The artificial pancreas (AP), known as closed-loop control of blood glucose in diabetes, is a system combining a glucose sensor, a control algorithm, and an insulin infusion device. AP developments can be traced back 50 years to when the possibility for external blood glucose regulation was established by studies in individuals with type 1 diabetes using intravenous glucose measurement and infusion of insulin and glucose. After the pioneering work by Kadish (1) in 1964, expectations for effectively closing the loop were inspired by the nearly simultaneous work of five teams reporting closedloop control results between 1974 and 1978: Albisser et al.(2), Pfeiffer et al.(3), Mirouze et al.(4), Kraegen et al.(5), and Shichiri et al.(6). In 1977, one of these realizations (3) resulted in the first commercial device—the Biostator (7; Fig. 1), followed by another inpatient system, the Nikkiso STG-22 Blood Glucose Controller, now in use in Japan (8). Although the intravenous route of glucose sensing and insulin infusion is unsuitable for outpatient use, these devices proved the feasibility of external glucose control and stimulated further technology development. Figure 2 presents key milestones in the timeline of AP progress. In 1979, landmark studies by Pickup et al.(9) and Tamborlane et al.(10) showed that the subcutaneous route was feasible for continuous insulin delivery. Three years later, Shichiri et al.(11) tested a prototype of a wearable AP, which was further developed in subsequent studies (12, 13). In the late 1980s, an implantable system was introduced using intravenous glucose sensing and intraperitoneal insulin infusion (14). This technology was further developed, leading to clinical trials and long-term use (15, 16); however, its clinical application remained limited because of the extensive surgical procedures needed for sensor and pump implantation. In all early intravenous and intraperitoneal AP systems, the closed-loop control algorithms belonged to a class known as proportional-derivative controllers, which used blood glucose values and blood glucose rate of change in a relatively straightforward calculation of insulin dose. However, as it is explained later in this article, proportionalderivative control and its enhanced version, proportionalintegral-derivative control, have inherent limitations that hinder their use in subcutaneous systems because of unavoidable time lags in subcutaneous glucose sensing and insulin action. Newer controllers, known as model-predictive control (MPC), avoid these limitations by using a mathematical model of the metabolic system of the person being controlled in their calculations. Many of these MPC algorithms are based on another 1979 milestone, the Minimal Model of Glucose Kinetics (17). Thus, since the early years of AP development, glucose sensing and insulin delivery technologies were accompanied by computer modeling and simulation (18–22). Review of methods for glucose control prior to 2000 can be found in two concurrent papers (23, 24).

The new wave—subcutaneous AP—developed after minimally invasive subcutaneous glucose sensing was commercially introduced in 1999 by the MiniMed continuous glucose monitoring (CGM) system. This set off an accelerating academic and industrial effort focused on the development of a subcutaneous-subcutaneous system (Fig. 2). The MiniMed (later, Medtronic) closed-loop project was the first to provide evidence for the feasibility of the subcutaneous-subcutaneous route for fully automated blood glucose control in type 1 diabetic patients (25). The 3-year ADICOL project funded by the European Commission showed the feasibility of using advanced MPC strategies …