint function in patients with knee OA. When ultrasound is used in conjunction with topical pharmaceuticals, sonophoresis drives the molecules deeper into tissue, providing improved pain relief compared to ultrasound or topical application of NSAIDs alone. In our SBIR Phase I/II project, we developed a novel diclofenac sonophoresis patch for the management of knee OA. We demonstrated that the sonophoresis technology could increase tissue penetration of NSAIDs by 3.8x compared to standard of care (p<0.01) and exhibit an excellent safety profile. We completed regulatory testing including sensitization, cytotoxicity, packaging/formulation stability, biocompatibility, microbial growth, shelf-life and home-use application of the sonophoresis patch. We also completed a human-factors study, clinical diathermy study and two knee OA clinical studies on patients with radiographically confirmed mild to moderate knee OA. The sonophoresis patch reduced knee pain by up to 2.96 points after 1-week (p<0.001) and by 3.43 points after 8-weeks (p<0.0001) of daily use; significantly more than topical diclofenac arthritis medication alone. Over 98% of study participants found the device easy to use and would continue treatment for their knee OA symptoms. For this SBIR Phase IIB renewal we (1) complete 3-year validation testing of the device to meet all remaining federal requirements for the sonophoresis patch, and (2) complete a 12-week, 3-arm, multi-site, placebo-controlled, randomized, clinical superiority study to expand upon our Phase I/II results and demonstrate the combined benefit of multi-hour ultrasound + diclofenac in reducing pain, improving mobility and quality of life for patients with knee OA. The overarching goal of this SBIR program is to bring a non-invasive, non-opioid, targeted, clinically superior, easy-to-use, knee OA treatment option to the aging patient population regar...