bubble dynamics and acoustic droplet vaporization in gas embolotherapy

168 Pages·2013·10.2 MB·English

B D
UBBLE YNAMICS AND
A D V
COUSTIC ROPLET APORIZATION
G E
IN AS MBOLOTHERAPY

by

David S. Li
A dissertation submitted in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy
(Biomedical Engineering)
in the University of Michigan
2014
Doctoral Committee:

Professor Joseph L. Bull, Chair
Assistant Professor Krzysztof J. Fidkowski
Professor J. Brian Fowlkes
Professor Shuichi Takayama
© David Shicheng Li
All rights reserved
2013
Dedication
To my loving mother, father, and sister
for their unconditional love and support
ii
Acknowledgements

I am grateful to have had the good fortune to interact with an amazing group of
individuals throughout my doctoral studies at the University of Michigan at Ann Arbor.
Without their collective efforts, advice, and moral support the work presented in this
dissertation could not have been possible. I would first like to credit the guidance and
training from my doctoral committee members – Professors Joe Bull, Chris Fidkowski, Brian
Fowlkes, and Shuichi Takayama. I would like to thank my advisor, Joe Bull, for the
mentorship, discussion, and support throughout the years. My understanding of bubble
dynamics and acoustics was only possible with the guidance from Brian Fowlkes. My
fundamental training in computational tools for fluid mechanics could not have been
complete without the advisement from Chris Fidkowski. Finally, the generosity from
Shuichi Takayama and access to resources did not go unappreciated. And to my committee
as a whole, I would like to thank them all for the mentoring and training that helped craft me
into the scientist and engineer I am today.
The assistance and thought provoking discussions from the current and former lab
members throughout the years was much appreciated. But more importantly, they created
the most light-hearted and enjoyable work atmosphere on a day-to-day basis I will ever
experience. For that reason, I will never forget my friends and colleagues from the
Biotransport Lab – Stanley Samuel, Robinson Seda, John Pitre, Adnan Qamar, Rob Dodde,
Sam Stephenson, Nelson Smith, Marty Schlicht and ZZ Wong.
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Aside from Biotransport Lab, my studies could not have been completed without the
generous help of collaborators throughout the years. I would like to thank Mario Fabiilli and
Oliver Kripfgans from the Basic Radiological Sciences ultrasound group for their help with
droplet supply, ultra-high speed camera setup, and thought-provoking discussion on all
things acoustic droplet vaporization related. From the histotripsy group, I am incredibly
grateful for Yohan Kim’s assistance and willingness to perform transducer calibrations upon
request. I would also like to thank Brian Johnson for the advice, training, and access to
resources allowing me to construct the microfluidic devices throughout academic pursuits.
Most importantly, the level of appreciation I have for the patience, counseling, and
encouragement throughout the years from my family cannot be sufficiently expressed in
words. My mother and father have always been an incredible source of inspiration and along
with my loving sister and best friend, Amy, my family has always provided laughter and love.
Once again, I would like to thank my dearest family for everything they provided throughout
my life. Without them, none of this could have been accomplished.

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Table of Contents
Dedication ............................................................................................................................................. ii
Acknowledgements ............................................................................................................................. iii
List of Tables ..................................................................................................................................... viii
List of Figures ...................................................................................................................................... ix
List of Appendices ........................................................................................................................... xvii
List of Symbols and Acronyms ..................................................................................................... xviii
Abstract ................................................................................................................................................ xx
CHAPTER I: INTRODUCTION ................................................................................................... 1
Background and Motivation ........................................................................................................ 1
Chapter I: Figures ......................................................................................................................... 9
Chapter I: References ................................................................................................................ 11
CHAPTER II: INITIAL NUCLEATION SITE FORMATION DUE TO ACOUSTIC
DROPLET VAPORIZATION ...................................................................................................... 16
Introduction ................................................................................................................................. 16
Methods ........................................................................................................................................ 18
Results and Discussion ............................................................................................................... 20
Conclusions .................................................................................................................................. 23
Chapter II: Figures ..................................................................................................................... 24
Chapter II: References ................................................................................................................ 31
CHAPTER III: FORMATION OF TOROIDAL BUBBLES DURING ACOUSTIC
DROPLET VAPORIZATION ...................................................................................................... 33
Introduction ................................................................................................................................. 33
v
Methods ........................................................................................................................................ 35
Results and Discussion ............................................................................................................... 35
Conclusions .................................................................................................................................. 39
Chapter III: Figures.................................................................................................................... 41
Chapter III: References ............................................................................................................. 47
CHAPTER IV: THE BUBBLE EVOLUTION FROM ACOUSTIC DROPLET
VAPORIZATION IN MICROCHANNELS .............................................................................. 50
Introduction ................................................................................................................................. 50
Methods ........................................................................................................................................ 52
Results and Discussion ............................................................................................................... 54
Conclusions .................................................................................................................................. 58
Chapter IV: Figures .................................................................................................................... 60
Chapter IV: References ............................................................................................................. 67
CHAPTER V: A BOUNDARY ELEMENT MODEL OF A MICROBUBBLE SLIDING
THROUGH A BIFURCATION .................................................................................................... 69
Introduction ................................................................................................................................. 69
Methods ........................................................................................................................................ 72
Results and Discussion ............................................................................................................... 77
Conclusions .................................................................................................................................. 84
Chapter V: Figures ...................................................................................................................... 85
Chapter V: References ............................................................................................................. 101
CHAPTER VI: ACOUSTIC ATOMIZATION PROCESS WITHIN BUBBLES
ATTACHED TO A SOLID BOUNDARY .............................................................................. 104
Introduction .............................................................................................................................. 104
Methods ..................................................................................................................................... 106
Experimental Setup ........................................................................................................... 106
vi
High Speed Camera Setup ................................................................................................ 106
Acoustics ............................................................................................................................. 107
Test Fluids .......................................................................................................................... 108
Results and Discussion ............................................................................................................ 109
Conclusions ............................................................................................................................... 113
Chapter VI: Figures .................................................................................................................. 115
Chapter VI: References ........................................................................................................... 122
CHAPTER VII: CONCLUSIONS AND FUTURE DIRECTIONS .................................. 125
Conclusions ............................................................................................................................... 125
Summary of Scientific Contributions .................................................................................... 129
Future Directions ..................................................................................................................... 130
Chapter VII: Figures ................................................................................................................ 135
Chapter VII: References .......................................................................................................... 137
APPENDICIES .............................................................................................................................. 140

vii
List of Tables
Table A1. 1: Spin times for varying channel heights used for idealized vessel models. ...... 142
Table A1. 2: Soft-bake times for varying channel heights used for idealized vessel models.
............................................................................................................................................................ 143
Table A1. 3: Exposure times for varying channel heights used for idealized vessel models.
............................................................................................................................................................ 143
Table A1. 4: Post-exposure bake times used for varying channel heights used for idealized
vessel models.................................................................................................................................... 144
Table A1. 5: Development times used for varying channel heights used for idealized vessel
models. Every minute additional developer solution was used to spray the surface of the
wafer molds to ensure removal of excess SU-8. ......................................................................... 144

viii
List of Figures
Figure 1. 1: Concept art of the gas embolotherpay. Gas emebolotherapy begins with the
introduction of PFC microdroplets via intravenous injection. At the feeder vessel of the
tumor, an ultrasound source is focused to vaporize the droplets. The subsequent bubbles
that are formed can then lodge and occlude blood flow to the tumor, thus “starving” the
tumor. Illustration by Carolyn Smith. ............................................................................................. 9
Figure 1. 2: Illustration showing the typical dynamics throughout the ADV timeline over the
first 200 μs. An initial droplet is present and at time zero an ultrasound wave initiates a small
gas nuclei to form within the droplet. On some occasions a second nucleation site forms on
the opposing end of the droplet shortly after the first. The gas nuclei expand as liquid PFC
is converted into its gas phase forming a high press bubble. Once the high-pressure bubble
is formed a rapid expansion process occurs over a 50 μs period and eventually reaches an
equilibrium size (on the order of 200 μs). Finally, the bubble can serve as a gas embolus
until diffusion processes take over and the bubble dissolves into the bulk fluid. .................... 10

Figure 2. 1: Schematic of the experimental setup. The transducer and light source were
oriented confocal with the inverted microscope objective. The ADV event was captured
using an ultra-high speed camera through the side port of the microscope. The acoustic
pulse was generated using an N cycle pulse from a function generator that was amplified
prior to reaching the transducer. ...................................................................................................... 24
Figure 2. 2: The simulation domain of the transient acoustic model. A PFC droplet was
placed the focal point of the transducer. The mesh density shown above was reduced by a
factor of 100 and the droplet size was exaggerated for illustrative purposes. ........................... 25
Figure 2. 3: (A) Transient acoustic signal and the (B) frequency response of the 7.5 MHz
transducer at the focal point. The power spectrum reveals significant contribution from
higher harmonics at the focus. The inset image shows the non-linear acoustic response from
a 4 cycle sine input recorded from a fiber optic hydrophone at the focal spot. ....................... 26
Figure 2. 4: (A) Time convergence and (B) grid convergence of the acoustic finite element
model. Both time and grid convergence error reduced at a slope of 1.4. ................................. 27
Figure 2. 5: An 18 µm PFC liquid microdroplet undergoing the ADV process due to a single
7.5 MHz pulse of 8 cycles at 3.6 MPa PNP. The “*” indicates the presence of the
ultrasound pulse in the field of view and the arrow indicates the direction of the ultrasound
wave. Note that the diameter is smaller than the carrier frequency (λ =54 µm). The
DDFP
primary gas nucleus is formed in the second frame with secondary nucleation sites form in
frames 3 and 5 (70 and 210 nanoseconds after the first nucleation side is formed). ............... 28
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