PROJECT SUMMARY The long-term goal of this project is to develop a scalable, user-friendly, continuous metabolic monitoring (CMM) system to improve the performance and reliability of hormone replacement therapy for millions of diabetes patients. IMS has developed the world's smallest wireless electrochemical analyte sensing platform based on an application-specific integrated circuit (ASIC) using Complementary Metal-Oxide Semiconductor (CMOS) technology. This design offers some unique advantages due to its active digital sensor (compared to passive analog sensors in competitor designs) including extreme miniaturization, on-chip integration of multiple sensors, improvement in signal-to- noise (SNR) ratio (thus improving hypoglycemia accuracy), decrease in sensor capacitance and membrane thickness (thus improving response speed), universal interference rejection (using a background reference sensor and subtracting its signal from all sensors), and on-chip temperature calibration (improve accuracy, reliability by confirming the sensor is in the tissue and measuring the correct temperature). The proposed CMM will enable users to benefit from useful drugs (e.g., metformin, SGLT2 inhibitors), exercise, and automated insulin delivery systems without meal announcements, carbohydrate counting, and the risk of adverse side effects. Hence, the design is highly innovative. We have demonstrated the function of the first-generation platform for continuous glucose monitoring (CGM) in humans. Continuous lactate monitoring (CLM) can significantly improve the system's value to detect impending Lactic Acidosis that goes unnoticed with the current CGM systems. We have demonstrated the CLM in animals and a multiplexed CGM-CLM at the proposed size scale in the lab. Our objective in this proposal is to develop a CMM that can sense glucose, lactate, and temperature in the interstitial fluid (ISF) using a single wireless sensor smaller than half a sesame seed. The small and flexible (20um thick with polymer coatings) sensor minimizes the foreign body response (FBR). This research is significant as it will enable the first CMM system capable of a small, pain-free needle insertion (26-gauge needle) that can work for a long time (>30 days) with factory calibration (no finger sticks). Once proven, this system can be extended to include other important analytes (e.g., ketones, insulin, glucagon) without increasing its size, owing to the on-chip integration of multiple sensors. The team includes original inventors of the core technology from the California Institute of Technology (Dr. Nazari, Dr. Rahman, Mr. Sencan), a seasoned and respected researcher in electrochemical sensor technology (Bill Van Antwerp, former CSO of Medtronic MiniMed), 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), clinical experts (Dr. Alan Ma...