Force controlled biomanipulation for biological cell mechanics studies

Force-controlled Biomanipulation for Biological Cell Mechanics Studies Nam Joo Hoo (B Tech., NUS) A thesis submitted for the degree of Doctor of Philosophy Department of Mechanical Engineering National University of Singapore 2011 Acknowledgments This thesis would not have been possible without the guidance and support of many people who in one way or another contributed and extended their valuable assistance in the preparation and completion of this study I am heartily thankful to my supervisor, Asst Prof Peter Chen Chao Yu from Department of Mechanical Engineering, National University of Singapore, and my co-supervisor, Dr Lin Wei from Singapore Institute of Manufacturing Technology (SIMTech), for their invaluable encouragement, enthusiasm and guidance from the initial to the final level of this project Without their knowledge and support, this thesis would not have been successful I would like to express my appreciation to Dr Yang Guilin, Dr Luo Hong, Dr Lin Wenjong, Dr Chen Wenjie, Ms Lu Haijing, Mr Ng Chuen Leong, Mr Wong Lye Seng and all other staffs from SIMTech, for sharing their knowledge and invaluable assistance Special thanks also to Prof Franck Alexis Chollet, Mr Hoong Sin Poh, Mr Wong Kim Chong, Mr Pek Soo Siong, Mr Ho Kar Kiat, Mr Nordin Bin Abdul Kassim and all others staffs from Micromachines Lab, Nanyang Technological University, for their technical guidance and assistance I would like to thank A/P Ge RuoWen, Mr Yan Tie, Mr Subhas Balan, Miss Li i ACKNOWLEDGMENTS Yan and Mr Nilesh Kumar Mahajan from Department of Biological Science, National University of Singapore, for preparation of the zebrafish embryos and micropipettes Last but not the least, I wish to thank all my fellow colleagues, especially group members; Lu Zhe, Zhou Shengfeng, Sahan Christie Bandara Herath, Yang Tao, Chua Yuanwei, Nellore Sri Vittal and all the staffs from Control and Mechatronics Lab, for their friendship, assistance and kindness Finally, my deepest gratitude goes to my beloved wife and families, for their understanding, emotional support and endless love, through the duration of my studies I would like to acknowledge the financial support from the Singapore Ministry of Education under research grant R265000249112 Lastly, I would like to take this opportunity to offer my regards and blessings to all of those who supported me in any respect during the completion of the thesis ii Table of Contents Acknowledgments i Table of Contents iii Summary vii Publications x List of Tables xiii List of Figures xiv Introduction 1.1 Mechanobiology, Mechanosensing and Mechanotransduction 1.1.1 Mechanoinduced Variation in Cellular Properties 1.2 The needs of force sensing and control in biomanipulation 1.3 Motivation and Objectives 10 1.4 Organization of the thesis 15 iii TABLE OF CONTENTS Background and Literature Review 2.1 17 Mechanosensors 18 2.1.1 Membrane Potential 22 2.1.2 Surface Charge and Double Layer 24 2.2 Zebrafish Chorion Architecture 26 2.3 Devices and Techniques for Mechanotransduction Study 30 2.3.1 2.3.2 Microelectromechanical (MEMS) 33 2.3.3 2.4 Atomic Force Microscope (AFM) 31 Micropipette Aspiration 35 Concluding Remarks 37 The Viscoelastic Nature of Zebrafish Chorion 39 3.1 Introduction 40 3.2 Linear Viscoelastic Models 42 3.2.1 3.2.2 Voigt Model 46 3.2.3 3.3 Maxwell Model 44 The Maxwell-Weichert Model 48 Viscoelastic Model of Zebrafish Chorion 51 3.3.1 3.3.2 Results 55 3.3.3 3.4 Experiment Setup 51 Discussion 56 Concluding Remarks 59 iv TABLE OF CONTENTS Explicit Force-feedback Controlled System 60 4.1 Introduction 61 4.2 Explicit Force-Controlled System for Mechanotransduction 62 4.2.1 4.2.2 Force Transmission 64 4.2.3 4.3 Force Generation 63 Force Sensing 77 Force Control 82 4.3.1 4.3.2 PID Explicit Force Control 82 4.3.3 4.4 Dynamic Model of Force Transmission stage 82 Robust Explicit Force Control 86 Concluding Remarks 95 Mechano-induced Change in Electrical Property of Cellular Organism: Variation in Impedance of Zebrafish Embryos by Explicit Force Feedback Control 99 5.1 Introduction 100 5.2 Motivation and Objective 101 5.3 Materials and Methods 102 5.3.1 Collection of Zebrafish Embryos 102 5.3.2 Electrochemical Impedance Measurement 103 5.3.3 Force Control 112 5.4 Results and Discussion 112 5.5 Concluding Remarks 117 v TABLE OF CONTENTS Mechano-induced Change in Mechanical Property of Cellular Organism: Reduction in Zebrafish Chorion Stiffness by External Perturbation 119 6.1 Introduction 120 6.2 Motivation 122 6.3 Materials and Methods 123 6.3.1 6.3.2 Force Control 124 6.3.3 6.4 Young’s Modulus Determination 123 Methodology 125 Results and Discussion 126 6.4.1 Influences of Step Perturbation on the Stiffness of Zebrafish Chorion 126 6.4.2 Influences of Periodic Forces on the Stiffness of Zebrafish Chorion 131 6.5 Concluding Remarks 135 Conclusion and Future Direction 138 7.1 Concluding Discussion 139 7.2 Contribution 142 7.3 Future Direction 145 Bibliography 147 vi Summary Constantly exposed to various forms of mechanical forces inherent in their physical environment, cellular organisms are able to sense such forces and convert them into biochemical signals through the processes of mechanosensing and mechanotransduction The two processes eventually lead to physiological and pathological changes in their internal structures and activities The effect might manifest in changes of the physiological properties, such as stiffness and impedance, of the organism This suggests that timely application of appropriate external forces may be used as a means to directly manipulate the dynamics of the internal processes (e.g., cell division and gene expression) of a cellular organism, which leads to the ultimate objective of mechano-control of biological systems Quantitative investigation of how cellular organisms respond to mechanical force requires proper sensing and control of an applied mechanical force to the organisms and simultaneously measure changes in their physiological properties However, an engineering challenge remain in explicitly controlling the applied force to achieve force regulation and trajectory tracking without causing damage to the internal or external structures of the organism This thesis explores the development of an explicit force-controlled system which is capable of applying and controlling a prescribed force on a zebrafish embryo accurately The vii SUMMARY established explicit force-controlled system consists of a linear voice-coil actuator for force generation, a micro-indenter equipped with a piezoresistive microforce sensor for applying a prescribed force on the cellular surface, and a compound flexure stage for transmitting the force from the voice coil actuator to the micro-indenter The interaction force between the micro-indenter and the cellular surface is measured and feedback to the controller by the micro-force sensor The explicit force-controlled system is able to apply an indentation force that can be controlled in magnitude and different types of force trajectory (e.g., step, sinusoidal, and rectangular), with various durations or frequencies, directly on the zebrafish embryo In this thesis, a series of experiments have been conducted to detect and investigate, in a quantitative manner, the mechano-induced variation in the physiological properties of a zebrafish chorion The purpose of this thesis is not to explain how any particular mechanotransduction pathway is operated, but rather to explore the dynamic changes in the physiological properties (e.g., the real-time force-induced variation in the stiffness and impedance) of a cellular organism when the organism encounters changes in its external loadings from its mechanical environment, especially in the dynamics of the cellular responses to indentation force The experimental data provides evidence supporting the hypothesis that certain physiological properties of some cellular organisms can be modified by applying an appropriate mechanical force The findings provide a basic milestone for future study to reveal the correlation between the changes in cellular physiological properties and the possible signalling pathways of the organisms (e.g., the zebrafish embryo) in response to an external mechanical force To the best knowledge of the author, no studies of the dynamics behaviours and influence viii SUMMARY of the external forces, of different rates or frequencies, on the physiological properties of zebrafish embryos were previously undertaken The experimental setup and method proposed in this thesis therefore provide a useful approach for the study of the interactions involving the rheological and physical properties of a cellular organism Moreover, it is now an important emerging area of research in mechanotransduction, and the approach proposed in this thesis could also be used to study the mechanism of cellular biomechanical response and signal transduction pathway in more detail, which ultimately may allow the clinicians to alter the biological functions and disease properties by applying suitable mechanical force directly, leading to a new strategy for treatment ix 7.3 Future Direction ness The experimental results from and above point to the possibility for manipulating cellular biological functions though direct control of an external mechanical force 7.3 Future Direction Improvements in imaging and observation devices Although the experimental results obtained in this thesis have demonstrated that the physical properties of zebrafish chorion can be experimentally altered in response to mechanical forces, extensive works still need to be done to create a coherent theory of the signalling pathway processes For example, the experimental results reported in Chapter provide evidence to support a plausible explanation that activities of pore canals and pore plugs in the chorion are responsible for the observed change in impedance Nevertheless, further research beyond this initial results are needed to understand the in-vivo mechanotranduction and mechanosensing mechanisms related to the ion influxes for further study of mechano-control of biological systems In future studies, the experimental set-up described in Chapter and can be improved by integrating the explicit force-controlled system with a high resolution imaging device, such as SEM, fluorescence microscopy, or commercialised voltage-clamped apparatus, that can enable researchers to observe the dynamic behaviours of the pore canals, pore plugs, and glycoprotein networks in realtime 145 7.3 Future Direction Viscoelastic model In Chapter 3, the viscoelastic model of the zebrafish chorion membrane to an indentation force had been developed, and its response to the force had been analysed with a linear viscoelastic model Since zebrafish chorion are considerably complex, the objective is to use a simplest model that may adequately account for the experimental findings From the analysis, the model, derived from the Maxwell-Weichert viscoelastic model (Figure 3.6), adequately represented the response of zebrafish chorion to an indentation force However, even in the event that the linear analysis for the applied forces correctly reflects the response of the zebrafish chorion, beyond a certain limit, the relationship would break down since the chorion would be damaged or destroyed Furthermore, as suggested in some literatures [12, 15, 42, 69, 78, 86, 158], mechanical forces may manifest the structural heterogeneity of the cellular organisms In order to determine the dynamic behaviours of zebrafish chorion accurately, as the extension of Chapter and 6, the viscoelastics model that governs the cellular reorganisation of the zebrafish chorion in response to mechanical force and the detailed interactions of glycoprotein networks is necessary to be established and identified respectively In summary, in the direction towards the objective of mechano-control of biological systems, some further 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CONTENTS Explicit Force- feedback Controlled System 60 4.1 Introduction 61 4.2 Explicit Force- Controlled System for Mechanotransduction 62 4.2.1 4.2.2 Force Transmission... Block diagram for robust explicit force control 96 4.23 Step-response of the robust explicit force control system 96 4.24 The force response of the robust explicit force control