PROJECT SUMMARY The long-term goal of this project is to develop a scalable, user-friendly, continuous glucose monitoring (CGM) system for better diabetes management. IMS has developed the world's smallest 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 current leading CGMs) including extreme miniaturization, on-chip integration of multiple sensors and processing electronics, improvement in signal-to-noise (SNR) ratio (thus improving hypoglycemia accuracy), and on-chip temperature calibration (improve accuracy, reliability by confirming the sensor is in the tissue, and performing on-site temperature calibration during sickness, exercise, and sleep). Moreover, the system uses extremely scalable semiconductor and flexible electronics manufacturing methods, increasing lot sizes by > 50,000x (simplifying factory calibration) and reducing cost (improving affordability and broadening usage). The proposed system is named CGM+ since it goes beyond just glucose monitoring (v1 measures glucose and temperature, v2 will measure glucose, ketones, temperature, and pH). Hence, the design is highly innovative. We have demonstrated the function of the CGM+ platform in humans in a First-In-Human (FIH) feasibility study in Phase II. Recently, we verified the feasibility of system operation for 14 days in a second human study (ongoing). Our objective in this CRP grant is to optimize the manufacturing and the quality framework to enable larger human studies, paving the way towards enabling an FDA IDE for approval trials. This work is significant as it will catalyze the commercialization of the first CGM+ system capable of the smallest needle insertion (28-gauge needle) that can work for a long time (>14 days) with factory calibration (no finger sticks). After the first approval, this system can be extended to include other 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), regulatory and IP expert (John Heithaus, JD), commercialization expert (Mr. Paul Strasma, former CEO of Capillary Biomedical which was recently acquired by Tandem Diabetes), clinical expert (Dr. Alan Marcus, MD; former Chief Medical Officer of Medtronic Diabetes), and a biosensors and biomaterials expert (Dr. Natalie Wisniewski, Ph.D., former CTO of Profusa, Inc.).