A Modular Design Framework for Lab-On-a-Chips By Aung Kyaw Soe (Master of Technological Design, Embedded Systems) Technical University of Eindhoven, The Netherlands and National University of Singapore, Singapore Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Deakin University June, 2016 To my family Acknowledgements First, I would like to express my gratitude to Professor Saeid Nahavandi for his constant guidance and unwavering support throughout my HDR research. Without his kindness, vision, knowledge, experience, advice, and encouragement, this thesis would not have been feasible. Also, I would like to thank Dr. Khashayar Khoshmanesh and Dr. Michael Fielding for their help and other colleagues from Institute for Intelligent Systems Research at Deakin University for their support and friendship during my candidature. More importantly, I would like to thank my wife, May, who has left her career at an oilfield services firm in Perth, Western Australia to be with me in Deakin University in Geelong. Without her, it would have been impossible to finish my PhD. Finally, I appreciate my mother and my late father for their love, inspirations and encouragement, without them, I would not have reached here. i A Modular Design Framework for Lab-On-a-Chips Abstracts Microfluidic based Lab-on-a-Chip (LoC) devices exhibit potentials to become cheaper and better replacement for bench-top instrumentations. The current practice of designing LoCs starts from an empty design space, focuses less on design reuse, which is labor intensive and difficult to scale, making reusing, modifying and extending designs and sharing tasks challenging for researchers without all or many sets of skills. It takes broad and deep sets of skills to design LoCs. LoC researchers will probably not possess the necessary skills and knowledge to design chips: fabrication methods, materials, 3D modelling and numerical simulation etc. Collaboration among researchers across disciplines from different laboratories is challenging, reusing designs is not possible and scaling design effort is difficult. One way to help researchers focus on their research strengths, without needing to learn every detail LoCs design, is to design LoCs for them and to reuse existing LoC designs. Facilitating collaboration among researchers emulates best practices from the discipline of system engineering. Complexity in LoC designs can be reduced by separating tasks performed by LoC users and designers. If the design-by-assembly method is used, neuroscientists, as application designers, can design LoCs using components designed by low-level microfluidic component designers. By employing this approach, a LoC can be prototyped by assembling subsystems of different configurations. This method can help researchers in designing and constructing LoCs. Another benefit of this design framework is the accompanying construction methods and techniques, which integrate commercial-off-the-shelf (COTS) systems, meaning sophisticated ii yet low-cost LoCs can be constructed. Therefore, the design framework should enable researchers to design LoCs with different fluidic control, analytical features and modify them as needed without having all or many skills. The design framework could make the task of designing LoCs less challenging, and fabricating LoCs and collaborating among laboratories more feasible. It can be used to create new microfluidic LoCs for neuroscience and neurophysiological investigations. Firstly, SoftMABs were created. Secondly, they were assembled like LEGO bricks to design an LoC. Next, SoftMABs were reconfigured by replacing modules, by dragging-and-dropping modules to make a different LoC. In addition, a neuroscience LoC such as continuous-flow Polymerase Chain Reaction (PCR) SoftMABs can be designed. The construction framework, for designing single- layer control valves and using normally closed and normally opened valves programmable LoCs to achieve experiment-time configurability, is demonstrated and discussed. Also, an operational technique method for fabricating a cell-culture LoC with non-planar cell-culture chambers is discussed. Construction methods are reported for constructing microelectrodes arrays integrated cell culture platforms (MEA-LoCs). Cell culture LoC designs are numerically validated, results are analyzed and interpreted. Finally, SoftMABs are modified, new LoCs are designed using remodeled modules, reverse masters are cast. The LoCs will be cast using the mold and flow validation experiments were done using the fabricated LoCs. This design framework will reduce complexity and cost in LoC design while increasing flexibility, reusability and scalability. SoftMABs and design-by-assembly method can be useful for designing and fabricating cell-culture LoCs and polymerase chain reaction platforms. iii Papers published during candidature [1] A. K. Soe, S. Nahavandi and K. Khoshmanesh, “Neuroscience Goes on a Chip” Biosensors and bioelectronics, 2012, 35, 1-13. [2] Soe, Aung K., Michael Fielding, and Saeid Nahavandi. "Lab-on-a-Chip turns soft: Computer- aided, software-enabled microfluidics design." Advances in Social Networks Analysis and Mining (ASONAM), 2013 IEEE/ACM International Conference on. IEEE, 2013, 968-971. [3] Soe, A.K. and S. Nahavandi, “Degassing a PDMS mixture without a vacuum desiccator or a laboratory centrifuge and curing the PDMS chip in an ordinary kitchen oven.” Chips and Tips, Lab on a Chip, RSC Blog, 2011. [4] L. Wei, H. Zhou, A. K. Soe and S. Nahavandi, "Integrating Kinect and haptics for interactive STEM education in local and distributed environments." Advanced Intelligent Mechatronics (AIM), 2013 IEEE/ASME International Conference on. IEEE, 2013, 1058-1065. iv Table of Contents Abstracts ......................................................................................................................................... ii Papers published during candidature ............................................................................................. iv Table of Contents ............................................................................................................................ v List of Symbols ............................................................................................................................... x List of Abbreviations .................................................................................................................... xii Chapter 1 Introduction .................................................................................................................... 1 1.1. Lab-on-a-Chip ...................................................................................................................... 2 1.2. Modularising ........................................................................................................................ 4 1.3. Neuroscience Tools .............................................................................................................. 7 1.4. Micro Blood Brain Barrier ................................................................................................. 10 1.5. Motivation .......................................................................................................................... 12 1.6. Thesis Lay-out .................................................................................................................... 16 Chapter 2 Microfluidic Materials and Methods ............................................................................ 19 2.1. Fundamentals of Microfluidics .......................................................................................... 19 2.2. Microfluidics Fabrication ................................................................................................... 22 2.3. Materials for Lab-On-a-Chip ............................................................................................. 24 2.3.1. Silicon and Glass ......................................................................................................... 24 2.3.2. Negative photo-resist ................................................................................................... 25 2.3.3. Polydimethylsiloxane .................................................................................................. 26 2.3.4. Other Polymers ............................................................................................................ 30 2.3.5. New materials .............................................................................................................. 32 v 2.4. Fabrication Methods ........................................................................................................... 36 2.4.1. Photo-lithography ........................................................................................................ 36 2.4.2. Soft-lithography ........................................................................................................... 37 2.4.3. Micro-embossing ......................................................................................................... 39 2.4.4. Laser Ablating ............................................................................................................. 39 2.5. Miscellaneous methods for Lab-on-a-Chips ...................................................................... 40 2.5.1. Sacrificial layer micro-molding ................................................................................... 40 2.5.2. Plasma