Project Summary: Narcotic use in pain management of underserved minority populations and minority United States veterans has played a major role in the ongoing opioid crisis. According to the NIH, veterans are more susceptible to opioid addiction and are 40% more likely to suffer from severe chronic joint pain then non-veterans. Over the next decade, the percentage of minority veterans will increase from 23% to 34% and is expected to rise. This shift of racial and ethnic minorities directly correlates to the growing demographics of minority active-duty soldiers that make up over 40% of our nation’s military forces. The federal government considers the 18.2 million veteran and 42 million non-veteran minority Americans to be "potentially vulnerable patient populations” with health disparities particularly related to joint diseases care. Osteoarthritis (OA) is one of the most common of these joint diseases affecting the entire US population, and of considerably higher 19-fold incidence and prevalence in the service- disabled veteran population. Although the disease itself does not appear to occur more frequently in minorities, its effects and progression are more severe. This is especially true among minorities with arthritis, 36.7% of Black patients and 35.5% of Hispanic patients reported severe joint pain compared to only 23.0% of non-Hispanic Whites. The economic burden of veterans with OA is estimated to approach or exceed $60 billion annually due to longer life expectancies. Arthritis is also a significant economic and health burden in the United States at large which is estimated to exceed $394 billion in healthcare costs by 2030. In our SBIR HEAL Phase I, we developed a wireless long-duration low-intensity ultrasound NSAID-enhanced (2.5% diclofenac) sonophoresis system for use by the underserved OA population. We first demonstrated that the sonophoresis technology could increase tissue penetration of NSAIDs by 3.8x compared to standard of care (p<0.01). Secondly, the miniature device was evaluated in a 25-subject human-factors study, 54-subject diathermy study and a 52-subject OA clinical study on patients with radiographically confirmed mild to moderate knee OA. In 8-weeks of daily 4-hour use, symptomatic pain was significantly reduced by 3.43 point (55%) NRS (n=34, p<0.0001) versus 1.00 point (22%) NRS (n=18, p=0.0847) for subjects treated with topical diclofenac pain cream. Over 98% of the study population found the device easy to use and would continue treatment for their knee OA symptoms. For this Phase II HEAL renewal application (1) First ZetrOZ Systems will refine the design and optimize the wireless sonophoresis technology for shelf-life stability and device functionality/usability by the veteran and aging population. A series of regulatory testing standards including sensitization, cytotoxicity, packaging/formulation stability, biocompatibility, microbial growth, shelf-life and home-use will be completed on the wireless sonophoresis...