Control Theory in Biomedical Engineering: Applications in Physiology and Medical Robotics

Peru

Preface

Olfa Boubaker, University of Carthage, National Institute of Applied Sciences and Technology, Tunis, Tunisia

As I write the preface for this book, Control Theory in Biomedical Engineering, COVID-19 continues to spread, with more than 4 000 000 cases around the world and more than 270 000 deaths as declared the World Health Organization (WHO). In this crucial moment, when developed countries like the United State, Spain, the United Kingdom, Italy, France, Germany and Canada are facing difficult choices in their healthcare systems, regardless of their sophisticated biomedical systems, advanced robotic systems, and innovative technologies in resuscitation services. Developing countries with very modest medical materials but high-level medical skills, like Tunisia, are trying to control the crucial situation relying only on mathematical models of the pandemic. Restrictive confinement measures are being implemented as a way to control the spread of the virus. In all ways, control remains the target solution.

In China, however, where COVID-19 began as an epidemic before making its way around the world in a matter of months, no new domestic cases were reported. According to recent press reports, several sophisticated medical robots are being deployed there in an effort to combat the spread of the deadly virus. Robotics is being used to sanitize hospitals, some of which use ultraviolet light to clean, to reduce workers’ exposure to the virus as much as possible. Besides disinfection and street patrols, the robots are also deployed to deliver food and support nurses in communication with patients in quarantine to reduce human-to-human contact. Dancing robots lead patients in exercises and entertain bored quarantined patients. Robots are used to patrol public spaces to identify people who may be running a fever. Robots completely replaced humans in a coronavirus care hospital in Wuhan, China, where a humanoid robot worked 24/7 measuring heart rates and blood oxygen levels via smart bracelets and rings worn by patients.

Undoubtedly, mathematical modeling, control theory, and medical robotics are fundamental sciences for healthcare systems. Modeling-based control is of huge importance as it can be used to understand feedback paths in physiological systems, establish medical diagnoses, understand the interrelationship among physiological variables in the human body, and predict the dynamic behavior of some diseases and epidemics. They can contribute to regulate human physiology via commercial artificial organs and assistive technologies. Furthermore, control theory is probably of great significance in the pervasiveness of medical robots in surgery, exploration, diagnosis, and therapy. Control theory is absolutely at the heart of medical sciences and the future of medicine.

On one hand, the human body has a natural and autonomous control process responsible for maintaining human life called homoeostasis. Homeostasis is the property of a physiological system to regulate its internal environment to a given set point in the presence of specific stimulus-producing changes in that variable. The control process in the human body is ensured through the coordination of the control center and the natural sensors and effectors. The roster of vital parameters concerned by homeostasis is long and includes blood pressure, blood oxygen, heart rate, blood calcium, blood glucose, and so on. In this framework, there are several well-known examples of mathematical model-based control. The most eminent ones are the endocrine system, the immune system, the neurological system, the cardiac and pulmonary system, and the locomotor system. These models are widely used in the medical field and have shown great advances in prediction, diagnosis, and therapy. However, further progress is still expected for several domains, especially to prevent, detect, and control several chronic diseases (e.g., chronic respiratory diseases, cardiovascular diseases, diabetes mellitus, thyroid disease, cancers, HIV/AIDS, etc.) and to predict the evolution of and control devastating epidemics (severe acute respiratory syndrome (SARS), yellow fever, cholera, Ebola, hepatitis B, H1N1/09 virus, COVID-19, etc.).

On the other hand, control theory deeply impacts the everyday life of a large part of the human population like disabled and elderly people using assistive and rehabilitation robots for improving their quality of life and increasing their personal independence. For this large community, the body process requires external control laws in order to regulate its natural functions via artificial organs, including artificial arms, legs, pancreas, heart, lungs, liver, and so on, and assistive technologies, including wheelchairs, prostheses, walkers, exoskeletons, and companion robots.

Medical robotics has undergone a profound revolution in the past three decades. Nowadays, they are used to perform delicate surgical procedures in specific disciplines including orthopedics, urology, cardiac surgery, neurosurgery, ophthalmology, pediatric surgery, general surgery, and so on. Robots help in drug administration and disinfection duties and perform a growing number of other health tasks. Compared to manual machines in healthcare, medical robotic systems offer a wide range of advantages. They can eliminate human fatigue and contamination risk as well as improve dexterity, precision, and many other capabilities of doctors and surgeons. They reduce patient trauma, offer faster recovery, and limit scarring. The most widely used surgical robot worldwide is the da Vinci surgical system, which is used in 67 countries and used to perform more than 7.2 million surgical procedures.

This book is a timely and comprehensive guide for graduate students and researchers in both control engineering and biomedical engineering fields. It is also useful for medical students and practitioners who want to enhance their understanding of physiological processes and medical robotics. Written by eminent scientists in the field, this book is a unique reference illustrating the many facets of control theory in biomedical engineering through concrete examples.

It contains 12 chapters organized into two parts. Part I introduces applications of control theory in physiology, and Part II describes the related applications in medical robotics.

Chapter 1 presents key definitions and principles of modeling and control physiological systems. A comprehensive literature survey is compiled to provide an overall picture of this application area and reveals its impact in our human life. Challenges and future trends are also presented.

In Chapter 2, a simplified mathematical model of cholesterol homeostasis is introduced to describe the rate of changes in the cholesterol level in the blood and liver. The proposed model helps to understand causes of cholesterol homeostasis disorders, the different ways to lower its concentration, and possible investigations in its therapy.

Chapter 3 presents an artificial pancreas system for the treatment of type 1 diabetes. The proposed system is a fully automated insulin delivery system working with no meal and physical activity announcements. It uses an adaptive-learning model with a predictive control algorithm designed to compute a safe and optimal insulin amount.

Chapter 4 presents a mathematical model of tumor-immune interactions under chemotherapy treatment. The model is described by a system with delay differential equations and governed by an optimal control law. It shows the impact of the optimal treatment after few days of therapy.

In Chapter 5, a cardiac arrhythmia classification method based on the fuzzy logic controller and the genetic algorithm is introduced. The proposed approach is used to classify the MIT-BIH arrhythmia database recordings into five cardiac cases.

Chapter 6 reviews the handwriting models proposed in literature. The relationship between hand or/and forearm electromyography (EMG) signals and writing parameters is described. Advantages and drawbacks are summarized.

Chapter 7 highlights the impact of medical robotics to improve human abilities. Different classification approaches of these robots, including surgical robots, rehabilitation, and assistive devices, is presented via a historical viewpoint and a comprehensive survey of the literature.

In Chapter 8, the state of the art of wearable devices for upper limb amputees is presented. New directions are also exposed to go further in continuous development.

In Chapter 9, a review of existing upper limb exoskeletons was done to find key challenges that need to be solved for improved functionality.

Chapter 10 focuses on the human locomotion system and its complex dynamics. Double-pendulum based models are exploited to design controllers for walking on a treadmill. The step length, time, velocity, and position on the treadmill are considered as walking parameters. For the designed controllers, time series of those parameters are compared to real experimental data of human walking.

In Chapter 11, an inexpensive endoscope design for nasopharyngeal cancer investigation is introduced. This cancer is the most widespread one in Asia. The prototype is a small portable device with the main aim of being affordable and home-based. A comparison between the current nasopharyngoscope and the proposed prototype is evaluated via metrics and needs. A list of acceptance criteria is also specified to ensure safety regulations and effectiveness.

Chapter 12 proposes a new design of an emerging class of invertebrate-like continuum robots for minimal invasive surgery. It is a combined actuation and tunable stiffness mechanism obtained by using 3D-printed auxetic structures as well as origami and kirigami structures. It uses simple and cost-effective structures that can also be highly miniaturized.

In conclusion, control is a crucial theory in medicine and this book treats all the previous themes together in a very educational way. I owe an enormous debt of gratitude to all those who helped me through the years that have led up to this achievement. I want to thank EVERYONE who ever said anything positive to me or taught me something. I heard it all, and it meant something.

To Professor Mekki Ksouri from the National Engineering School of Tunis and Private Higher School of Engineering and Technology, Tunisia, thank you for being a leader in whom I have confidence, honor, and respect. I will always be happy to have been your PhD student, part of your research team, and having had the chance to represent you. Your training and guidance in control theory were of undeniable value.

Thank you to everyone who strives to grow and help others grow with generosity. All my thoughts go here to Professor Hichem Kallel from the National Institute of Applied Sciences and Technology, Tunisia, who initiated my training in robotics and helped me to progress in this field. To Professor Quanmin Zhu from the University of the West of England, Bristol, UK, thank you for the undeniable encouragement and generosity, which were essential for my last five books. I greatly appreciate your guidance, support, and friendship, and perhaps most of all, your examples.

The following researchers are particularly acknowledged for the honor they bestowed upon me by contributing artwork and for their professional efforts to provide comments and reviews: Professor Hongliang Ren from the National University of Singapore, Singapore; Emeritus Professor Mohamed Benrejeb from the National Engineering School of Tunis, Tunisia; and Professor Ali Cinar from the Illinois Institute of Technology, USA.

I am also immensely grateful to everyone on the Elsevier editorial team who helped me so much. Special thanks to the ever patient Acquisitions Editor Sonnini Yura, from Brazil, who was behind the idea of editing this book, Mariana Henriques, from Brazil, the amazing Editorial Project Manager for her help, guidance and for being a great cover designer, and Kamesh Ramajogi, the production project manager from India, for his patience and skills.

Thanks to my former doctoral student, Dr. Abir Lassoued, Assistant Professor at the National School of Engineers of Tunis, Tunisia, for all didactic efforts to design many diagrams and figures joining control theory to physiology.

Finally, thanks to my daughter, Sarra Boubaker, External Doctor at the Faculty of Medicine of Sousse, Tunisia, for her continuous encouragement, but mostly for fruitful discussions and comments on the accuracy and proof of medical information.

Part I

Applications in physiology

Chapter 1

Modeling and control in physiology

Abir Lassoued; Olfa Boubaker    University of Carthage, National Institute of Applied Sciences and Technology, Tunis, Tunisia

Abstract

Mathematical modeling and control theory in physiology is a rather new area of research compared to other control applications such as chemical processes, robotics and aerospace. Yet, several significant developments have recently emerged. As control theory is in the center of future medicine, and to have a better understanding of these complex processes, this chapter presents a comprehensive literature survey of recent developments in mathematical modeling and control of physiological systems. These new investigations and results are of great importance as they can be used by doctors to establish a diagnosis, to understand the interrelationship among physiological variables and to predict the dynamic behavior of some diseases. Furthermore, the human body contains a natural and autonomous control process that can maintain human life and, in many cases, certain failures in the body process require external control laws in order to regulate its natural behavior via commercial artificial organs and assistive technologies. In this chapter, more than 200 references in the open literature are compiled to provide an overall picture of this application area in control theory and reveal its wealth and significance. Challenges and future trends based on the review of this research field are also expanded.

Keywords

Artificial organs; Biomedical applications; Chaos in physiology; Control theory; Control in physiology; Control-based modeling in physiology; Homeostasis; Mathematical modeling; Practical and structural identifiability; Physiological systems

1 Introduction

According to World Health Organization (WHO) statistics for 2019, the major causes of death in the world are cardiovascular diseases, cancer and infectious diseases (World Health Organization, 2019). To have a better understanding of these physiological processes, it is imperative to describe these complex systems by mathematical models. Indeed, many challenging problems are still pending for which these models can be exploited in several contexts, namely to help doctors to establish a diagnosis, to understand the interrelationship among physiological variables and to predict the dynamic behavior of some diseases.

Modeling physiological systems has a long history interconnected with the history of medicine. In this field, the research work of Denis Noble in 1960 on cardiac cell mode (Noble, 1960) can be considered as the cornerstone for the development of the current research works related to modeling in biomedical engineering. Various research works related to mathematical modeling in physiology have been proposed since then, leading to an extensive bibliography revealing the prosperity of this field. These include a handbook (Bronzino, 1999), several valuable books (Ottesen and Danielsen, 2000; Beuter et al., 2003; Ottesen et al., 2004; Takeuchi et al., 2007; Cherruault, 2012; Banks, 2013; Hacısalihzade, 2013; Carson and Cobelli, 2014; Reisman et al., 2018; Cobelli and Carson, 2008; Devasahayam, 2012; Sanft and Walter, 2020), a number of survey papers (Brown, 1980; Bekey and Beneken, 1978; Perelson, 2002; Makroglou et al., 2006; Boutayeb and Chetouani, 2006; Anderson and Quaranta, 2008; Leng and MacGregor, 2008; Bertram, 2011; Glynn et al., 2014; Chowell et al., 2016; Zavala et al., 2019), and software tools (Hester et al., 2011). Mathematical models in biology (Roberts, 1976; Brown and Rothery, 1993; Allman and Rhodes, 2004; Edelstein-Keshet, 2005) can be categorized into several classes: linear and nonlinear models, continuous or discrete models, deterministic or stochastic models, parametric or nonparametric models, and lumped or distributed parameter models.

The human body contains a natural and autonomous control process that can maintain human life (Cherruault, 2012; Banks, 2013; Hacısalihzade, 2013). However, in many cases, certain failures in the body process require external control laws in order to regulate its natural behavior (Morari and Gentilini, 2001; Iii et al., 2011). The external controllers can be based on different control algorithms such as predictive, adaptive and optimal control laws principles (Swan, 1981; Hajizadeh et al., 2018; Turksoy and Cinar, 2014). These different types of controllers can be also applied in commercial artificial organs and assistive technologies in order to simulate natural human functions (Turksoy and Cinar, 2014; Smith et al., 2018).

This chapter provides comprehensive information on mathematical modeling and control-based modeling in physiology in order to explain the complexity of the human body process. In addition, the chapter examines challenges in this wealth domain.

The chapter is structured as follows. Section 2 presents a comprehensive review of mathematical modeling in physiology. Section 3 investigates various control principles by pointing out their applications in physiology. Finally, Section 4 provides the possible challenges for modeling and controlling systems in medicine. It also describes commercial artificial organs and assistive technologies that guarantee easier life for patients.

2 Mathematical modeling in physiology

A physiological model is a mathematical representation that approximates the behavior of an actual physiological system. Physiological models can serve mainly for the following purposes: (1) to understand the physiological system, (2) to predict its dynamics, and (3) to control the system under desirable conditions. However, the main problem in physiological systems is to find the appropriate mathematical models to describe real problems, especially disease dynamics. In fact, mathematical modeling represents a valuable tool for understanding the human body processes.

2.1 Modeling methodology

Fig. 1 describes the modeling process generally adopted for designing mathematical models for physiological systems (Kuttler, 2009). There are various modeling approaches and their number is still increasing. Some modeling methods were based on linear systems due to their simplicity analysis. However, nonlinearities are ubiquitous in physiology. Peculiar critical aspects of physiology should be described and analyzed by nonlinear systems. The nonlinear dynamic of physiological systems is a daunting challenge owing to its considerable complexity. In the following, we present the main modeling approaches and some classes of mathematical models in physiology. We also include some examples of applications of mathematical models in physiology.

Fig. 1 The modeling process for real physiological problems. (The figure has been adopted from Kuttler, C., 2009. Mathematical Models in Biology.)

2.2 Modeling approaches

There are different modeling approaches in the literature for physiological systems (Ottesen and Danielsen, 2000; Ottesen et al., 2004; Takeuchi et al., 2007; Cobelli and Carson, 2008; Carson and Cobelli, 2014). Of them, the compartmental approach is the most familiar. In this subsection, we describe the most recognizable approaches.

2.2.1 Compartmental modeling approach

The compartmental modeling approach is the most familiar and one of the oldest approaches used to describe interactions between physiological variables. For more details about this approach, see the survey paper by Brown (1980), Compartmental Modeling and Tracer Kinetics (Anderson, 2013), Compartmental Analysis in Biology and Medicine (Jacquez, 1972), and chapter 7 in Introduction to Biomedical Engineering (Enderle and Bronzino, 2012). In this framework, several applications in different areas of physiology were represented by the compartmental approach, such as in diabetes dynamics (Chiarella and Shannon, 1986), the respiratory system (Similowski and Bates, 1991), tumor resistance to chemotherapy (Alvarez-Arenas et al., 2019), metabolic systems (Cobelli and Foster, 1998; Staub et al., 2003), pharmacokinetics (Garcia-Sevilla et al., 2012b), and so on. A software tool allowing implementation of linear compartmental models is also available and is described in Garcia-Sevilla et al. (2012a).

Compartmental modeling is very attractive to users because it formalizes physical intuition in a simple and reasonable way. According to this method, the governing law is conservation of mass. Compartmental models are lumped parameter models, in that the events in the system are described by a finite number of changing variables (Cobelli and Foster, 1998). Each compartment characterizes both the physical-chemical proprieties and its environment and the corresponding mathematical model is a collection of ordinary differential equations (ODEs). Each equation defines the time rate of change of amount material in a particular compartment. Thus, the basic equations of compartment model with n compartments are defined as (Brown, 1980):

where xi is the amount of material in compartment i, xi0 is its corresponding initial value and fji is the mass flow rate of compartment j from compartment i. Fig. 2 illustrates the compartment structure. The index 0 denotes the environment of the physiological system.

Fig. 2 Basic compartment structure. (The figure has been modified from Brown, R.F., 1980. Compartmental system analysis: state of the art. IEEE Trans. Biomed. Eng.)

2.2.2 Equivalent modeling approach

The main goal of the equivalent approach is to describe physiological systems by using equivalent physical systems such as electrical or mechanical systems. The equivalent models are used in physiology to simplify their dynamic analysis. Each variable in a physical system has its corresponding variable in an analog physical system. In the literature, some basic physiological measurements have their analog physical variables (Aidley, 1998). Table 1 describes some of these.

Table 1

In neurophysiology and cell physiology the use of equivalent circuits is well known, where the classic examples are circuits simulating the generation of membrane potential (Aidley, 1998), the cable properties of nerve and muscle fibers, and action potential and neuromuscular transmission. Using analogue circuits to model and simulate physiological systems is also considered as a modern approach for teaching physiology to postgraduate medical students. The aim is to promote qualitative as well as quantitative analogue thinking about physiological processes (Rupnik et al., 2001; Ribarič and Kordaš, 2011; Sever et al., 2014).

In the last decades, particular physiological systems were modeled by equivalent electronic circuits such a pulmonary ventilation (Ghafarian et al., 2016) and blood circulation (Ismail et al., 2018). In Ismail et al. (2018), for example, to understand the cardiovascular system, the thermodynamics of vessels was represented by an electronic circuit as described in Fig. 3. In this circuit, the voltage represents the blood pressure when the current represents the blood flow. C and R are the compliance and the resistance of the systemic arterial tree, respectively. L is the impedance of proximal aorta.

Fig. 3 Equivalent electronic circuit of blood vessels system.

For the use of mechanical equivalent models, several systems are also proposed. For example, the reader can found a pneumatic model given for the respiratory system (Shi et al., 2016) and a mass-spring-damper inverted pendulum model for a bipedal-compliant walking system (Joe and Oh, 2019). The related model is given in Fig. 4.

Fig. 4 Equivalent mechanical model of the human bipedal walking process. (The figure has been adopted from Joe, H.M., Oh, J.H., 2019. A robust balance-control framework for the terrain-blind bipedal walking of a humanoid robot on unknown and uneven terrain. Sensors 19 (19), 4194.)

2.2.3 Data-driven modeling approach

Data-driven modeling (DDM) approach is an empirical approach that does not involve mathematical equations derived from physical processes but instead involves analysis of time series data. Examples include linear regression models and popular biologically inspired computational models including neural networks and genetic algorithms. DDM is based on analyzing the data about input, internal and output variables of a system without explicit knowledge of the physical behavior as described by Fig. 5. The availability of sufficient patient historical data has paved the way for the introduction of machine learning and its application for intelligent and improved systems for diabetes management (Dutta et al., 2018; Paoletti et al., 2019), immunology (Fong et al., 2018), brain diseases (Karim et al. 2018; Oxtoby et al., 2018), and so