Patient-Specific Controller for an Implantable Artificial Pancreas

97 Pages·2019·2.897 MB·English

by  Yvonne Ho

Springer Theses
Recognizing Outstanding Ph.D. Research
Yvonne Ho
Patient-Specific
Controller for
an Implantable
Artificial
Pancreas
Springer Theses
Recognizing Outstanding Ph.D. Research
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Yvonne Ho
fi
Patient-Speci c Controller
for an Implantable
fi
Arti cial Pancreas
Doctoral Thesis accepted by
the National University of Singapore, Singapore
123
Author Supervisor
Dr. Yvonne Ho Prof. Chee-KongChui
Department ofMechanical Engineering Department ofMechanical Engineering
National University ofSingapore National University ofSingapore
Singapore, Singapore Singapore, Singapore
ISSN 2190-5053 ISSN 2190-5061 (electronic)
SpringerTheses
ISBN978-981-13-2401-7 ISBN978-981-13-2402-4 (eBook)
https://doi.org/10.1007/978-981-13-2402-4
LibraryofCongressControlNumber:2018952888
©SpringerNatureSingaporePteLtd.2019
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’
Supervisor s Foreword
Artificialpancreasthatcanprovidetightbloodglucosecontrolforadiabeticisone
of the most challenging problems of engineering in medicine. This book by Dr.
Yvonne Ho will be an especially useful reference book for those working on
diabetes mellitus and artificial pancreas. After an introductory chapter, which
includesashortsummaryofthebackgroundofthisresearchtopic,Chap.2presents
a detailed description about diabetes mellitus andits related physiology. Chapter 3
presents a state-of-the-art review of the various treatment options. The emphasis
oftheremainingchaptersisonnewresultsfromtheresearchanddevelopmentofan
implantable artificial pancreas. The implantable artificial pancreas regulates blood
glucose level by delivering appropriate dosage of insulin when necessary. By
sensing the blood glucose and injecting insulin directly into the vein, the implan-
table device aims to remove delays from subcutaneous blood glucose sensing and
insulin delivery. Preliminary in vitro and in vivo experimental results suggest that
the implantable approach for blood glucose control could be a clinically viable
alternative to pancreas transplant. There is deep knowledge in the modeling and
control of blood glucose level as well as design of implantable devices. This book
should provide a valuable addition to the library of the scientist and engineer
working at the interface of engineering and medicine.
Singapore Chee-Kong Chui
January 2018
v
Parts of this thesis have been published in the following articles:
Yvonne Ho, Binh P. Nguyen, Chee-Kong Chui, “Ant colony optimization for
model predictive control for blood glucose regulation”, SoICT ’12: Proceedings
of the Third Symposium on Information and Communication Technology, 2012
Binh P. Nguyen, Yvonne Ho, Zimei Wu, Chee-Kong Chui, “Implementation of
model predictive control with modified minimal model on low-power RISC
microcontrollers”,SoICT’12:ProceedingsoftheThirdSymposiumonInformation
and Communication Technology, 2012
Chee-Kong Chui, Binh P. Nguyen, Yvonne Ho, Zimei Wu, Mai Nguyen,
Geok-SoonHong,DanielMok,SumeiSun,StephenChang,“EmbeddedReal-Time
Model Predictive Control for Glucose Regulation”, World Congress on Medical
Physics and Biomedical Engineering, Beijing, China, 2012
Yvonne Ho, Chee-Kong Chui, Daniel Mok, Sumei Sun, Stephen Chang. “Fluidic
Flow Connection Designs for Venous Delivery of an Artificial Pancreas”, World
Congress on Medical Physics and Biomedical Engineering, Beijing, China, 2012
Presented but not published
vii
Acknowledgements
These past few years have been an interesting journey and I have learned and
gained much fromthe experience. Iwould like toexpressmythanks and gratitude
to people whose support and influence were invaluable.
First,IwouldliketoexpressmydeepestgratitudetomysupervisorAssoc.Prof.
Chui Chee Kong, for his guidance, advice, and most of all for his patience and
kindness.Itrulyappreciatethetimehetookfordiscussions,andforallthesupport
and research opportunities he has given.
ThanksalsotomycollaboratorsintheBRICGSproject.ToDr.BenMa(MaDi),
Mr.DanielMok,Dr.HoChinKeong,andDr.SunSumeifortheircontributionsand
knowledge shared. Dr. Stephen Chang from NUHS for his advice and expertise
sharedaboutsurgeryandimplantation.Dr.EricKhoofromNUHSforsharingabout
diabetesandforprovidingthepatientdatafortheparameter estimation. Ms.Wang
Xiaoyan in NUHS for kindly arrangingexperiments and laboratory analysis.
EspecialthankstoDr.NguyenPhuBinhandDr.WuZimeibothofwhoseworks
havelaidthefoundationforthiswork.Inaddition,toDr.NguyenPhuBinhforhis
computing expertise willingly shared, and also for much advise on writing and
research. And to Dr. Wu Zimei for her kind instruction, guidance, and much
supportshehasextended.ToMs.MaiNguyenfortakingtimeafterhergraduation
toprovidedetailsandanswermyqueriesaboutherFYP.AlsotoDr.LuciaSantoso
for discussion and materials about blood glucose regulation.
TomylabmatesMr.ChngChinBoon,Dr.MatthewChua,Dr.LeeChunSiong,
Ms. See Hian Hian, Dr. Xiong Linfei, and Dr. Wu Jichuan for their friendship,
camaraderie, advise, technical discussions, and life discussions, without whom the
timeinthelabwouldhavebeenverydull.ToAdrianOliveiro,ChuaSohAnn,and
FooMeiYengfortheirfriendship,love, companionship,alisteningear,andnever
ending encouragement.
Andmostofall,thankstomyparents,withoutwhosesupportIwouldnoteven
have embarked on this endeavor.
ix
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1.1 Diabetes Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.1.2 Blood Glucose Measurement and Monitoring . . . . . . . . . . 3
1.2 Artificial Pancreas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3 Patient Specific Controllers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.4 Objective and Scope. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.5 Thesis Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2 Glucose Metabolism and Diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.1 Glucose and Its Utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.2 Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.3 Diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3 Literature Review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.1 Artificial Pancreas State of the Art. . . . . . . . . . . . . . . . . . . . . . . . 19
3.1.1 Blood Glucose Measurement . . . . . . . . . . . . . . . . . . . . . . 21
3.1.2 Insulin Delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.2 Control Schemes for Blood Glucose Regulation. . . . . . . . . . . . . . 24
3.2.1 Optimization Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.3 Mathematical Models and Modeling of Glucose-Insulin
System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.3.1 Parameter Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4 Design of an Implantable Artificial Pancreas . . . . . . . . . . . . . . . . . . 35
4.1 Design Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
4.2 Design Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
xi
xii Contents
4.2.1 Glucose Sensing and Insulin Delivery. . . . . . . . . . . . . . . . 38
4.2.2 Electronics and Embedded Software . . . . . . . . . . . . . . . . . 39
4.3 Scalable Micropump Units and Insulin Reservoir . . . . . . . . . . . . . 40
4.3.1 Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4.4 Fluidic Connections for Insulin Delivery . . . . . . . . . . . . . . . . . . . 42
4.4.1 Experiments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.5 Discussion and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5 Model Predictive Controller using Interior Point and Ant
Algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
5.1 Model Predictive Controller . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
5.1.1 MPC with Constraints . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.2 Optimization Methods for MPC . . . . . . . . . . . . . . . . . . . . . . . . . 52
5.2.1 Primal-Dual Interior Point Method . . . . . . . . . . . . . . . . . . 52
5.2.2 Ant Algorithm for Optimization in MPC. . . . . . . . . . . . . . 53
5.3 MPC-on-a-Chip Implementation . . . . . . . . . . . . . . . . . . . . . . . . . 54
5.4 Experimental Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
5.4.1 Modified Minimal Model. . . . . . . . . . . . . . . . . . . . . . . . . 55
5.4.2 UVa/Padova Simulator Virtual Patient . . . . . . . . . . . . . . . 56
5.5 Discussion and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
6 In Vivo Experiment of the Implantable Artificial Pancreas . . . . . . . 63
6.1 Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
6.2 Implantable Artificial Pancreas Prototype. . . . . . . . . . . . . . . . . . . 63
6.3 Experimental Method and Results . . . . . . . . . . . . . . . . . . . . . . . . 65
6.4 Discussion and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
7 Parameter Estimation for Nonlinear Mathematical Model . . . . . . . . 69
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
7.1.1 Minimal Model for Glucose-Insulin Dynamics . . . . . . . . . 70
7.2 Experimental Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
7.2.1 Preprocessing of Data Sequences . . . . . . . . . . . . . . . . . . . 71
7.2.2 Nonlinear Least Squares. . . . . . . . . . . . . . . . . . . . . . . . . . 72
7.3 Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.3.1 Virtual Patient Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
7.3.2 Free-Living Patient Data . . . . . . . . . . . . . . . . . . . . . . . . . 75
7.4 Discussion and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
8 Conclusion and Future Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
8.1 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
8.2 Future Work. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83