Artificial Pancreas: from in-silico to in-vivo

Abstract Type 1 diabetes is a disease caused by an autoimmune reaction. The Artificial Pancreas (AP) is an automatic closed-loop system composed of a subcutaneous glucose sensor, a subcutaneous insulin pump and a device on which a control algorithm and a human interface are implemented. The last years have seen an accelerated improvement of these three components that became more reliable and compact, making the system safer, wearable, and usable in real life. An overview on AP and its components is presented together with an introduction on the in-silico tools used to develop and tune the control algorithm and to make pre-clinical tests. Particular attention is devoted to the design of a Model Predictive Control, to the choice of the model and of the constraints, and to the definition of the most relevant performance indices. Most of the choices have been driven by the experience gained by both in-silico and in-vivo trials. In-silico experiments involved thousand of hours of simulations on the Food and Drug Administration accepted simulator equipped with 100 adult virtual patients. In-vivo experiments, of which a complete list is presented, involved about forty thousand hours of trials, first, conducted in a clinical environment and, then, at home.

[1]  Giuseppe De Nicolao,et al.  MPC based Artificial Pancreas: Strategies for individualization and meal compensation , 2012, Annu. Rev. Control..

[2]  Claudio Cobelli,et al.  Automatic adaptation of basal therapy for Type 1 diabetic patients: a Run-to-Run approach , 2014 .

[3]  B. Wayne Bequette,et al.  Challenges and recent progress in the development of a closed-loop artificial pancreas , 2012, Annu. Rev. Control..

[4]  Claudio Cobelli,et al.  Multicenter closed-loop/hybrid meal bolus insulin delivery with type 1 diabetes. , 2014, Diabetes technology & therapeutics.

[5]  R. Hovorka Continuous glucose monitoring and closed‐loop systems , 2006, Diabetic medicine : a journal of the British Diabetic Association.

[6]  Robert G. Sutherlin,et al.  A Bihormonal Closed-Loop Artificial Pancreas for Type 1 Diabetes , 2010, Science Translational Medicine.

[7]  C. Cobelli,et al.  Artificial Pancreas: Past, Present, Future , 2011, Diabetes.

[8]  Roman Hovorka,et al.  Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study. , 2014, The lancet. Diabetes & endocrinology.

[9]  J. Stockman,et al.  Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial , 2011 .

[10]  E. Atlas,et al.  MD-Logic Artificial Pancreas System: A Pilot Study in Adults with Type 1 Diabetes Mellitus Running Title: Closed-Loop System In Type 1 Diabetes , 2010 .

[11]  C. C. Palerm,et al.  A Run-to-Run Control Strategy to Adjust Basal Insulin Infusion Rates in Type 1 Diabetes. , 2008, Journal of process control.

[12]  R.S. Parker,et al.  A model-based algorithm for blood glucose control in Type I diabetic patients , 1999, IEEE Transactions on Biomedical Engineering.

[13]  A H Clemens,et al.  The artificial beta cell--a continuous control of blood sugar by external regulation of insulin infusion (glucose controlled insulin infusion system). , 1974, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[14]  E. Atlas,et al.  MD-Logic Artificial Pancreas System , 2010, Diabetes Care.

[15]  Eyal Dassau,et al.  Multicenter closed-loop insulin delivery study points to challenges for keeping blood glucose in a safe range by a control algorithm in adults and adolescents with type 1 diabetes from various sites. , 2014, Diabetes technology & therapeutics.

[16]  Francis J. Doyle,et al.  Run-to-run control strategy for diabetes management , 2001, 2001 Conference Proceedings of the 23rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[17]  Francis J. Doyle,et al.  Run-to-run control of blood glucose concentrations for people with type 1 diabetes mellitus , 2006, IEEE Transactions on Biomedical Engineering.

[18]  Eyal Dassau,et al.  Modular Artificial β-Cell System: A Prototype for Clinical Research , 2008 .

[19]  David M Nathan,et al.  Outpatient glycemic control with a bionic pancreas in type 1 diabetes. , 2014, The New England journal of medicine.

[20]  Janet M. Allen,et al.  Day and Night Closed-Loop Control in Adults With Type 1 Diabetes , 2013, Diabetes Care.

[21]  Robert S. Parker,et al.  Advanced model predictive control (MPC) for type I diabetic patient blood glucose control , 2000, Proceedings of the 2000 American Control Conference. ACC (IEEE Cat. No.00CH36334).

[22]  Howard C. Zisser,et al.  Fully Integrated Artificial Pancreas in Type 1 Diabetes , 2012, Diabetes.

[23]  Борис П. Ковачев,et al.  Unified platform for monitoring and controlling blood glucose levels in diabetic patients , 2012 .

[24]  Gade Pandu Rangaiah,et al.  A Novel Multi-Objective Optimization based Experimental Design and its Application for Physiological Model of Type 1 Diabetes , 2012 .

[25]  Roman Hovorka Management of diabetes using adaptive control , 2005 .

[26]  Howard C. Zisser,et al.  Prandial Insulin Dosing Using Run-to-Run Control , 2007, Diabetes Care.

[27]  Marc D. Breton,et al.  Modular Closed-Loop Control of Diabetes , 2012, IEEE Transactions on Biomedical Engineering.

[28]  Eyal Dassau,et al.  Zone Model Predictive Control: A Strategy to Minimize Hyper- and Hypoglycemic Events , 2010, Journal of diabetes science and technology.

[29]  Claudio Cobelli,et al.  A Constrained Model Predictive Controller for an Artificial Pancreas , 2014 .

[30]  G. Steil,et al.  Feasibility of Automating Insulin Delivery for the Treatment of Type 1 Diabetes , 2006, Diabetes.

[31]  L. Magni,et al.  Multicenter outpatient dinner/overnight reduction of hypoglycemia and increased time of glucose in target with a wearable artificial pancreas using modular model predictive control in adults with type 1 diabetes , 2015, Diabetes, obesity & metabolism.

[32]  Antoine Robert,et al.  The Diabetes Assistant: A Smartphone-Based System for Real-Time Control of Blood Glucose , 2014 .

[33]  Marco Forgione,et al.  Run-to-Run Tuning of Model Predictive Control for Type 1 Diabetes Subjects: In Silico Trial , 2009, Journal of diabetes science and technology.

[34]  Efstratios N. Pistikopoulos,et al.  Model-based blood glucose control for type 1 diabetes via parametric programming , 2006, IEEE Transactions on Biomedical Engineering.

[35]  L. Magni,et al.  First Use of Model Predictive Control in Outpatient Wearable Artificial Pancreas , 2014, Diabetes Care.

[36]  Giuseppe De Nicolao,et al.  Model predictive control of glucose concentration in type I diabetic patients: An in silico trial , 2009, Biomed. Signal Process. Control..

[37]  Claudio Cobelli,et al.  Artificial Pancreas: Model Predictive Control Design from Clinical Experience , 2013, Journal of diabetes science and technology.

[38]  J. Leahy,et al.  Fully Automated Closed-Loop Insulin Delivery Versus Semiautomated Hybrid Control in Pediatric Patients With Type 1 Diabetes Using an Artificial Pancreas , 2008 .

[39]  Giovanni Sparacino,et al.  Diabetes: Models, Signals, and Control , 2009 .

[40]  Giordano Lanzola,et al.  Monitoring Artificial Pancreas Trials Through Agent-based Technologies , 2014, Journal of diabetes science and technology.

[41]  H. Zisser,et al.  Run-to-run control of meal-related insulin dosing. , 2005, Diabetes technology & therapeutics.

[42]  C. Cobelli,et al.  The UVA/PADOVA Type 1 Diabetes Simulator , 2014, Journal of diabetes science and technology.

[43]  Panagiotis D. Christofides,et al.  Improved postprandial glucose control with a customized Model Predictive Controller , 2015, 2015 American Control Conference (ACC).

[44]  Eyal Dassau,et al.  Control to Range for Diabetes: Functionality and Modular Architecture , 2009, Journal of diabetes science and technology.

[45]  R. Hovorka,et al.  Nonlinear model predictive control of glucose concentration in subjects with type 1 diabetes. , 2004, Physiological measurement.

[46]  Giordano Lanzola,et al.  Bringing the Artificial Pancreas Home: Telemedicine Aspects , 2011, Journal of diabetes science and technology.

[47]  Marc D. Breton,et al.  Safety of Outpatient Closed-Loop Control: First Randomized Crossover Trials of a Wearable Artificial Pancreas , 2014, Diabetes Care.

[48]  Giordano Lanzola,et al.  A generic telemedicine infrastructure for monitoring an artificial pancreas trial , 2013, Comput. Methods Programs Biomed..

[49]  L. Magni,et al.  Multinational Study of Subcutaneous Model-Predictive Closed-Loop Control in Type 1 Diabetes Mellitus: Summary of the Results , 2010, Journal of diabetes science and technology.

[50]  Francis J. Doyle,et al.  A run‐to‐run framework for prandial insulin dosing: handling real‐life uncertainty , 2007 .