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The Pennsylvania State University The Pennsylvania State University The Graduate School College of Engineering ACOUSTIC TWEEZERS: MANIPULATING CELLS IN MICROFLUIDICS A Dissertation in Engineering Science and Mechanics by Xiaoyun Ding 2013 Xiaoyun Ding Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2013 The dissertation of Xiaoyun Ding was reviewed and approved* by the following: Tony Jun Huang Professor of Engineering Science and Mechanics Dissertation Advisor Chair of Committee Bernhard R. Tittmann Schell Professor of Engineering Science and Mechanics Corina S. Drapaca Assistant Professor of Engineering Science and Mechanics Qiming Zhang Distinguished Professor of Electrical Engineering Judith A. Todd Professor P. B. Breneman Head of the Department of Engineering Science and Mechanics *Signatures are on file in the Graduate School iii ABSTRACT Techniques that can noninvasively and dexterously manipulate cells and other bioparticles (such as organisms, DNAs, proteins, and viruses) in a compact system are invaluable for many applications in life sciences and medicine. Historically, optical tweezers have been the primary tool used in the scientific community for bioparticle manipulation. Despite the remarkable capability and success, optical tweezers have notable limitations, such as complex and bulky instrumentation, high equipment costs, and potential damage to cells. To overcome the limitations of optical tweezers and other particle manipulation methods, we have developed a series of acoustic-based, on-chip devices called acoustic tweezers that can manipulate cells and other bioparticles using sound waves. The power density required by our acoustic device is 10,000,000 times less than that of optical tweezers, which renders the technique noninvasive and amenable to miniaturization. Cell viability, proliferation, and apoptosis assays are also conducted to confirm the non-invasiveness of our technique. The simple structure/setup of these acoustic tweezers can be integrated with a small radio-frequency power supply and basic electronics to function as a fully integrated, portable, and inexpensive cell-manipulation system. In this dissertation, we demonstrated an acoustic tweezers platform that can achieve the following functions: 1) trap and dexterously manipulate single microparticle, cell, and entire organism (i.e., C. elegans) along a programmed route in two-dimensions within a microfluidic chip; 2) dynamically tune the cell patterning in microfluidic channel; 3) precisely sort cell into five separate outlets in one step, rendering it particularly desirable for multi-type cell sorting; and 4) achieve high-efficiency (>95%) separation of human leukemia cells (HL-60) and human breast cancer cells (MCF-7) from human blood cells. iv TABLE OF CONTENTS List of Figures .......................................................................................................................... vi List of Tables ........................................................................................................................... xii Acknowledgements .................................................................................................................. xiii Chapter 1 Introduction and Background .................................................................................. 1 1.1 Motivation .................................................................................................................. 2 1.2 Fundamentals of SAW ............................................................................................... 5 1.2.1 Generation of SAW ......................................................................................... 5 1.2.2 SAW-induced streaming ................................................................................. 7 1.2.3 Formation of SSAWs ...................................................................................... 10 1.2.4 Primary acoustic radiation force in SSAWs .................................................... 12 1.3 Literature Review of SAW microfluidics .................................................................. 15 1.3.1 Fluid mixing .................................................................................................... 15 1.3.2 Fluid translation............................................................................................... 16 1.3.3 Jetting and atomization .................................................................................... 23 1.3.4 Particle/cell concentration ............................................................................... 25 1.3.5 Reorientation of nano-objects ......................................................................... 26 1.3.6 Phononic Crystal-Assisted SAWs ................................................................... 30 1.3.7 Microfluidic Technologies Enabled by SSAWs ............................................. 32 1.4 Goals and organization ............................................................................................... 38 Chapter 2 Single particle, cell, and organism manipulation using acoustic tweezers .............. 40 2.1 Introduction ................................................................................................................ 40 2.2 Working mechanism .................................................................................................. 42 2.3 Methods ...................................................................................................................... 45 2.3.1 Materials .......................................................................................................... 45 2.3.2 Device fabrication ........................................................................................... 46 2.3.3 Experimental Setup ......................................................................................... 49 2.3.3 Cell Viability and Proliferation Assays ........................................................... 50 2.4 Results and discussion ............................................................................................... 51 2.4.1 Characterization of the acoustic tweezers ....................................................... 51 2.4.2 Two-Dimensional Manipulation of Single Particles, Cells, and Organisms ... 53 2.4.3 Massive manipulation of particles ................................................................... 58 2.5 Conclusion ................................................................................................................. 61 Chapter 3 Multichannel cell sorting using acoustic tweezers .................................................. 62 3.1 Introduction ................................................................................................................ 62 3.2 Working mechanism .................................................................................................. 66 3.3 Methods ...................................................................................................................... 68 3.4 Results and discussion ............................................................................................... 69 3.5 conclusion .................................................................................................................. 73 v Chapter 4 Tunable patterning of particles and cells using acoustic tweezers .......................... 74 4.1 Introduction ................................................................................................................ 74 4.2 Working mechanism .................................................................................................. 77 4.3 Methods ...................................................................................................................... 81 4.3.1 Device design and fabrication ......................................................................... 81 4.3.2 System setup .................................................................................................... 82 4.4 Results and discussion ............................................................................................... 82 4.4.1 Tunable 1D patterning ..................................................................................... 82 4.4.2 Tunable 2D patterning ..................................................................................... 87 4.5 conclusion .................................................................................................................. 90 Chapter 5 High efficiency cell separation using acoustic tweezers ......................................... 92 5.1 Introduction ................................................................................................................ 92 5.2 Working mechanism .................................................................................................. 94 5.3 Results and discussion ............................................................................................... 97 5.3.1 Particle separation based on size ..................................................................... 97 5.3.2 Particle separation based on compressibility ................................................... 99 5.3.3 Cell separation ................................................................................................. 101 5.4 Methods ...................................................................................................................... 106 5.5 Conclusion
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