Despite the availability of increasingly effective treatment modalities, including insulin analogues, continuous glucose monitors (CGMs), and continuous subcutaneous insulin infusion (CSII) devices, a substantial proportion of patients with type 1 diabetes (T1D) cannot achieve adequate glycemic control and avoid acute complications such as hypoglycemia. NIDDK has long supported this area of research, especially through small business projects, and this support has contributed substantially to the development of new devices that are increasingly used in clinical practice. Nonetheless, the approved devices and current technologies still have significant limitations, and it is important to put renewed emphasis on the creation of a next generation of devices that will further the goals of relieving patients of the burden of diabetes self-management and achieving daily euglycemia to prevent acute and chronic complications. Several relevant projects have been supported because of the release of similar FOAs in the recent past. However, given the pace of technical progress in this field and the substantial room for improvement in reliability, accuracy, and patient burden of current devices, NIDDK considers it important to continue supporting research in this field. This FOA is intended to support cutting edge research conducted by small business leading to the development of innovative technologies that may advance progress toward integrated, long term, wearable/implantable, glucose regulated open and closed loop insulin/pancreatic hormone delivery systems. This announcement has two main purposes: a) to promote technical innovation and b) to conduct pre-clinical testing of single or combined components of open and closed loop systems. Research topics that this announcement intends to attract include but are not limited to: 1. Glucose sensors and pancreatic hormones delivery systems: Novel, accurate, reliable and user-friendly sensor technologies for glucose and other metabolically relevant signals/analytes to optimize open and closed loop diabetes management. Development of new miniaturized, implantable or minimally invasive continuous glucose sensors with long functional life (at least 4 weeks), real time measurement, no or minimal need of recalibration, easily implanted and replaced, unobtrusive to the user and accurate at all ranges of glycemia. Novel technologies for prediction and accurate detection of hypoglycemia (<54 mg/dl) and optimized hypoglycemia alert and insulin suspension systems. Application of nanotechnology advances to the design of new glucose sensing and insulin delivery devices. Development of novel biocompatible smart biomaterials to be used for the manufacturing and for the functional improvement and durability of implantable devices. Development of highly concentrated and stable insulin formulations that are more rapidly absorbed for more physiological insulin replacement. Novel, more stable and user-friendly glucagon formulations for effective hypoglycemia treatment and able to be used in a closed loop system. New, more advanced insulin/glucagon delivery devices/pumps, external or implantable which are also able to be integrated in a closed loop system. Development of biocompatible and durable hormone infusion systems for more physiological delivery and more efficient hormone absorption with improved kinetics. Smarter pump technologies - pumps that directly or indirectly monitor and track administered insulin.. Development of injectable/implantable glucose regulated insulin/glucagon delivery systems/depots able to function in a homeostatic fashion that may last days/weeks. 2. Algorithms and Integrated Systems: Development of reliable and integrated algorithms that translate accurate glucose and other relevant metabolite measurements into changes in the delivery of pancreatic hormones to maintain glucose excursions within the physiological range and able to detect/correct failure of the closed loop system components. More effective, reliable, and integrated wireless/inter-device communication systems. Technologies that improve or facilitate visualization of data for analysis and more efficient/user friendly self-management, including personalized digital insulin dosing decision support systems for open loop treatment. Closed loop systems algorithms for the delivery of counter-regulatory hormones to prevent or correct hypoglycemia effectively. New devices able to integrate the sensing, controller, and delivery components in one unit. Remote monitoring systems to optimize performance and safety of integrated platforms 3. Pre-Clinical Testing: Optimized In-silico simulation models that may facilitate the design of proper clinical studies to test new devices and multivariable systems. Pre-clinical testing of components of an open or closed loop system.