PROJECT SUMMARY The long-term goal of this project is to develop a scalable, user-friendly, continuous diabetes monitoring (CDM) system to minimize the risk of diabetic ketoacidosis (DKA) for millions of diabetes patients, especially those with type I diabetes by adding continuous ketone monitoring (CKM) to the IMS continuous glucose monitor (CGM). IMS has developed the world's smallest wireless electrochemical CGM using a novel semiconductor (CMOS) platform. This design offers some unique advantages due to its smart sensor (compared to passive sensors in competitor designs) including extreme miniaturization (system is smaller than half a sesame seed), on-chip integration of multiple sensors, improvement in signal-to-noise ratio (thus improving hypoglycemia accuracy), decrease in sensor capacitance and membrane thickness (thus improving response speed), and on-chip temperature calibration. This system can enable automatic closed-loop glucose control without meal announcements and carbohydrate counting and without the fear of missed hypoglycemic events; greatly simplifying patient experience and improving safety. We have demonstrated the function of our CGM platform in the lab, in animals, and recently in humans. The addition of CKM can significantly improve the value of the system to detect impending DKA that goes unnoticed with the current CGM systems, causing significant harm to the at-risk patients. Therefore, our objective in the original proposal was to develop a multi-analyte sensing platform that can sense both glucose and ketone in the interstitial fluid (ISF) using a single device. The sensing platform would be tested in the lab. This research is significant as it will enable the first CDM system with a small, pain-free needle- insertion (26-gauge needle) that can work for a long time (>30 days). Once proven, this system can be extended to include other important analytes (e.g., insulin, glucagon) without increasing its size or complexity, owing to on-chip integration of multiple sensors on a single microscale device. During our work, we discovered an unforeseen issue with the ketones sensing chemistry that prevents long-term stability. We have discovered a potential solution to that by using a conjugated enzyme. We need additional support via this supplement to enable us to test this solution. The team includes original inventors of the core technology from California Institute of Technology (Dr. Nazari, Dr. Rahman, Mr. Sencan), seasoned and respected researcher in Glucose sensor technology (Bill Van Antwerp, former CSO of Medtronic MiniMed), surgery and biomaterials expert (Dr. Jonathan Lakey of UC Irvine), regulatory and IP expert (John Heithaus, JD), commercialization expert (Mr. Peter Rule; former President of MiniMed, Chairman of Therasense, and OptiScan), and clinical expert (Dr. Alan Marcus, MD; former Chief Medical Officer of Medtronic Diabetes). The project is supported by patient advocacy groups like JDRF and practicing endocr...