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The Pennsylvania State University The Pennsylvania State University The Graduate School Department of Engineering Science and Mechanics ACOUSTIC TWEEZERS: MANIPULATING MICRO-OBJECTS WITH THE POWER OF SOUND A Dissertation in Engineering Science and Mechanics by Feng Guo 2015 Feng Guo Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2015 The dissertation of Feng Guo 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 Bruce J. Gluckman Associate Professor of Engineering Science and Mechanics Corina Drapaca Associate Professor of Engineering Science and Mechanics Siyang Zheng Associate Professor of Biomedical Engineering Judith A. Todd Professor of Engineering Science and Mechanics P.B. Breneman Head of the Department of Engineering Science and Mechanics *Signatures are on file in the Graduate School iii ABSTRACT Sound can be music to please the ear, however the waves produced can be utilized as “Acoustic Tweezers” for the manipulation of cells and particles in a fluid medium. The ability to dexterously and noninvasively manipulate biological specimens such as organisms, cells, proteins, and DNAs in a compact system is critical for many applications in the fields of life sciences, biomedicine and chemistry. Acoustic tweezer technology is a revolutionary way to satisfy this requirement. Firstly, this technique manipulates cells or particles using gentle mechanical vibrations. These vibrations create a pressure gradient in the medium to move suspended micro-objects yielding a contamination-free, non-contact, and label-free manipulation. Secondly, acoustic tweezers have minimal impact on cell viability and function, which operates at a power intensity and frequency similar to the widely used medical ultrasound imaging. Thirdly, the acoustic tweezer device can operate in a single micro-device without any external moving parts or complicate setups, which offer additional advantages in ease of use, versatility and portability. In this dissertation, we have developed a series of acoustic tweezers that can achieve manipulation of micro-objects in a liquid medium: 1) tunable acoustic wells to control cell-cell distance and geometry of suspended cell assemblies; 2) 3D acoustic tweezers to dexterously transport single cells in a three-dimensional manner; 3) simple, low-cost and reusable acoustic tweezers used for various disposable devices; and 4) application of the reusable acoustic tweezer technology in precisely manipulating and patterning micrometer-sized protein crystals for X-ray crystallography. iv TABLE OF CONTENTS List of Figures . ........................................................................................................................ vi List of Tables ........................................................................................................................... xii Acknowledgements .................................................................................................................. xiii Chapter 1 Motivation and Overview ........................................................................................ 1 1.1 Motivation .................................................................................................................. 2 1.2 Acoustic Tweezers Technology ................................................................................. 3 1.2.1 Basics of acoustic waves ................................................................................. 3 1.2.2 Bulk acoustic wave based acoustic tweezers .................................................. 6 1.2.3 Surface acoustic wave based acoustic tweezers .............................................. 8 1.3 Applications of Acoustic Tweezers ........................................................................... 10 1.3.1 Single particle/cell manipulation ..................................................................... 10 1.3.2 Particle/cell enrichment ................................................................................... 12 1.3.3 Particle/cell focusing ....................................................................................... 16 1.3.4 Particle/cell sorting .......................................................................................... 18 1.3.5 Particle/cell separation .................................................................................... 21 1.3.6 Liquid handing ................................................................................................ 24 1.4 Overview of dissertation ............................................................................................ 26 Chapter 2 Controlling Cell-Cell Interactions Using Tunable Acoustic Well .......................... 28 2.1 Motivation .................................................................................................................. 29 2.2 Working mechanism .................................................................................................. 32 2.3 Methods ...................................................................................................................... 34 2.3.1 Device fabrication ........................................................................................... 34 2.3.2 Experimental setup .......................................................................................... 35 2.3.3 Cell culture and sample preparation ................................................................ 36 2.3.4 Image acquisition and analysis ........................................................................ 37 2.4 Results and discussions .............................................................................................. 37 2.4.1 Manipulation of intercellular distance ............................................................. 37 2.4.2 Formation of suspended cell assembly ............................................................ 43 2.4.3 Formation of gap junctional coupling ............................................................. 44 2.4.4 Control cell assemblies from suspension to adherent state ............................. 47 2.4.5 Quantitative evaluation of gap junctional intercellular communication. ........ 50 2.5 Conclusion ................................................................................................................. 54 Chapter 3 3D Acoustic Tweezers: Three-dimensional Manipulation of Single Cells ............. 57 3.1 Motivation .................................................................................................................. 58 3.2 working mechanism ................................................................................................... 61 3.3 Methods ...................................................................................................................... 62 3.3.1 Experimental setup .......................................................................................... 62 3.3.2 Data analysis ................................................................................................... 63 3.3.3 Cell preparation and culture ............................................................................ 63 v 3.4 Results and discussions .............................................................................................. 64 3.4.1 Study on the induced three-dimensional acoustic and fluidic fields ............... 64 3.4.2 Manipulation in the vertical direction ............................................................. 69 3.4.3 Three-dimensional trapping and Manipulation ............................................... 70 3.4.4 Cell printing using 3D acoustic tweezers ........................................................ 73 3.5 Conclusion ................................................................................................................. 75 Chapter 4 Reusable Acoustic Tweezers for Disposable Devices ............................................. 77 4.1 Motivation .................................................................................................................. 78 4.2 Working mechanism .................................................................................................. 80 4.3 Methods ...................................................................................................................... 82 4.3.1 Device fabrication ........................................................................................... 82 4.3.2 Coupling the disposable devices onto SAW substrate .................................... 82 4.3.3 Experimental setups ........................................................................................ 83 4.4 Results and discussions .............................................................................................. 83 4.4.1 Demonstration of SSAW coupling .................................................................. 83 4.4.2 Quantitative study ........................................................................................... 87 4.4.3 Moving a single particle using the disposable acoustic tweezers .................... 87 4.4.4 Manipulating cells using the disposable acoustic tweezers ............................. 89 4.5 Conclusion ................................................................................................................. 91 Chapter 5 Precise Manipulating Protein
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