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introduction.tex
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\section{Introduction}
%Skriv om annen forskning innen samme område. ref mail fra andy 30.okt.
%Skriv noe om forskning ved NTNU
%short about background/motivation
%Migth mension methods used
%1-1 1/2 page
%Review of background information enabling the reader to understandt objective and significance
Cancer is currently the most common cause of disease, with approximately 14.1 million new incidents worldwide every year (per 2012)~\cite{cancer1}. In the United States, 1 of 4 deaths are caused by cancer~\cite{Siegel2014}, and only 50\% of the persons diagnosed with cancer survive for 10 years.
The available treatments are rarely satisfying, giving limited results and negative side effects~\cite{doi:10.1056/NEJM200106283442607}. Chemotherapy, surgery, and radiotherapy are the main treatment options, often combined to achieve the best result. Chemotherapy is based on systemic administration of toxic drugs. These drugs damage healthy as well as cancerous tissue, limiting the dose to a survivable amount. This amount may be too low for the cancer to be successfully treated.%[ref]
Targeted cancer treatment is an active field of research, where the goal is increased uptake of drug in cancerous tissue without harming healthy tissue. Several targeted treatments are already available, but none have so far been able to produce a precise, satisfying treatment. A reason to the limited success, is that the drug does not travel far enough into the tumor, after leaving the vasculature~\cite{Bae2009}. This leaves remote cancerous cells untreated.
Ultrasound may be the solution for precise and effective drug delivery. Microbubbles are already used as contrast agents in ultrasound examinations, and research has been conducted to use these bubbles as drug carriers as well. The main idea is to use ultrasound to trigger the release of the drug carried by the bubble. The drug might be loaded onto, or into, the shell encapsulating the microbubble. The thin shell of normal microbubbles is only able to carry small payloads. Therefore, thicker shells or different drug loading methods are under development~\cite{Mayer2008}\cite{Ibsen2011}. %(obs. review article).
Another concept is the use of nanoparticles to achieve the necessary properties. In a previous work by ~\citeauthor{Eggen2013} the drug is encapsulated in nanoparticles~\cite{Eggen2013}. The nanoparticles are then used to stabilize the shell of the gas microbubbles. The shell of the microbubble can also be developed with ligands able to attach to receptors present in cancer cells~\cite{Davis2008}. This is known as active targeting and can increase accumulation of drug in the cancerous tissue.
Phoenix Solutions is developing a new concept for ultrasound mediated drug delivery. In this concept, clusters consisting encapsulated gas microbubbles and drug-loaded emulsion droplets, are used. When exposed to ultrasound, the microbubbles oscillate and initiate a vaporization of the emulsion droplets. The phase-shift from liquid to gas releases the drug, and increase the size of the gas bubble to \SI{\sim 30}{\micro\meter}. That is roughly ten times the initial size. These bubbles are large enough to block small vessels, keeping the drug present at the diseased site for an extended time. Low frequency ultrasound is applied, initiating oscillations of the large bubbles. Applying ultrasound together with microbubbles has been shown to enhance drug delivery through enhanced vessel permeability and sonoporation~\cite{VanWamel2006a}. Similar mechanisms may be valid for the phase-shift bubbles. This new drug delivery concept is called Acoustic Cluster Therapy (ACT\texttrademark{}), and can be regarded a theranostic (combining therapy and diagnostics) product. It is possible to image the clusters and phase-shift bubbles while performing drug delivery.
The function of these phase-shift bubbles has to be proved \textit{in vivo}. This is carried out using mice with prostate cancer xenografts, where the administration and activation is imaged using high frequency (\SIrange{16}{18}{\mega\hertz}) ultrasound. These ultrasound images has already been recorded by Annemieke van Wamel and Andrew Healey. The next step is to process this data to quantify the amount activated phase-shift bubbles.
Identification and counting of stuck bubbles in ultrasound images is a field of image processing with limited available literature. One approach is described by ~\citeauthor{Needles2009}, where microbubbles bound to vessel walls are differentiated from tissue and flowing microbubbles~\cite{Needles2009}. Subharmonic imaging is used to separate tissue and microbubbles, before a low-pass inter-frame filter is applied to remove the free flowing microbubbles. Because the large phase-shift bubbles have a weak subharmonic response, this method is not applicable in this work.
Therefore, the main goal of this thesis is to develop a method to process the recorded data, and estimate the number of activated and stuck phase-shift bubbles, within the tumor. The developed method should produce high quality display and quantification of the phase-shift bubbles. Image processing involves motion correction, background subtraction and counting. The algorithm performing counting of phase-shift bubbles has to be validated, including an estimate of accuracy and precision. The algorithm should be applied to a data set containing ultrasound images of 16 tumors. The number of phase-shift bubbles in these 16 tumors has previously been counted manually by Andrew Healey. These manually obtained results will be used for comparison. A proper evaluation of the performance of the ACT\texttrademark{} concept is essential for further development toward clinical trials.
%What have been done?
%Summary of conflicting findings in literature
%What I want to do
%Purpose and significance of study
%\subsection{History}
%Ultrasound is sound with frequency above the upper limit of human hearing, considered to be at 20 kHz, and has a wide range of use. The first work on ultrasound related to spatial orientation was written in 1794 by Lazaro Spallanzini, after discovering bats ability to navigate, only using ultrasound. Yet, almost hundred years passed before Jacques and Pierre Curie discovered the piezoelectric effect and Sir Francis Galton invented a machine able to produce ultrasound at 40 kHz, both during 1880. The piezoelectric effect is the ability of some crystals to generate electrical charge, when subjected to mechanical stress.
%
%During the beginning of the 20th century the echo-locator was invented, and the first application was detecting submarines during World War 1. Use of ultrasound in medical imaging, also known as sonography, was first used in 1956 when Ian Donald measured the parietal diameter of a fetal head. Seven years later commercial sonography devices were available.
%
%The last decades there has been continuous development, and from the simple display modes used in the beginning, there is now possible to get real-time imaging in both two and three dimensions, and Doppler imaging enables continuous measurement and visualization of blood movement in vessels.
%\subsection*{Outline of thesis}