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Page 1 of 58 AUTHOR SUBMITTED MANUSCRIPT - PMB-105354.R1
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Magnetic Particle Imaging: From Proof of Principle
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16 to Preclinical Applications
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18 T Knopp1,2 , N Gdaniec1,2 and M Möddel1,2
19 1 Section for Biomedical Imaging, University Medical Center Hamburg-Eppendorf
20 2 Institute for Biomedical Imaging, Hamburg University of Technology
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E-mail: t.knopp@uke.de
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23
24 Abstract. Tomographic imaging has become a mandatory tool for the diagnosis of a majority
of diseases in clinical routine. Since each method has its pros and cons, a variety of methods is
25 regularly used in the clinics to satisfy all application needs. Magnetic particle imaging (MPI) is
26 a relatively new tomographic imaging technique that images magnetic nanoparticles with high
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27 spatio-temporal resolution in a quantitative way and in turn is highly suited for vascular and
28 targeted imaging. MPI has been introduced in 2005 and now enters the preclinical research
phase, where medical researcher get access to this new technology and exploit the potential
29 under physiological conditions. Within this paper we review the development of MPI since
30 its introduction in 2005. Beside an in depth description of the basic principle, we provide
31 detailed discussions on imaging sequences, reconstruction algorithms, scanner instrumentation,
32 and potential medical applications.
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34
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36 Contents
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1 Introduction 2
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2 Structure 3
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41 3 Historical Perspective 4
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43 4 Basic Principles 7
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4.1 Particle Magnetization . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

45 4.1.1 Particle Concentration . . . . . . . . . . . . . . . . . . . . . . . 8
46 4.1.2 Particle Magnetization . . . . . . . . . . . . . . . . . . . . . . . 8
47 4.2 Signal Generation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
48 4.3 Spatial Encoding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
49 4.4 Signal Reception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
50 4.5 Spatial Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
51 4.6 Temporal Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
52
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4.7 Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
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4.8 Instrumentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
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4.9 Analog Signal Chain . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
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AUTHOR SUBMITTED MANUSCRIPT - PMB-105354.R1 Page 2 of 58
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10 5 Imaging Sequences 19
11 5.1 Cartesian Imaging Sequences . . . . . . . . . . . . . . . . . . . . . . . 21
12 5.2 Lissajous Imaging Sequences . . . . . . . . . . . . . . . . . . . . . . . 21
13 5.3 Multi-Patch Imaging Sequences . . . . . . . . . . . . . . . . . . . . . . 22
5.4 Field-free Line Imaging Sequences . . . . . . . . . . . . . . . . . . . . 25
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16 6 Image Reconstruction 26
17 6.1 Analytic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
18 6.1.1 x-space reconstruction . . . . . . . . . . . . . . . . . . . . . . . 26
19 6.1.2 Chebyshev reconstruction . . . . . . . . . . . . . . . . . . . . . 28
20 6.2 Algebraic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
21 6.2.1 Discrete Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
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22 6.2.2 Determining the System Matrix . . . . . . . . . . . . . . . . . . 29
23 6.2.3 Frequency Selection . . . . . . . . . . . . . . . . . . . . . . . . 31
24 6.2.4 Least Squares Approach . . . . . . . . . . . . . . . . . . . . . . 33
25 6.2.5 Regularization . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
26 6.2.6 Linear Solvers . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
6.3 Matrix Compression . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
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7 Anatomical Background
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6.4 Online Reconstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
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31 7.1 Fiducial Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
32 7.2 Hybrid Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
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34 8 Multi-spectral MPI 40
35 8.1 Mobility MPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
36 8.2 Algebraic Multi-spectral Reconstruction . . . . . . . . . . . . . . . . . 41
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38 9 Force Application using MPI 42
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40 10 Potential Medical Applications 44
41 10.1 Vascular Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
42 10.2 Device Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
43 10.3 Targeted Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
44 10.4 Magnetic Hyperthermia . . . . . . . . . . . . . . . . . . . . . . . . . . 49
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46 11 MPI Data Format 49
47
12 Conclusion and Discussion 50
48
49
50 1. Introduction
51
52 Magnetic particle imaging (MPI) is a tracer based, functional, and tomographic
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53 imaging modality determining the spatial distribution of magnetic nanoparticles.

54 During the last 12 years since MPI has been initially proposed in 2005 the method has
55 undergone a rapid development starting from a 1D prototype (Gleich & Weizenecker
56 2005) to fully 3D commercialized systems (Bruker Biospin MRI GmbH 2014, Magnetic
57 Insight, Inc. 2017).
58 MPI requires the usage of tracers and only provides signal when tracer is present
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59 within the imaging volume. Common tracers being used are iron-oxide based magnetic
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10 nanoparticles (MNP) – also called superparamagnetic iron oxide nanoparticles (SPIOs)
11 – that have a long history as contrast agents in magnetic resonance imaging (MRI)
12 (Wang 2011). In MRI, the MNPs lead to accelerated relaxation behavior that can
13 be identified in the reconstructed images as regions with reduced signal intensity.
Hence, they yield a negative contrast making it difficult to distinguish tissue from
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14
15 MNPs. Furthermore, the quantification of the MNP concentration within tissue using
16 MRI is challenging. On the contrary, MPI provides a positive contrast without any
17 background and the MPI signal can be used for direct quantification. MPI has a very
18 high temporal resolution allowing to measure several volumes per second. The spatial
19 resolution is medium but can potentially be improved to reach 1 mm or even below
20 (Gleich & Weizenecker 2005). A further strength of MPI is its sensitivity, which is
21 worse than that of nuclear diagnostic methods but potentially better than that of CT
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22 and MRI. In addition to these properties MPI does not apply ionizing radiation and
23 is therefore potentially safe for patient and medical staff if the applied magnetic fields
24 do not exceed safety limits.
25 There are several medical applications that could also be addressed by MPI. In
26 particular vascular imaging including interventional applications are in the focus of
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27 MPI. Since the particles can be functionalized to target specific organs or tissues
28 (e. g. cancer tissue) MPI could be very interesting for functional applications where
29 currently PET/SPECT are the common methods of choice. Finally, hyperthermia
30 applications could be addressed with MPI combining diagnostic imaging and therapy
31 in a unified framework.
32
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2. Structure
34
35 This topological review aims to provide an overview about the most important progress
36
on MPI during the last 12 years. The main focus of the review is on imaging
37
sequences and image reconstruction methods. For the equally important area of tracer
38
development we refer to the recent review article by Bauer et al. (2015).
39
This review is structured as follows. We start in section 3 by providing an overview
40
over key advances in MPI since its introduction in 2005.
41
Next, in section 4 the basic imaging principles are explained, which remained
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43 roughly the same since MPI was introduced in 2005. In more detail, this section
44 will provide a discussion on the performance of MPI in terms of spatial resolution
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45 in section 4.5, temporal resolution in section 4.6, sensitivity in section 4.7, and the
46 instrumentation of MPI scanners in sections 4.8 and 4.9.
47 Section 5 reviews different imaging sequences that are commonly used in MPI
48 including the popular Lissajous and Cartesian as well as multi-patch and field-free
49 line imaging sequences.
50 In section 6 we will discuss the image reconstruction problem in MPI. The related
51 inverse problem is mathematically challenging since the MPI forward operator, i. e.
52 the MPI system matrix, is difficult to model accurately. We discuss both analytic
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53 methods suitable for the reconstruction of Cartesian measurement data in section 6.1
54 and algebraic methods that are commonly used to reconstruct data from Lissajous
55 imaging sequences in section 6.2. At the end of this section we review techniques that
56 are able to speed up reconstruction and enable the visualization of MPI tomograms
57 in near-real time.
58 Section 7 will focus on acquisition of anatomical reference data for MPI. We
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59 will first discuss a fiducial based imaging workflow that allows to automatically map
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10 MPI data on MRI reference images. Afterwards we will discuss recent approaches
11 for building hybrid MPI/MRI scanners allowing to measure an anatomical reference
12 without moving the subject.
13 Sections 8 and 9 will cover the most recent developments that are becoming
increasingly important for MPI related applications. Section 8 will cover multi-spectral
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15 MPI, a multi-channel variant of MPI. It enables discrimination of different particle
16 systems or functional imaging of the viscosity or temperature. Section 9 highlights
17 how an MPI scanner can be used to apply forces to appropriately coated materials.
18 In section 10 we will sketch a selection of the most interesting potential medical
19 applications that are currently under investigation in pre-clinical studies throughout
20 the MPI research community.
21 The topological review will conclude with a basic introduction to the Magnetic
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22 Particle Imaging Data Format (MDF), which aims to allow researchers from different
23 groups to exchange MPI raw data in a standardized format.
24
25 3. Historical Perspective
26 an
27 A short visual representation of the history of MPI including its major milestones
28 can be found in figure 1. MPI has been invented by Bernhard Gleich in 2001
29 at the research labs of the company Philips in Hamburg, Germany (Gleich 2001).
30 Starting from the initial idea, together with his colleague Jürgen Weizenecker he
31 developed the first prototype that was capable of tomographic imaging. Some years
32 later Gleich & Weizenecker (2005) published their findings and thereby initiated the
33
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worldwide investigation of MPI. This very first description of MPI already sketched
34 many groundbreaking ideas like the upscaling to human-sized scanners including the
35 potential risk of nerve stimulation and a potential solution involving multi-patch
36
sequences. For their invention of MPI, Gleich, Weizenecker and team won the
37
European Inventor Award (2016).
38
After the initial publication in 2005, the first researchers outside of Philips started
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investigating MPI in Berkeley (USA), Braunschweig (Germany), Darthmouth (USA),
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Lübeck (Germany), Seattle (USA), Tokyo (Japan), and Würzburg (Germany). Today
41
MPI is a worldwide distributed research field with an ever growing community of
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43 more than 20 research groups. Since 2010 the MPI community meets annually at
44 the International Workshop on Magnetic Particle Imaging (IWMPI). Just recently, in
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45 2015 the MPI community started its own scientific reasearch journal: the International
46 Journal on Magnetic Particle Imaging (IJMPI) (Knopp 2015).
47 The initial MPI scanner published by Gleich & Weizenecker (2005) had a long
48 acquisition time of several minutes. Gleich et al. (2008) improved the scanner to
49 rapidly acquire data using a 2D Lissajous trajectory yielding frame rates in the order
50 of 25 frames per second. The scanner was then extended to a 3D system, which
51 was used to measure the first in-vivo MPI data. It was proven that MPI is capable
52 of 4D imaging with high temporal resolution (46 frames per second) (Weizenecker
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53 et al. 2009). The experiments were carried out using a healthy mouse showing the
54 flow of a bolus through parts of the cardiovascular system.
55 Weaver et al. (2008) and Biederer et al. (2009) introduced a spectroscopic variant
56 of MPI. The so-called magnetic particle spectroscopy (MPS) is basically a zero
57 dimensional MPI scanner. I. e. an MPI scanner without selection field which creates
58 the spatial encoding. The MPS turned out to be a very important technique to analyze
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59 the performance of different tracers directly after synthesis. It even allowed research
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51 Figure 1. History of MPI. Shown are the major milestones during the development of MPI from
52 2001 until 2016. Images of human scanner courtesy of Jürgen Rahmer, images of Braunschweig
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53 scanner courtesy of Thilo Viereck, images of traveling wave scanner courtesy of Patrick Vogel,
54 images of high gradient scanner courtesy of Steven M. Conolly. Images of the hybrid MPI/MRI
system are courtesy of Jochen Franke.
55
56
57 groups having no MPI scanner available to develop tailored tracers for an optimal
58
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MPI performance (Pasmans et al. 2009). However, MPS has a second benefit. Many
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10 fundamental ideas could be tested in spectroscopic studies before a corresponding proof
11 of principle was provided for MPI. For instance Rauwerdink et al. (2009) showed in
12 2009 the feasibility to determine the particle temperature using an MPS. The results
13 were just recently carried over to MPI by Stehning et al. (2016a).
Hardware has undergone some important developments during the last 12 years.
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15 While the scanner layouts published by Gleich & Weizenecker (2005) and later by
16 Gleich et al. (2008) had a bore diameter of 32 mm, Gleich et al. (2010) presented a
17 prototype with a bore diameter of 12 cm. It was equipped with focus fields that could
18 be used for moving a rapidly sampled field-of-view (FOV) slowly through the larger
19 bore diameter. During the years 2011 and 2015 the research group at Philips worked
20 on the first human scanner that was presented at the IWMPI 2016. Beside upscaling
21 to larger scanner geometries, the spatial resolution of small animal scanners has been
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22 steadily improved by increasing the gradient strength of the applied selection field.
23 Konkle et al. (2015a) developed a preclinical scanner with a gradient strength of 7
24 Tm−1 μ−10 .
25 Apart from the traditional MPI technology proposed by Gleich & Weizenecker
26 (2005), several alternatives have been developed. Sattel et al. (2009a) proposed a
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27 scanner technology with all field generating and receiving coils located on a single side
28 and the measuring field located in front of the scanner assembly. Vogel et al. (2014b)
29 introduced a new scanner technology called traveling-wave MPI (TWMPI), which
30 allows to increase the size of the measuring field along the scanner bore without any
31 increase of the total electrical power consumption. Viereck et al. (2016) developed the
32 first imaging system capable of switching the excitation frequency (between 10 kHz and
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25 kHz). Using two different excitation frequencies provides additional information,
34 which can be used for multi-spectral MPI imaging. As MPI does only image the
35 distribution of a tracer, it requires a second imaging modality – like MRI – to map the
36 results to an anatomical reference. Vogel et al. (2014a) and Franke et al. (2016) showed
37 the feasibility to implement hybrid scanners performing MPI and MRI measurements
38 within the same scanning device. A further very important milestone of MPI were the
39
introduction of first field-free line (FFL) imagers by Goodwill et al. (2012) and Bente
40
et al. (2015). Finally, while the MPI signal chain is usually realized using sinusoidal
41
excitations, Tay et al. (2016) showed just recently that in principle MPI could be done
42
using an arbitrary waveform for signal excitation.
43
First commercial MPI scanners for preclinical applications have been successfully
44
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developed by two independent vendors (Bruker Biospin MRI GmbH 2014, Magnetic
45
46 Insight, Inc. 2017). These systems are especially important to allow clinical experts
47 focus their research on possible medical applications of MPI, which requires reliable
48 scanner hardware.
49 In the field of MPI image reconstruction important milestones were the
50 system-function analysis paper by Rahmer et al. (2009), the introduction of x-
51 space reconstruction by Goodwill & Conolly (2010), the introduction of iterative
52 reconstruction techniques by Knopp et al. (2010h), and the development of matrix
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53 compression techniques by Lampe et al. (2012). One of the most recent milestones
54 was the introduction of colored or multi-spectral MPI by Rahmer et al. (2015). This
55 imaging method provides additional information, which allows to discriminate different
56 MPI tracers or determine environment parameters such as the temperature or the
57 viscosity of the medium surrounding the tracer. Finally, it was important for the
58 practicability of MPI to introduce a low latency online reconstruction framework
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59 (Knopp & Hofmann 2016) that allows real-time reconstruction and visualization
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10 during MPI measurements. For FFL imaging Knopp et al. (2011b) derived a Fourier
11 slice theorem, which laid down the theoretical foundation for the first experimental
12 FFL based tomographic image reconstruction by Konkle et al. (2013).
13 Beyond imaging applications it has been shown by Nothnagel et al. (2016) that
it is possible to steer magnetic materials by exploiting the force that is generated by
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15 the gradient field used for spatial encoding. This can be exploited for instance to steer
16 a catheter through the FOV without any manual actuation of the medical operator.
17 This is especially important for interventional applications, which have been initially
18 proposed by Haegele et al. (2012) and Haegele et al. (2013).
19 Within the tracer research community the first results on dedicated tailored
20 tracers to maximize the MPI performance have been published by Ferguson et al.
21 (2009). One of the best MPI tracer developed so far has been published by Ferguson
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22 et al. (2015). It consists of a highly monodisperse iron core coated with polyethylene
23 glycol (PEG). Similar tracer performance has been achieved by Starmans et al. (2013).
24 A comparison of the MPI performance of various commercially available MPI tracers
25 has been done by Lüdtke-Buzug et al. (2013).
26 The important area of safety aspects of MPI has been investigate by Bohnert
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27 et al. (2009a), Bohnert et al. (2009b), Bohnert & Dössel (2010), Saritas et al. (2013b),
28 Schmale et al. (2015), and Saritas et al. (2015). Potentially, the applied excitation
29 fields can lead to tissue heating – measured by the specific absorption rate (SAR) –
30 and/or peripheral nerve stimulation. It has been shown that the initially applied fields
31 of 20 mT at 25 kHz are too high for human whole body applications. Instead it is the
32 proposal of Schmale et al. (2015) to use higher excitation frequencies in combination
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with lower field amplitudes.
34 Beside technical improvement, various works have been published in the field of
35 medical application research within the last two years (Kaul et al. 2015, Nishimoto
36 et al. 2015, Zheng et al. 2015, Them et al. 2016b, Salamon et al. 2016, Sedlacik
37 et al. 2016, Haegele et al. 2016a, Haegele et al. 2016). Furthermore, MPI has been
38 used to track stem cells with high sensitivity by Zheng et al. (2015) and Bulte et al.
39
(2015). A further strength of MPI is the feasibility of long term monitoring. It was
40
shown that the encapsulation of tracers into red blood cells allows circulation times of
41
several days (Rahmer et al. 2013). Moreover, it was shown by Nishimoto et al. (2015)
42
that MPI enables imaging of lungs using inhaled nebulized magnetic nanoparticles.
43
A further application of MPI is hyperthermia. Hyperthermia applications combine
44
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diagnosis and therapy by heating the tracers with additional coils and have been
45
46 successfully performed by Ohki et al. (2016).
47
48 4. Basic Principles
49
50 In this section we will introduce the basic principle of MPI. In order to get MPI to
51 work it needs three ingredients:
52 (i) signal generation
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(ii) spatial encoding
54
55 (iii) signal detection
56 We will discuss all three concepts in sections 4.2, 4.3, and 4.4. Prior to that the
57 behavior of an ensemble of ideal magnetic nanoparticles suspended in a carrier fluid
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in an external magnetic field is discussed.

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10 4.1. Particle Magnetization
11 MPI requires tracers for imaging. These tracers contain MNPs which can be
12 magnetized in an external magnetic field with a magnetization proportional to the
13 local density of the particles. A large class of MPI tracers are ferro fluids, which usually
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14 consists of MNP suspended in organic solvents or water. These particles usually consist
15 of a magnetic core, which is surrounded with an appropriate coating as for instance
16 Dextran or PEG to ensure bio-compatibility and prevent particle agglomeration.
17
Signal generation in MPI relies on the magnetization response of an ensemble
18
of particles in an external magnetic field. Changing the strength and/or direction of
19
the external field will cause strength and/or direction of the magnetization to change,
20
effectively summing up the rich dynamic processes of the magnetic moments of the
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particles.
22
In MPI one usually describes the effective dynamics of the ensemble magnetization
23
24 by two relaxation processes. Both the Néel and Brownian relaxation process cause
25 the mean magnetic moment of the ensemble to be oriented towards the external field.
26 In general both processes will govern the overall dynamic of the magnetization. The
former does not affect the spatial orientation of the particles and only changes strength
27
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29
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and direction of the magnetic moments to be oriented towards the external field. The
later process causes the particles to spatially rotate together with their magnetic
moment until the moments are oriented towards the external field.
30
31 To illustrate the working principle of MPI we will consider an ideal MPI tracer,
32 i.e. a ferrofluid containing particles with monodisperse spherical superparamagnetic
33 magnetite core suspended in a carrier fluid. Note however that this description will
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34 not provide an accurate insight into the physical behaviour of realistic magnetic
35 nanoparticles in a ferrofluid. For a more in depth discussion on MPI tracers we refer
36 to the excellent review of Bauer et al. (2015) and the references within.
37
38 4.1.1. Particle Concentration Rather than determining the position of individual
39 particles MPI provides information about the spatial distribution of the particle
40 ensemble. Let c : R3 → R+ be the number density, i.e. a function of the spatial
41 position to the non-negative real numbers R+
0 then the total number of particles within
42 a certain volume V ∈ R3 is given by
43
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N= c(r)d3 r (1)
45 V
46
47 Within the MPI context one also refers to the number density c as particle
48 concentration. The precise aim of MPI is to recover a tomogram which is an
49 approximation of the mapping c.
50 In pre-clinical experiments the iron density rather than the particle density
51 is provided. A typical iron density of a bolus inside the blood stream is about
52 nFe = 1 mmol L−1 . To estimate the particle concentration we will consider magnetite
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53 (Fe3 O4 ) particles with a diameter of Dcore = 30 nm. Each particle then has a volume of
54 Vcore = 61 πDcore
3
= 1.41 · 10−23 m3 . Magnetite has a density of ρFe3 O4 = 5200 kg m−3 .
55 Therefore, each particle core has a weight of mcore = ρFe3 O4 Vcore = 7.35 · 10−20 kg.
56 Using the molar mass of magnetite MFe3 O4 = 0.232 kg mol−1 one can estimate the
57 total amount of iron atoms inside a particle to be Ncore
Fe
= 9.53 · 10−19 mol. Therefore,
58 the particle concentration inside the blood is about c = 1015 L−1 .
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10 4.1.2. Particle Magnetization The dynamics of the magnetic particles caused by
11 dynamic magnetic fields are very complex and have in general no analytic description.
12 To understand the underlying principles of signal generation in MPI one can make
13 the simplifying assumption that the magnetization of particles is described by the
Langevin theory.
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15 Langevin theory describes the ensemble magnetization of non-interacting
16 superparamagnetic particles in thermal equilibrium exposed to static external
17 magnetic fields H. Exposed to such a field the individual magnetic moments of the
18 particles will start orienting towards the external field and establish a measurable net
19 magnetization
20
21 M (H) = M (H)eH , (2)
us
22
23 where eH is the direction of the magnetic field and
24
M (H) = c mL (βH) (3)
25
26 is the magnitude of the magnetization vector in dependence of the strength of the
an
27 magnetic field H := H2 . M (H) depends on the Langevin function
28
⎧
29 ⎨coth (ξ) − 1 ξ = 0
30 L(ξ) := ξ (4)
31 ⎩0 ξ=0
32
33 and the scaling factor
dM
34
μ0 m
35 β := . (5)
36 kB T P
37 μ0 is the permeability of free space, kB is the Boltzmann constant, T P is the particle
38 temperature, and m is the mean magnetic moment of the particles.
39
For monodisperse spherical particles the mean magnetic moment is given by
40
41 m = Vcore Mcore
S
, (6)
42
43 where Mcore
S
is the saturation magnetization of the material of which the particle core
44 is made and Vcore = 16 πDcore
3
pte
is the particle core volume derived from the core diameter

45 Dcore .
46 In the absence of an external magnetic field, the directions of these moments
47 will be randomly distributed due to Brownian motion and the net Magnetization of
48 the ferrofluid will be zero. For weak magnetic fields, the magnetization will linearly
49 increase with H. However, at some point the majority of magnetic moments will be
50 oriented towards the external magnetic field and therefore a saturation effect can be
51 observed as shown in Figure 2.
52
ce
53
54 4.2. Signal Generation
55 Signal generation in MPI is done by cyclic excitation of the magnetic nanoparticles
56 using dynamic magnetic fields. To illustrate the signal generation consider a
57 homogeneous sinusoidal drive field
58
Ac
59 H D (t) = −AD cos(2πf D t)eD , (7)

60
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8 CONTENTS 10
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10 10
11 saturation region dynamic region saturation region
12
13
5
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15
16
M [m
A
]
17
0
18
19
20
21
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−5
22
23
24
25 −10
26 −20 −15 −10 −5 an 0 5 10 15 20
27 H [ mT
μ0 ]
28
29
30 Figure 2. The ensemble magnetization of 30 nm monodisperse spherical magnetite particles at
T = 300 K is shown as a function of the external magnetic field H. The particle concentration
31 is about 1015 particles per liter corresponding to an iron concentration of 1 mmol L−1 . If the
32 external field is small, the particles are not yet in saturation, and the magnetization shows a
33 sharp increase. For larger external fields, the particle reaches saturation and the magnetization
dM
34 hardly changes with the external field.
35
36 particle magnetization particle signal
37
M
38
39 H
40
41
42
43
44 excitation signal t
pte M
45
46 t
47
48
49
50
51
52 H
ce
53
54 Figure 3. A sinusoidal excitation field (bottom left) drives the magnetization of 30 nm Langevin
55 particles along the non-linear magnetization curve (top left). The signal generated (right) by
the drive fields has the same period as the excitation signal but is no longer sinusoidal.
56
57
58 with field amplitude AD , frequency f D , and field direction eD . If an ensemble of
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59 Langevin particles is excited by this field it generates the signal

60 M (t) = M (H D (t)), (8)
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8 CONTENTS 11
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10 particle magnetization particle signal
11
12 M
13 H
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14
15
16
17
18 excitation signal t
M
19
20 t
21
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22
23
24
25
26 H an
27
28 Figure 4. An illustration of the basic principle of spatial encoding is shown. Due to the
29 selection field the excitation signal is spatially dependent. Three identical samples positioned at
the FFP, at a position with negative H, and at a position with positive H are excited by different
30
local fields (bottom left) in black, gray, and light gray respectively. These local excitation fields
31 cause three distinguishable signal patterns (right).
32
33
dM
34 with M (H) given by (2). In figure 3 the signal generation is illustrated for 30 nm
35 Langevin particles. However, in practice the signal will be much more complex as
36 the drive field is usually slightly inhomogeneous and the magnetization dynamic is
37 manifold. In any case generated signal and periodic drive field will have the same
38 period length.
39
40 4.3. Spatial Encoding
41
42 Since the drive field is homogeneous in space, all particles in space experience the
43 same magnetic field and in turn the same magnetization response. Therefore, only
44 the mean particle concentration can be obtained from the signal.
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45 To encode the spatial position of the particles within the particle signal a static
46 magnetic selection field H S (r) is superimposed with the drive field. The static field
47 is chosen such that the effective excitation signal
48
49 H E (r, t) = H D (t) + H S (r) (9)
50 is unique at each spatial position.
51
Particles at different locations will now respond differently to the effective
52
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excitation as illustrated by figure 4. The signal then reads

53
54 M (r, t) = M (H E (r, t)). (10)
55
56 In more general terms the selection field introduces a dynamic region and a saturation
57 region. Particles inside the dynamic region respond to the drive field by significantly
58 changing the absolute value of their magnetization. Particles inside the saturation
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59 region will have approximately the same absolute magnetization value throughout the
60
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8 CONTENTS 12
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10 field-free point field-free line
11
12
13
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14
15
16
17
18
19
20
21
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22
23
24
25
Figure 5. Comparison of the FFP field and the FFL field in a plane intersecting the FFP and
26 FFL respectively. Light gray indicates low and dark gray high field strengths. The direction of
an
27 the magnetic field is indicated for exemplary positions using arrows.
28
29
30 drive-field cycle. The precise dynamics of their magnetization will depend on their
31 location, which allows to distinguish particles at different positions.
32 Usually, a magnetic gradient field
33 ⎛ ⎞
dM
34 Gx 0 0
35 H S (r) = ⎝ 0 Gy 0 ⎠ r (11)
36 0 0 Gz
37
38 as shown in figure 5 is used for spatial encoding. Such a field creates a field-free point
39 (FFP) at the origin and linearly increases towards the periphery. The dynamic region
40 has the FFP as its center. Alternative selection fields use a field-free line (FFL),
41 which either allows for projection imaging or, if the FFL is rotated, also for fully 4D
42 tomographic imaging.
43
44 4.4. Signal Reception
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45
Similar to MRI the dynamic magnetization M (r, t) is not measured directly. Instead,
46
one usually measures the voltage u(t) induced into nearby inductive pick up coils.
47
Due to the excitation signal being always present this voltage is a superposition of
48
two signals
49
50 u(t) = uH (t) + uM (t). (12)
51
52 A part uH (t) induced by the magnetic excitation field and a part uM (t) induced by
ce
53 the net magnetization generated by the magnetic nanoparticles.

54 To illustrate signal reception consider a pick up coil consisting of a single wire
55
spanning the surface S and boundary ∂S. The voltage induced into this coil is given
56
by Faraday’s law
57

58 d
Ac
59 u(t) = − B(r, t) dS, (13)

dt S
60
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7
8 CONTENTS 13
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9
10 where dS is the differential vector laying perpendicular to S and B(r, t) is the
11 magnetic flux density at the surface S, which is a superposition of two components
12 B(r, t) = B H (r, t) + B M (r, t). The first component B H (r, t) is the flux density
13 of the external excitation field and
B M (r, t) is the flux density generated

by the
MNPs. Therefore, uH (t) = − dt S B H (r, t) dS and uM (t) = − dt
d d
B M
(r, t) dS
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14 S
15 respectively.
16 For the moment we will ignore the signal induced by the excitation fields and
17 take a closer look at uM (t). The magnetic flux density can also be expressed as
18 B M = ∇ × AM by the magnetic vector potential AM . Using the Coulomb gauge
19 ∇AM = 0 and exploiting stokes theorem the voltage induced by changing net particle
20 magnetization can be expressed as
21
us
d
22 uM (t) = − AM (l, t) · dl. (14)
dt ∂S
23
24 Assuming that the MNPs are located far away from the receive coil wire, so that only
25 the dipolar component will dominate the net magnetic field at the location of the coil
26 wire, the magnetic vector potential is given by

27
28
29
AM (l, t) =
μ0
4π V
M (r, t) ×
l−r
l − r32
an
d3 r, (15)
30 where V is the compact set at which the particle concentration c(r) is non-zero.
31 Inserting (15) into (14) and using the triple product rules we obtain
32
d μ0 l−r
33 uM (t) = − M (r, t) · × dl d3 r.
dM
(16)
34 dt V 4π ∂S l − r32

35 p (r )
36
37 Here p(r) is the coil sensitivity, which is equal to the magnetic flux density generated
38 by the coil per unit current at position r. This result is well known in the MRI
39 community (Jin 1998, Haacke et al. 1999) and also holds true for volumetric receive
40 coils. Note that due to the induction principle no static part of the magnetization can
41 be measured.
42 In practice, the non-linear magnetization response of magnetic particles creates
43 a signal which has many spectral components apart from the excitation frequency.
44 Therefore, spectral methods to separate uM (t) and uH (t) can be used. A detailed
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45 introduction into methods that separate uM (t) from the induced voltage can be found
46 in (Graeser et al. 2013).
47 The voltage induced by the dynamic ensemble magnetization of three samples of
48 ideal Langevin particles located at different positions inside the excitation field into a
49 coil with unit sensitivity is shown in figure 6. Two large peaks can be observed. These
50 occur whenever the net magnetization of a sample rapidly changes its direction, i.e.
51 whenever the excitation field has a zero crossing close to the sample location. The
52 peak voltage is directly related to the steepness of the magnetization curve. The peak
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53 width mainly depends on the ratio of the width of the dynamic region as shown in
54 figure 2 and the amplitude of the drive field AD .
55
56
4.5. Spatial Resolution
57
58 One important imaging characteristic of any tomographic method is the spatial
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59 resolution. In MPI the spatial resolution is limited by the steepness of the gradient
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10 particle signal receive signal signal spectrum
11
log |ûM |
12
13
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t t
uM
15
M
16 1 7 13 19
17 f /f E
18
19
20
21 Figure 6. The signal (left) of three identical samples positioned at the FFP, at a position
us
with negative H, and at a position with positive H (see Figure 4) induces a voltage u = uM (t)
22 into an ideal receive coil (middle), which is aligned with excitation direction eD . The signal
23 spectrum (right) contains many components apart from the excitation frequency f D due to the
24 non-linear magnetization response.
25
26
field and magnetization curve, and the SNR of the measurement data. The size of the
27
28
29 curve is mainly affected by the particle size.
an
FFP is determined by the gradient strength of the selection field and the magnetization
A very simple criterion for the achievable spatial resolution has been developed by
30
31 Rahmer et al. (2009). It exploits that the MPI measurement signal can be formulated
32 in a simplified model by a spatial convolution with a kernel depending on the particle
33 magnetization curve and the applied gradient strength. The FWHM of the convolution
dM
34 is then given by
35
1
36 RFWHM = 4.16 . (17)
37 βG
38
where β as defined in (5) was the scaling factor that determined the steepness of the
39
magnetization curve and G is the gradient strength of the selection field.
40
Figure 7 shows the dependence of the spatial resolution on particle diameter and
41
gradient strength. While the resolution improves linearly with the gradient strength
42
43 it scales cubically with the particle diameter.
44 It is important to note that the gradient strength G is anisotropic for an FFP MPI
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45 scanner. For instance the preclinical MPI scanner (Bruker Biospin MRI GmbH 2014)
46 has a maximum gradient strength of 2.5 Tm−1 μ−1 0 in vertical direction and only half
47 of this value in the horizontal imaging plane. Consequently, also the spatial resolution
48 is anisotropic with a reduced resolution in horizontal directions. FFL scanners as
49 published by Erbe et al. (2011) in contrast have isotropic spatial resolution due to an
50 isotropic gradient strength perpendicular to the FFL.
51 The FWHM resolution given in (17) provides an upper bound for the spatial
52 resolution and can be observed for measurement data of low SNR. For medium to
ce
53 high SNR the actual spatial resolution can be considerably better since an image
54 reconstruction step is capable of partly undoing the smoothing effect of the MPI
55 imaging operator. In a simplified 1D model image reconstruction corresponds to a
56 deconvolution using the aforementioned imaging kernel. Since a deconvolution is an
57 ill-posed problem that can seriously amplify noise the gain in spatial resolution will
58 depend highly on the SNR of the input data. By analyzing the modulation transfer
Ac
59 function (MTF) it has been shown by Knopp et al. (2011a) that the spatial resolution
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8 CONTENTS 15
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10 3
11 20 nm
12 25 nm
2.5 30 nm
13
35 nm
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14
15 2 40 nm
RFWHM [mm]
16
17
1.5
18
19
20 1
21
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22
23 0.5
24
25 0
26 1 2 3 4an 5 6 7 8
27 G T
[ mμ ]
28 0
29
30 Figure 7. The FWHM of the convolution kernel RFWHM for different magnetite core diameters
in dependence of the gradient strength at T = 300 K.
31
32
33 can be predicted to be
dM
34
35 2π 2π
RMTF = = RFWHM (18)
36 ln (SNR(0)) βG ln (SNR(0))
37
38 where SNR(0) is the SNR of the particle signal at the excitation frequency. One can
39 see that the dependence of the spatial resolution on the SNR is logarithmically.
40
41 4.6. Temporal Resolution
42
43 The temporal resolution of MPI basically depends on the SNR, the velocity of the
44 FFP, the size of the sampling area/volume, and the density of sampling pattern. The
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45 last will be subject of section 5. The FFP velocity is determined by

46 • the excitation frequency (or frequencies in case of Lissajous trajectories),
47 • the amplitude of the excitation field,
48
49 • the gradient strength of the selection field.
50 In a high SNR 1D experiment the FFP oscillates along a line at positions
51
52 1 D
xFFP (t) = A cos(2πf D t)
ce
(19)
53 Gx
54
55 The velocity of the FFP is in turn given by
56
dxFFP (t) 2πf D AD
57 vFFP (t) = =− sin(2πf D t). (20)
58 dt Gx
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59
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8 CONTENTS 16
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10 Its maximum is given by
11
2πf D AD
12 max{vFFP (t)} =
13 Gx
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14
Assuming feasible values (AD = 10 mTμ−1 0 , Gx = 1.5 Tm
−1 −1
μ0 and f D = 25 kHz)
15
one obtains for instance max{vFFP (t)} ≈ 1047 m/s. When considering a voxel size
16
of 1 mm the resulting voxel rate is about 1 mega-voxel per second. This is about
17
18 a factor of ten better than MRI but roughly two orders of magnitude lower than
19 CT. If low SNR measurements are considered measurements have to be averaged. In
20 turn the temporal resolution drops by the number of averaged measurements, which
21 could potentially negate the speed advantage compared to MRI. However, MPI has
us
22 one practical advantage compared to MRI and CT that makes it very suitable for
23 dynamic imaging, i.e. MPI samples the object under examination directly in image
24 space and therefore has the flexibility to adjust the field of view. Hence, in practice
25 one can put the focus on single vessels or organs and in turn achieve effective voxel
26 rates that are much higher than in other imaging modalities.
A practical example of high speed data acquisition has been given by Weizenecker
27
28
29
an
et al. (2009). A volume of about 20.4 × 12 × 16.8 mm3 has been acquired in about
21.5 ms resulting in 46 volumes per second. This speed was sufficiently fast to capture
the beating mouse heart and perform in-vivo cardiac imaging.
30
31
32 4.7. Sensitivity
33
dM
34 Beside spatial resolution and imaging speed a further crucial imaging characteristic is
35 the sensitivity. In MPI the sensitivity is given by the minimum amount of iron that
36 can be detected in a small isolated sample inside the MPI system. Knopp & Buzug
37 (2012) estimated a detection limit of about 1 pg. Assuming a sensitive spot (i.e.
38 sensitive area around the FFP) of about 3 mm3 , which would allow for submillimeter
39 spatial resolution, the resulting detection limit in terms of the iron concentration would
40 be about 100 nmol(Fe) L−1 . Weizenecker et al. (2007) derived a scaling law for the
41 sensitivity in MPI assuming Langevin particles as described in section 4.1. It is given
42 by
43
√ pR f D
44 SNR ∝ T meas c0 G−3 √
pte
(21)
45 RP
46
47 where, T meas is the total measurement time, c0 is the mean particle concentration
48 within a considered voxel, pR is the sensitivity of the receive coil, f D is the excitation
49 frequency, and RP is the noise resistance of the receive coil. As mentioned by
50 Weizenecker et al. (2007), the noise in the coil might not be the limiting factor if
51 patient noise gets dominant but RP still allows for a rough estimation of the noise in
52 the system.
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53 From this one can directly see that one can trade off temporal resolution for
54 sensitivity by adjusting the measurement time T meas . In practice this can be
55 implemented by block averaging the induced voltage signal over time.
56 A further insight of (21) is that the sensitivity in MPI is inversely proportional
57 to the third power of the gradient strength, i.e. the volume of the sensitive spot
58 around the FFP. Hence, by adjusting the gradient strength one can trade off spatial
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59 resolution for sensitivity by reducing the gradient strength G. Using more effective
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18

19
20
21
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22
23
24
25

26

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27
28 Figure 8. An exemplary generic 3D MPI scanner. The FFP field is generated by the red coils,
which can also be used to apply a focus-field shift. The orange coils are used for focus-field shifts
29 in orthogonal directions. The green coils are responsible for applying homogeneous excitation
30 in three orthogonal directions. The blue coils are used for signal reception along each of the
31 three scanner axes.
32
33
dM
encoding patterns as the FFL one can reduce the dependency of the sensitivity on the
34
gradient strength to G−2 since all particles along an FFL will simultaneously induce
35
a signal in the receive coil.
36
In practical scanner implementations the theoretical limit of 1 pg has not been
37
reached yet. One major challenge is to construct a low-noise amplifier that transforms
38
39 the low voltage signal into the range of the analogue-digital-converter (ADC) without
40 adding noise. Weizenecker et al. (2009) implemented a J-FET based LNA reaching
a noise level of about 80 pV Hz− 2 at an input capacity 1 nF. Rahmer et al. (2013)
1
41
42 reported on a detection limit of 50 μmol(Fe)L−1 using this LNA which is about three
43 orders of magnitude over the theoretical limit of 100 nmol(Fe)L−1 . This indicates
44 further possibilities for improving the sensitivity by optimizing both the scanner
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45 instrumentation and the particle performance.

46
47 4.8. Instrumentation
48
49 After discussing the basic physical principles of MPI we will next give an overview of
50 the hardware components being required to actually build an MPI scanning device.
51 In general an MPI scanner consists of three main components:
52 (i) a generator for the selection field, optionally with the possibility of “slow“ FFP
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53 movements (also called focus-field shifts),

54
(ii) a generator for the excitation field,
55
56 (iii) a receiver for signal recording.
57 Each of these components has its own needs and can be realized in different ways. In
58 the following we will discuss a generic 3D MPI scanner exemplarily shown in figure 8.
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59
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10 The FFP or FFL gradient field can either be generated by permanent magnets or
11 by electromagnetic coils. Even a combination of both can be used as has been shown
12 by Weizenecker et al. (2009). A simple FFP field can be realized by two permanent
13 magnets facing each other with either their north or their south poles. Due to the
symmetry of the setup, the field at the center between both magnets cancels out.
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14
15 When moving closer to one of the magnets the magnetic field increases linearly in
16 space. Instead of permanent magnets one can also use electromagnetic coils that have
17 the disadvantage of electrical power losses but the advantage of being easily adjustable.
18 Due to physiological reasons (risk of nerve stimulation), the size of the FOV
19 covered by rapid FFP movements applied by the excitation coils is limited. For this
20 reason one needs to refocus the FFP position slowly in space as will be discussed in
21 more detail in section 5.3. This refocusing can be done using dedicated focus-field
us
22 coils generating a homogeneous field. When superimposing this focus field onto the
23 selection field, a shift of the FFP is induced. In practice it turned out to be very
24 ineffective to think of the selection field and the focus field as two different things.
25 Independently it has been shown by Knopp et al. (2012) and Vogel et al. (2014b) that
26 it is better to design the FFP field generator in a way that it inherently allows to put
an
27 the focus at different positions. This is for instance realized by Vogel et al. (2014b)
28 using a cylinder of several stacked coils. To move the FFP along the scanner axis, the
29 currents in all coils are simply “shifted“ along the scanner axis. Knopp et al. (2012),
30 Kaethner et al. (2014), and Mrongowius (2016) optimized the currents of multi-coil
31 setups numerically to reduce the overall power loss leading to highly power efficient
32 field generators. In the human scanner outlined by Borgert et al. (2013) the use of
33
dM
appropriately shielded iron cores has been proposed reducing the total electrical power
34 loss even further.
35 The excitation or drive-field coils are mounted closer to the scanner to reduce
36 eddy current losses. Usually the drive-field coils are made of Litz wire to mitigate the
37 skin effect (Kaden 2006). They are supposed to generate a homogeneous magnetic field
38 to ensure that all particles in space are equally excited. However, the homogeneity
39
requirements for the drive field are much weaker than in MRI. Homogeneous drive
40
fields can be realized by solenoids or Helmholtz coil pairs. In case of two or three
41
drive-field coils one has to decouple the channels appropriately.
42
The receive coils are also made of Litz wire and realized as solenoids or Helmholtz
43
coil pairs. In some scanners the drive-field coils are also used for signal reception as
44
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for instance in the scanner developed by Weizenecker et al. (2009).

45
46 Actual scanner implementations can differ more or less from the discussed generic
47 scanner. For instance many scanner only have a single excitation direction making the
48 scanner setup much simpler (Goodwill et al. 2009, Goodwill & Conolly 2010, Vogel
49 et al. 2014b). Due to an asymmetric coil design, the single-sided scanner developed
50 by Sattel et al. (2009b) and by Gräfe et al. (2016) have very inhomogenous send and
51 receive coil sensitivities. The type of FFL scanners published by Bente et al. (2015),
52 Knopp et al. (2011b), and Konkle et al. (2013) have an additional need to rotate
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53 the FFL to generate tomographic images. Projection FFL scanners require only the
54 generation of an FFL along a static direction in space.
55
56 4.9. Analog Signal Chain
57
58 In the former section we have discussed the general coil setup of an MPI scanner.
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59 Next, we investigate the analog signal chain of the send and receive coils in more
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12

13

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15
16
17
18
19
20
21
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22

23

24
25
26

27
28
29
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Figure 9. Overview of a typical MPI signal chain. The excitation signal is generated using a
30
power amplifier and after filtering applied to the excitation coil. The induced receive signal is
31 first filtered, then amplified, and finally digitized.
32
33
dM
34 detail.
35 An overview of the MPI signal chain is given in figure 9 showing the chain of one
36 pair of send and receive coils. In case of multiple send and receive coils a dedicated
37 signal chain will be realized for each excitation direction. The signal for moving the
38 FFP is generated using a power amplifier. Since MPI requires a pure sinusoidal for
39 signal excitation, the quality of the power amplifier signal is improved using a band-
40 pass filter. Then the signal is applied to the send coils, which are usually realized as
41 oscillating circuits being resonant at the send frequencies.
42 The MNP sample will respond to the excitation signal with a time varying
43 magnetization that is measured with a receive coil. This signal is rich of higher
44
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harmonics and therefore requires a broadband receive chain. It is unavoidable that

45 the send signal directly couples into the receive coil. Since the direct feedthrough of
46 the send coils is several orders of magnitude larger (109 – 1012 in practice) than the
47 particle signal one needs to get rid of the excitation signal within the analog receive
48 chain. To this end, one can use a gradiometric approach that uses a second receive
49 coil that sees the same signal from the receive coil but no particle signal. Putting both
50 signals in series but with opposing winding directions will then cancel out the send
51 signal by up to a factor of 103 – 105 . An alternative to the gradiometric approach is to
52
ce
use a band-stop filter as is shown in figure 9. The filter cancels out the excitation signal
53
but only a small part of the particle signal. All higher harmonics of the excitation
54
signal can be used for the reconstruction of the particle distribution. Both approaches
55
can also been combined as has been proposed by Graeser et al. (2013).
56
After signal compensation and/or filtering the voltage is usually in the pV range
57
and therefore has to be amplified to fit into the input range of the digital-to-analog
58
Ac
converter. The amplifier needs a very low noise characteristic (LNA: low noise
59
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3
4
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8 CONTENTS 20
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9
10 amplifier) to detect the small pV signal. After amplification the signal is digitized using
11 the ADC and stored in a file on the measurement computer for further processing.
12 Realizing an ultra low noise amplifier is a major engineering effort. Weizenecker
13 et al. (2009) developed a liquid cooled J-FET-based LNA reaching a noise level of
1
80 pV Hz 2 at 1 nF input capacity. The receive amplifiers are usually designed in several
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14
15 stages where only the first stage has to maintain the ultra low noise characteristic.
16 The MPI signal chain discussed so far was based on a sinusoidal excitation. Tay
17 et al. (2016) developed a relaxometer that allows to apply an arbitrary waveform to
18 the send coils. This can be achieve by avoiding filters in the send and receive chain
19 using a gradiometric approach for removing the direct feedthrough signal.
20 An entirely different receive concept has been discussed by Colombo et al. (2016).
21
us
The authors proposed to use atomic magnetometers that have the advantage of
22 allowing to record not only the time derivative of the magnetization but M (H) directly.
23 The sensitivity of this concept compared to the classical inductive signal detection
24 approach still has to be investigated.
25
26
5. Imaging Sequences
27
28
29
an
As discussed in the last section, the MPI imaging principle is based on the fast
movement of the dynamic region through space to generate a signal from all particles
30 within. This dynamic region is usually either the region around a FFP or a FFL.
31 Here, we will discuss on how to move the FFP or the FFL to generate a signal from
32
particles in a predefined region-of-interest (ROI) being usually a 2D slice or a 3D
33
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volume. The main discussion will focus on FFP based imaging sequences, which are
34
more commonly used at the moment. At the end of this section a small introduction
35
into FFL imaging sequences will be given.
36
In MPI an imaging sequence can be categorized with respect to its sampling
37
trajectory, i.e. the trajectory of the FFP through the ROI
38
39
Ψ : R → R3 , H(Ψ(t), t) = 0.
40
41 Knopp et al. (2009) performed the first comprehensive comparison between
42 different FFP MPI sampling trajectories in a simulation study. In particular the
43 authors compared Lissajous, Cartesian, bidirectional Cartesian, Radial, and Spiral
44
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trajectories, which are sketched in figure 10 (a) to (e) respectively. The authors
45 observed a rough correlation between sampling density and image quality. As such
46
the Radial trajectory resulted in low image quality in outer regions and a good quality
47
in the center. The Lissajous and the bidirectional Cartesian trajectory resulted in the
48
best image quality whereas the unidirectional Cartesian trajectory had a reduced
49
spatial resolution orthogonal to the direction of the fast FFP movement. This
50
observation was latter explained by Goodwill & Conolly (2011) using a theoretical
51
model, where the authors derived that the associate MPI convolution kernel is much
52
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53 sharper in direction of the FFP movement compared to orthogonal directions.

54 The initial simulation study by Knopp et al. (2009) investigated a variety of
55 possible trajectories but did not account for the effort required to implement a certain
56 trajectory. In fact all published scanners world wide either implemented a Lissajous
57 or the Cartesian trajectory while the later was done mostly in a unidirectional fashion.
58 To date the only scanner capable of applying bidirectional Cartesian trajectories was
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59 published by Goodwill et al. (2014). In the following two sections a more detailed
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10 (a) Lissajous (b) Cartesian (c) Bidirectional
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(d) Radial (e) Spiral (f) Rose
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26 an
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32 Figure 10. Graphical illustration of different possible MPI sampling trajectories.
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34
discussion on the Lissajous and the unidirectional Cartesian MPI trajectory will be
35
given.
36
37
38 5.1. Cartesian Imaging Sequences
39 The (unidirectional) Cartesian trajectory (see figure 10 (b)) has been used in the very
40 first MPI publication (Gleich & Weizenecker 2005). It consists of several sequential 1D
41 excitations shifting the FFP back and forth using a single drive field-coil orientated
42 in a certain static direction. This 1D sampling line is then shifted perpendicular
43
to the fast FFP movement. This can either be done mechanically (e.g. by moving
44
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the object) or electromagnetically by applying focus fields. In order to achieve 3D

45
Cartesian trajectories the scanline has to be shifted to all positions within the plane
46
being orthogonal to the scanline. For instance, when the excitation is done in x-
47
direction the 1D scanline has to be shifted within the yz-plane.
48
Compared to other image sequences a scanner using the unidirectional Cartesian
49
50 trajectory requires much less hardware effort to build. In particular only a single
51 drive field channel is required in contrast to three drive field channels for the Lissajous
52 trajectory. While in principle the Cartesian trajectory can be realized to enable real-
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53 time imaging (Vogel et al. 2016), most of the other published scanners have a low
54 temporal resolution requiring several minutes to capture a 3D dataset. Vogel et al.
55 (2016) proposed a traveling wave sampling scheme using a sophisticated combination
56 of the selection and focus field allowing for rapid movement of the 1D scanline through
57 the scanner bore. At last, the reconstruction of data from Cartesian sequences is much
58 less comprehensive than the reconstruction of data from Lissajous type sequences.
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10 ND = 5 ND = 10 ND = 15
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21 Figure 11. Influence of the density parameter ND on a 2D Lissajous trajectory.
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24 5.2. Lissajous Imaging Sequences
25 A Lissajous trajectory (see figure 10 (a)) has been first used by Gleich et al. (2008).
26 In principle Lissajous trajectories are a straight forward extension to unidirectional
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27 Cartesian trajectories. Instead of one excitation coil which moves the FFP along a line
28 two or three mutually orthogonal coils are used. Each coil is driven by a frequency
29 which moves the FFP in two respectively three dimensions. If the frequencies are
30 commensurable the FFP moves along a Lissajous trajectory. In this section we will
31
review this basic principle for two coils creating a 2D Lissajous trajectories. The
32
extension to 3D is straight forward and can be found in (Knopp & Buzug 2012).
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A 2D Lissajous trajectory can be realized by applying two drive fields in
34
orthogonal direction. The drive fields have a similar frequency, i.e.
35
36 fx ≈ fy . (22)
37
38 In order to keep the repetition time T R finite, one has to choose commensurable
39 frequencies fulfilling the relation
40
41 fy Kx
= . (23)
42 fx Ky
43
44 Here, Kx and Ky are natural numbers determining the frequency ratio. Similar
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45 frequencies can for instance be obtained for

46
47 fy ND
= . (24)
48 fx ND + 1
49
When increasing the parameter ND the frequencies get more similar and the repetition
50
time
51
52 ND + 1 ND
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53 TR = = (25)
fx fy
54
55 increases. Hence, the parameter ND controls the density of the Lissajous trajectory.
56 Figure 11 shows the influence of the density parameter ND on a 2D Lissajous
57 trajectory.
58 The Lissajous trajectory is known for its fast imaging speed. During one cycle the
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59 FFP samples a 2D region. Covering the same region with a unidirectional Cartesian
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10 trajectory requires to use focus fields, which are switched much slower resulting in a
11 longer overall scan time. Moreover, Cartesian trajectories are usually measured piece-
12 wise by dropping the data when shifting the scanline from one position to the next,
13 whereas the Lissajous trajectory inherently has a continuous sampling with 100% duty
cycle. A further advantage of the Lissajous trajectory is the two-fold crossing of each
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15 location in almost orthogonal fashion. Therefore, the spatial resolution is isotropic
16 and high.
17 One challenge for the Lissajous trajectory is that the reconstruction is in practice
18 much more sophisticated compared to the reconstruction of Cartesian data. For the
19 latter there exists a variety of possible reconstruction methods, whereas the former
20 requires a reconstruction based on tedious calibration measurements (see section
21 6.2.2). This is due to the complicated particle dynamics during Lissajous type
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22 measurements, which is much easier to predict for Cartesian FFP trajectories.
23
24 5.3. Multi-Patch Imaging Sequences
25
26 The area/volume captured by a single FFP cycle is usually referred to as drive-
field field-of-view, short DF FOV. For sinusoidal excitations the size of the DF FOV
27
28
29
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is proportional to the quotient of drive-field amplitude and selection field gradient
strength. Due to physiological constraints, i.e. the risk of peripheral nerve stimulation
(PNS) (Saritas et al. 2013a, Schmale et al. 2013, Saritas et al. 2015)), the amplitude
30
31 and the frequency of the drive field is limited for measurements involving living
32 subjects. Considering a potential drive-field limit of 10 mTμ−1 0 , a gradient strength
33 of 2 Tm−1 μ−1 in z-direction, and -1 Tm −1 −1
μ in x-/y-directions, the DF FOV has a
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0 0
34 size of 2×2×1 cm3 , which is too small for most human applications.
35 To mitigate the limitation of a small DF FOV, Gleich et al. (2010) introduced the
36 focus-field concept (also referred to as partial FOV scanning by Goodwill & Conolly
37 (2011)). A homogeneous focus field is superimposed onto the selection field leading
38 to a shift of the FFP position and in turn a shift of the entire DF FOV. Physiological
39 constraints allow the application of much higher magnetic fields due to the low focus-
40 field frequency and in turn much larger volumes to be imaged.
41 In general one has to distinguish continuous focus-field sequences and discrete or
42 stepped focus-field sequences. The latter moves the DF-FOV from station to station
43 and data is measured at each station for reconstruction. An illustration of such a
44
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stepped focus-field sequence can be found in figure 12.

45 Focus-field sequences are very commonly applied for Cartesian trajectories. These
46 trajectories inherently require focus fields to shift the scanline perpendicular to the
47 excitation direction. Furthermore, shifts in scanline direction are required in order to
48 enlarge the FOV in that direction. A typical 2D Cartesian trajectory includes FOV
49 extension in excitation direction and is shown in figure 13.
50 One very important practical question for stepped multi-patch imaging sequences
51 is if the individual patches have to overlap or can be located edge to edge, which will
52
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decrease the number of patches required to cover a certain region. Knopp et al. (2015)
53
have shown that an artifact-free reconstruction is possible for non-overlapping multi-
54
patch data. The overlap has been studied in more detail by Ahlborg et al. (2016)
55
where these findings have been confirmed.
56
When considering the reconstruction of multi-patch data one can either use
57
58 a separate or a joint approach. The former reconstructs the data of each patch
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59 individually and merges the reconstruction results in a post-processing step. In the

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Figure 12. Static multi-patch focus-field sequency. The individual patches can be placed edge
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to edge without any overlap.
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46
Figure 13. Multi-patch Cartesian trajectory with a FOV extension in the excitation direction.
47
48
49 joint case, all patches are reconstructed in a single step using a joint imaging equation,
50 which couples the individual patches. This usually requires the handling of very huge
51 data sets. As shown by Knopp et al. (2015), a joint reconstruction approach is the key
52 to reconstruct non-overlapping multi-patch data without image artifacts at the patch
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53 borders.
54 The reason for the coupling between different patches was theoretically analyzed
55 by Weber et al. (2016). It was found that particles outside the DF FOV generate a
56 signal in the receive coils since the particle magnetization curve is no step function.
57 Weber et al. (2016) introduced the so-called overscan that extends the DF FOV by
58
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a certain margin that covers all positions with detectable particle signal (see figure
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10 DF-FOV overscan SF-FOV
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16 2Ay
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22 2Ax
23 Gx
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25 Figure 14. Graphical illustration of the overscan that extends the DF FOV by a certain margin
26 where MNPs still generate an MPI signal. The union of the DF FOV and the SF FOV is usually
used to sample the MPI system matrix.
27
28
29
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14). When sampling the MPI system matrix at the entire system function FOV (SF
30
FOV) it is possible to quantitatively reconstruct the data within the DF FOV without
31
32 introduction of artifacts. If the overscan is omitted during reconstruction one can
33 observe artifacts at the boundaries stemming from particles located outside the DF
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34 FOV.
35 In summary, the research field of multi-patch imaging sequences can be expected
36 to gain more significance in the future. Considering clinical MPI scanners the number
37 of focus-field patches will increase to hundreds and thousands. Since the scan time
38 increases linearly with the number of patches, partial focus-field sampling techniques
39 will be required to keep the scan times within acceptable ranges.
40
41 5.4. Field-free Line Imaging Sequences
42
Field-free line imaging was initially proposed by Weizenecker et al. (2008). However,
43
the proposed scanner required currents that would be unfeasible to realize in practice.
44
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45 Knopp et al. (2010a) and Knopp et al. (2010f) developed much more efficient coil
46 topologies requiring power similar to FFP scanners of the same size.
47 When using an FFL one can chose between projection imaging and tomographic
48 imaging. Projection imaging has been introduced by Goodwill et al. (2012). From an
49 imaging sequence perspective projection FFL imaging is straight forward and involves
50 a regular 2D trajectory in the plane orthogonal to the FFL. This is usually done along
51 a Cartesian trajectory though other trajectories like the Lissajous trajectory could
52 also be used.
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53 Tomographic imaging using an FFL is technically much more challenging since it

54 requires a scanner topology allowing the rotation of the FFL. A first prototype of a
55 rotating FFL has been introduced by Erbe et al. (2011) and first imaging experiments
56 have been performed by Konkle et al. (2013) and Bente et al. (2015).
57 The trajectory of choice for tomographic FFL imaging is shown in figure 15. The
58 FFL moves rapidly back an forth within the imaging plane. During or in-between
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59 this rapid movement, the FFL rotates slowly. Thus, the FFL follows a rose or a
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19

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22
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26 an
27
28 Figure 15. Exemplary 2D FFL sampling trajectory. The FFL moves rapidly back and forth
29 while rotating slowly. The rotation can either be realized in a continuous (as shown) or in a
30 step-wise fashion.
31
32
radial trajectory. It is well known from CT that data acquired in this way allows
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to reconstruct an object since the projection through the object has been measured
34
35 at several different angulations covering a range of at least 180 degrees. This fact is
36 mathematically described by the Fourier slice theorem that has been derived for FFL
37 MPI imaging by Knopp et al. (2011b).
38
39 6. Image Reconstruction
40
41 Unlike the projection data in CT, MPI raw data is not suitable for direct visualization.
42 Instead, one has to perform a reconstruction step first that transforms the measured
43 voltages into particle concentrations. Within this section we will review the MPI image
44 equations and the corresponding reconstruction algorithms developed during the last
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45 12 years. A good overview about different reconstruction approaches has been given
46 by Grüttner et al. (2013).
47 The key assumption shared by all MPI reconstruction techniques is that the
48 relation between the particle concentration c(r) at position r ∈ Ω ⊂ R3 and the
49 measurement signal ul (t) is linear:
50
51 ul (t) = sl (r, t)c(r) d3 r. (26)
52 Ω
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54 This linearity is a direct consequence of (3) and can be derived directly from (16). In
55 practice most systems use coils to measure the generated signal in which case ul (t) is
56 a voltage signal, and l = 0, . . . , L − 1 is the index of the receive coil and sl (r, t) is the
57 integral kernel describing the mapping between particle concentration and voltage.
58 Due to the analog band-stop filter in the analog receive path (see section 4.9),
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59 neither ul (t) nor sl (r, t) are usually measurable at the excitation frequencies. Since a
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10 certain portion of the excitation signal is still present it is very common to consider
11 both signals in frequency space where the excitation signal can be easily removed.
12 Since, ul (t) and sl (r, t) are both periodic functions they can be expanded into Fourier
13 series such that the integral equation (26) can be reformulated as

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15 ûl,k = ŝl,k (r)c(r)d3 r, (27)
16 Ω
17 where ûl,k is the k-th Fourier coefficient of the measurement signal ul (t), usually
18 limited by some upper frequency index K that is derived by the sampling bandwidth.
19 ŝl,k (r) is the system function in frequency space.
20 The measurements ûl,k are indexed by the number of the receive channel l and
21
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the frequency index k. For reconstruction it is often more convenient to introduce a
22
linear index j that traverses l and k using the unique mapping
23
24 j = k + lK k = 0, . . . , K − 1; l = 0, . . . , L − 1. (28)
25
26 In this case j runs from 0, . . . , M − 1 with M = KL. Therefore, ûj := ûl,k as
well as ŝj (r) := ŝl,k (r) are the linearly indexed measurement and system function
27
28
29
respectively.
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30 6.1. Analytic Methods
31
32 We first discuss analytic reconstruction methods. Instead of explicitly arranging the
33 linear system (34), these methods make certain assumptions allowing to formulate an
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34 explicit algorithm for direct reconstruction of the particle reconstruction.
35
36 6.1.1. x-space reconstruction The so-called x-space reconstruction has been initially
37 proposed by Goodwill & Conolly (2010). x-space reconstruction aims to reconstruct
38 MPI data from 1D measurements usually acquired with Cartesian trajectories. In its
39 original formulation a linear selection field, a homogeneous drive field and particles
40 having infinitely fast relaxation times are assumed. Each of these points can be
41 partially relaxed but we will first assume that all assumptions hold.
42 Considering a 1D excitation in x-direction with the drive field
43
44 H D (t) = −AD
x cos(2πf t)
D
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45
46 the MPI time domain image equation can be formulated as
47 ∞
D
48 ũ(t) = (H ) (t) c(x)m̃(−G−1
x H (t) − x) dx
D
49 −∞

50 = (H D ) (t) (c ∗ m̃) −G−1x H (t) ,
D
(29)
51
52 where ũ is the measured signal that is normalized by all constant factors occurring
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53 in (16). The kernel m̃(x) is derived from the derivative of the particle magnetization
54 curve M (H) with respect to the magnetic field strength H (Goodwill & Conolly 2010).
55 Thus, the 1D imaging equation can be expressed as a spatial convolution of the particle
56 concentration c and the kernel m̃(x) weighted with the derivative of the drive-field
57 (H D ) (t), i.e. the speed of the FFP at time t.
58 Using (29) one can derive a direct reconstruction algorithm consisting of the
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10 (i) FFP speed normalization:
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ũ(t)
12 uN (t) := D
= (c ∗ m̃) −G−1
x H (t) ,
D
(30)
13 (H ) (t)
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14 (ii) Gridding of data onto FFP trajectory:
15
16
1 Gx FFP
17 ux (xFFP ) = uN arccos x = (c ∗ m̃) (xFFP ), (31)
2πf D AD
x
18
19 with
20
21 H D (t) AD
= x cos(2πf D t),
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xFFP (t) = − (32)
22 Gx Gx
23
and
24
25 (iii) Deconvolution of the gridded data:
26 c(x) is obtained by deconvolution of ux (xFFP ) with the kernel m̃(x).
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27 We note that we have formulated the algorithm in a continuous form whereas in
28 practice both ũ(t) and ux (xFFP ) will only be available on equidistant sampling grids
29 after proper discretization.
30 The big advantage of x-space reconstruction is its simplicity. Step (i) is a
31 weighting of the input signal whereas step (ii) requires interpolation to obtain the
32
gridded signal at equidistant FFP positions. The deconvolution (step (iii)) is a well
33
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understood inverse problem for which efficient algorithms like Wiener filtering are
34
available.
35
One challenge of x-space reconstruction is that the signal ũ(t) is not fully
36
accessible since the analog filter (see section 4.8) has effectively removed the signal at
37
the excitation frequency. But as Lu et al. (2011) and Lu et al. (2013) have shown, the
38
39 missing excitation frequency only leads to a DC offset in the reconstructed particle
40 concentration that can be corrected using appropriate boundary conditions.
41 Field inhomogeneities have been first addressed by Tateo et al. (2016). The
42 authors proposed a method that determines the position of the FFP over time using
43 a calibration procedure taking into account all field imperfections. This calibration
44 curve describes the precise position of the FFP xFFP (t), which then can be used during
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45 the gridding step of x-space reconstruction.

46 In measured data a relaxation behavior of the MNPs can be observed. This leads
47 to a slightly delayed response of the particle magnetization leading to deviations in
48 the spatial mapping during the gridding step. Croft et al. (2012) have shown that the
49 relaxation behavior can be modeled using a convolution with an effective exponential
50 relaxation function. By taking this into account Croft et al. (2012) were able to correct
51 the relaxation behavior in the x-space reconstruction. Later, this algorithm has also
52 been used by Bente et al. (2015) to reconstruct FFL measurements.
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53 It remains an open question if it is feasible to reconstruct Lissajous type data

54 using an x-space algorithm. Schomberg (2010) and März & Weinmann (2016) have
55 developed theoretical algorithms for multidimensional x-space reconstruction that
56 have been validated on simulated MPI data. However, till now no experimental data
57 has been reconstructed using these algorithms. The general problem of handling
58 Lissajous type data are particle relaxation effects which are much more challenging to
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10 In its original form x-space reconstruction is applied to Cartesian 2D/3D data line
11 by line and the final image is obtained by stitching together the individual scanlines. In
12 addition, for overlapping scanlines a continuation algorithm is applied (Lu et al. 2011)
13 to determine the unknown DC part of the reconstructed data. A joint reconstruction
algorithm for x-space has been first proposed by Konkle et al. (2015b). It accounts for
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15 the coupling between neigbouring scanlines and in turn yields improved reconstruction
16 results. The approach is similar to those discussed in the next section but does not
17 explicitly arrange the MPI imaging matrix S. Instead, multiplications involving S are
18 calculated on-the-fly significantly reducing the memory load during reconstruction.
19
20 6.1.2. Chebyshev reconstruction A further analytic reconstruction algorithm for 1D
21
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experiments has been developed by Rahmer et al. (2009). It uses a frequency space
22 representation of the induced signal and exploits that the signal (in frequency space)
23 can be represented by the coefficients of a weighted Chebyshev transformation that
24 can be efficiently and directly inverted. Grüttner et al. (2013) have shown that x-space
25 reconstruction and weighted Chebyshev reconstruction are mathematically equivalent
26 and in turn lead to the same reconstruction result. an
27
28 6.2. Algebraic Methods
29
30 Next, we will review algebraic reconstruction methods that solve the inverse problem
31 in Eq. (34). All these methods have in common that they require knowledge of the
32 system matrix S prior to reconstruction.
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34 6.2.1. Discrete Setting Prior to algebraic reconstruction, the continuous imaging
35 equation (27) has to be discretized using a suitable quadrature rule. To this end, Ω is
36 usually covered by a rectilinear grid with N integration points r n , n = 0, . . . , N − 1.
37 These are then used to approximate the integral using for example the rectangular
38 quadrature rule. One obtains the discrete imaging equation
39
N
−1
40
41 ûj = ŝj,n cn . (33)
n=0
42
43 Here, ŝj,n := wn ŝj (r n ) and ĉn := ĉ(r n ) are the sampled system function and particle
44 concentration, respectively. The quadrature weights wn are constant for rectilinear
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45 grids but can also be spatially dependent for non-regular sampling schemes as were
46 used by Kaethner et al. (2016). The system matrix S is obtained by calibration
47 measurements. A small tracer sample of volume Vsample is placed at each position r n
48 followed by a MPI measurement u(r n ). To account for the finite size of the sample
49 and the quadrature weights the measurements are normalized and stored in the system
50 matrix ŝj,n = wn /Vsample uj (r n ). Eq. (33) can be compactly written in matrix vector
51 form
52
ce
53 Sc = û, (34)
54 where
55
56 S = (ŝj,n )j=0,...,M −1;n=0,...,N −1 ∈ CM ×N (35)
57 M −1
58 is the MPI system matrix, u := (ûj )j=0 ∈ CM is the measurement vector, and
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59 c := (cn )n=0 ∈ R+
0 is the particle concentration vector.
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Figure 16. Left: The robot used to acquire the system function by calibration measurements in
25 a preclinical MPI system (Bruker Biospin MRI GmbH 2014). Right: Two different calibration
26 samples. A cube like sample to obtain 3D system functions and a glass capillary to measure 2D
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27 system functions.
28
29
30 6.2.2. Determining the System Matrix The system matrix S can be obtained by a
31 calibration-based, a model-based, a hybrid, or a compressed-sensing approach, all of
32 which will be discussed in the following subsections.
33
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34 Calibration Based: The calibration based method can be considered to be the gold
35 standard to obtain a system matrix, since it has been used in many publications with
36 great success. The basic idea is to measure the system matrix directly by placing a
37 small delta sample into the FOV. In fact if the size of the delta sample matches the size
38 of the grid cells used for discretization one can directly measure the discrete system
39 matrix. Measuring the delta sample at positions r n yields measurements ûj (r n ),
40 which are directly related to the system matrix entries ŝj,n
41
42 ûj (r n ) = cdelta wn ŝj (r n ) = cdelta ŝj,n . (36)
43
44 Here, cdelta is the particle concentration within the delta sample. If cdelta is known
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45 the system matrix can be obtained by ŝj,n = cjdeltan .
46 The positioning of the delta sample at the N sampling positions is usually realized
47 using a 3-axis robot that has sufficient positioning accuracy (see figure 16). The delta
48 sample is usually mounted at the tip of a rod which is inserted into the scanner bore.
49 MPI measurements are performed at each position when the robot is fully rested. To
50 estimate the total time for the measurement of the system matrix, the robot movement
51 time and the time for rod oscillations to die away have to be taken into account. When
52 considering a measurement time of 1 s, a time delay between measurements of 1 s,
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53 and 30 × 30 × 30 positions to be measured in a 3D volume, the required calibration

54 time is Tcalib = 15 h.
55 This quite long acquisition time is also the main drawback of the calibration based
56 method. Additionally, since the voxel size is usually chosen as small as possible the
57 SNR of the measurement in the calibration is usually low. The SNR can be improved
58 by averaging the signal over multiple measurement cycles, which comes at the cost of
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10 is that it does not require any models for scanner hardware or the physical behavior
11 of the particles, since the system matrix takes all system imperfections into account.
12
13 Model Based: An alternative way to determine the system matrix has been proposed
by Knopp et al. (2010c). Instead of measuring the system matrix using a delta sample,
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15 the entire MPI system is simulated using an appropriate model of the signal chain.
16 This includes modeling
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• all magnetic fields and the sensitivity profiles of the receive coils,
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19 • the dynamic response of the particles to the excitation signal, and
20 • for each receive channel the transfer function of the receive chain.
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It has been shown by Knopp et al. (2010c) that a model-based system matrix can be
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used to reconstruct images with similar quality compared to reconstructions using a
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calibration based system matrix. These findings were verified on 2D measurement data
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25 acquired using a Lissajous trajectory by Knopp et al. (2010d). Nonetheless, modeled
26 and measured system matrix show deviations if the particle dynamics is approximated
by a simple Langevin function based particle model (Knopp et al. 2010d). More
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accurate particle models are therefore a key research field to model more accurate
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31 Hybrid: A very promising approach for determining system matrices in MPI has
32 been proposed by Grüttner et al. (2011) and Halkola et al. (2012). The so-called
33 hybrid system matrix approach uses both simulation and calibration measurements
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34 to obtain an accurate system function. The idea is to decouple the magnetic fields
35 in the scanner and the field dependent particle magnetization response. While the
36 magnetic fields can be accurately modeled, the field dependent particle magnetization
37 response is measured using calibration measurements. Calibration measurements can
38 be performed, such that they are not restricted by the main drawbacks of the robot
39 based approach:
40
• The measurements do not require robot movements, which takes a lot of time in
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the calibration based system matrix acquisition.
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43 • The resulting system matrix has a much better SNR, since the size of the delta
44 sample can be chosen independent of the system matrix voxel size.
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45 The basic principle of hybrid system matrix acquisition is illustrated in figure 17. The
46 selection field is turned off and the homogeneous focus fields are used to create an
47 offset field being equal to the selection field at a specific point in space. A prerequisite
48 is that the focus fields are able to emulate each field, which is usually present within
49 the selection field. Instead of moving a small delta sample around, a large sample
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is placed inside the scanner. The pre-selected offset fields corresponding to certain
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positions within the selection field are switched and measurements of the delta sample
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position within the selection field.
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Instead of using the MPI scanner itself for the hybrid measurements it is also
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possible to use a dedicated device. In particular a multidimensional MPS with offset
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57 fields as has been introduced by Graeser et al. (2015) and Schmidt et al. (2016) is
58 suitable for this task.
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44 Figure 17. Hybrid system function determination. Instead of moving a small delta sample
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45 through space (left), the selection field is emulated using a homogeneous focus field (right).
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48 Compressed Sensing Calibration: Alternative ways to significantly reduce the
49 acquisition time of the calibration based approach have been proposed by Knopp
50 & Weber (2013), Weber & Knopp (2015b), and Weber & Knopp (2015a).
51 In the first publication the authors brought the concept of compressed sensing to
52 MPI by exploiting that the MPI system matrix is highly compressible. They showed
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53 that a compressed sensing reconstruction (Lustig et al. 2007) can be used to measure
54 the MPI system matrix at only few randomly chosen positions and then calculate the
55 full system matrix by solving an L1 minimization problem. Both the DCT and the
56 FFT have been shown to be suitable sparsity transformations for the MPI system
57 matrix.
58 Next, Weber & Knopp (2015b) proposed that the spatial symmetries of the system
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10 system matrix has to be acquired. The remaining three quarters can then be filled
11 by mirroring the measured quarter and multiplication with appropriate symmetry
12 factors.
13 Finally, Weber & Knopp (2015a) showed that the former methods can be
combined, requiring even less calibration scans to obtain an MPI system matrix. It
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15 is worth mentioning that both methods could also be applied to the hybrid system
16 matrix approaches discussed in the previous subsection.
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18 6.2.3. Frequency Selection Within section 4.4 we already found that for inductive
19 receive chains the measured signal does not only stem from excited particles but
20 also from the excitation signal directly coupling into the receive coils. However, one
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implicit assumption of image reconstruction is that the measured signal solely contains
22 the particle signal, whereas one usually measures a superposition of the particle signal
23 and other sources
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25 û = ûBG + ûparticles .
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Here, the background signal ûBG adds up all other signal sources like e.g.:
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• the excitation signal, which directly couples into the receive coils,
• other background sources stemming from hardware imperfections.
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31 If ûBG is static, it can be measured using an empty scanner bore. Afterwards, uBG
32 can be subtracted from any following regular measurement yielding the pure particle
33 signal uparticles (Them et al. 2016a). If the background signal is changing with time it
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34 is not possible to remove the background signal by subtraction. In this case it is more
35 effective to apply a frequency filter that excludes frequency components (i.e. matrix
36 rows) distorted by the background signal. Usually this is required at least for the
37 excitation frequency components. Henceforth, let IBG denote the set of frequencies
38 for which the particle signal is distorted by time dependent background.
39 Even if all the stationary background and time dependent sources are removed
40 the remaining signal still contains noise. Therefore, it can be advantageous to remove
41 frequency components with poor SNR prior to reconstruction. To this end, the SNR
42 values of the system matrix can be determined based on empty reference measurements
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(Franke et al. 2016, Rahmer et al. 2012). Based on these values a threshold σmin is
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applied to filter out low signal frequency components. The remaining frequencies are
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given by
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47 ISNR = {fk | SNR(fk ) > σmin }. (37)
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49 For reconstruction one can then restrict the frequencies to the set ISNR \IBG (Knopp
50 et al. 2010h). If one removes the blacklisted frequencies from both the system matrix
51 S and the measurements vector û, one obtains the reduced linear system
52
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53 S red c = ured . (38)

54
55 Due to the frequency removal the system matrix S red has only M̃ rows and thus is of
56 dimension M̃ × N . Knopp & Hofmann (2016) have shown that the reduction of active
57 frequency components used for reconstruction is effectively a regularization technique
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10 λ̃ = 0 λ̃ = 10−4 λ̃ = 5 · 10−3 λ̃ = 10−1 λ̃ = 102
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19 Figure 18. Influence of the regularization parameter λ̃ on the least squares solution for
20 experimental 2D MPI data measured with a three-point phantom.
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23 6.2.4. Least Squares Approach After background subtraction and frequency selection
24 the reduced system (38) has to be inverted. Due to noise the existence of a solution
25 can not be guaranteed if the system is inverted directly. Hence, one solves the least
26 squares minimization problem an
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28 argminS red c − ured 22 , (39)
c
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30 to obtain a solution describing the measured data as good as possible. The norm in
31 equation (39) is referred to as data term. In the next section we will discuss how this
32 term can be used as the basis for more advanced reconstruction methods.
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34 6.2.5. Regularization Since the MPI system matrix is known to be ill-conditioned
35 (Knopp et al. 2008), the least squares approach (39) will fail if the noise in the
36 measured data is too high. This is due to noise amplification that is only bounded
37 by the condition number of the system matrix. The standard approach to handle
38 this issue is to add a penalty term c22 to the data term penalizing solutions with
39 large L2 norm, which is known as Tikhonov regularization. The Tikhonov regularized
40 optimization problem then reads
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42 argminS red c − ured 22 + λc22 . (40)
43 c
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The regularization parameter λ ∈ R+ is used to weight data and penalty term. Usually
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instead of λ one reports λ̃ = λλ0 with λ0 = trace(S red S red )N −1 .
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47 The influence of the regularization parameter λ̃ is shown in figure 18. If λ̃ is
48 chosen too small, the image will be very noisy and the phantom data will hardly be
49 detectable. Increasing λ̃ reduces the noise but smoothes the data leading to a loss in
50 spatial resolution. For the shown noisy measurement of a phantom the optimum is
51 found at λ̃ = 5×10−3 leading to a good compromise between noise supression and over-
52 regularization. In practice the regularization parameter is usually hand-tuned with
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53 respect to visual inspection of the reconstructed images. Automatic determination of

54 an optimal λ̃ using the L-curve method has been proposed by Knopp et al. (2008).
55 The Tikhonov regularization functional (40) is usually extended to additionally
56 take physical constraints into account. In particular it is known that the particle
57 concentration vector c should only contain values that are real and non-negative. Due
58 to noise in the measurement data and due to the bias induced by the regularization,
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10 Phantom Tikhonov regularization TV and L1 regularization
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22 Figure 19. Reconstruction results of experimental 3D MPI data taken from a vessel phantom
23 with an induced stenosis (left). In the middle the result using Tikhonov regularization is shown
while on the right a combined total variation and L1 regularization has been applied.
24
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26 with a non-zero imaginary part. As it has been discussed by Weizenecker et al. (2009)
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27 applying a real and non-negativity constraint improves the overall image quality.
28 Quite recently, Storath et al. (2016) have proposed a more sophisticated
29 regularization approach. The authors proposed to use the nonnegative fused lasso
30 model
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32 argminS red c − ured 22 + αc1 + βT V (c) (41)
33 c
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35 that accounts for prior knowledge. Instead of the penalty term from the Tikhonov
36 regularization using the L2 norm, an L1 prior is used. This is motivated by the
37 sparsity of MPI data in image space. Additionally, a total variation term is added
38 preserving edges known to be oversmoothed by Tikhonov regularization especially for
39 vascular images. A comparison of Tikhonov and fused lasso regularization taken from
40 (Storath et al. 2016) is shown in figure 6.2.5. Compared to the Tikhonov solution, the
41 advanced regularization scheme clearly reduces the noise while preserving sharp edges
42 of the vessel phantom.
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44 6.2.6. Linear Solvers To solve the optimization problems (39) and (40) one can use
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45 iterative and factorization methods. These two problems can be expressed in form of
46 a regularized normal equation
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48 (S red S red + λI)c = S red ured . (42)
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50 Here, I is the N × N identity matrix and S red is the Hermitian conjugate of S red .
51 Direct solvers usually factorize the system matrix in such a way that the inversion of
52 the square linear system (42) becomes trivial. Examples are the LU decomposition
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53 and the singular value decomposition (SVD). The latter has been used in the first
54 publications on MPI (Gleich & Weizenecker 2005, Weizenecker et al. 2007, Knopp
55 et al. 2008, Knopp et al. 2009) and has the advantage that it allows to optimize the
56 regularization parameter λ efficiently using the L-curve method (Knopp et al. 2008).
57 In practice direct solvers are rarely used since they are computationally very
58 demanding for large MPI matrices. For this reason it was a key finding of Knopp
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59 et al. (2010h) that iterative methods are a suitable alternative for the reconstruction
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10 of MPI data. In particular the Kaczmarz methods was shown to converge rapidly
11 requiring in practice even for large 3D matrices less then 10 iterations. The Kaczmarz
12 method performs the fixed-point iteration
13 u j − sT l
jc
cl+1 = cl + sj ,
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15 sj 22
16 where sj is the j-th row of the system matrix S red and uj is the j-th entry of the
17 measurement vector ured . l denotes one sub-iteration and j is usually chosen to be
18 j = l mod M . One sweep through all matrix row is referred to as one Kaczmarz
19 iteration. The fixed point provides a solution to the inverse problem (39) and hence
20 does not account for any regularization. In order to solve the regularized least-squares
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problem (40) one has to apply the Kaczmarz iteration to the extended linear system
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23 c
= ured .
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S red λ 2 I (44)
24 v
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26 Here, v is an auxiliary vector that is upon convergence equal to the scaled residual
v = −λ− 2 S red c − ured . A further advantage of the Kaczmarz method is that it
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can be extended to converge to a non-negative solution vector. This can be done by
orthogonal projection onto the set of real non-negative numbers after each iteration.
The Kaczmarz method has been used in various publications and can be seen as
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31 the gold standard for matrix-based reconstruction of MPI data. The reason for the
32 popularity is its fast convergence and simple implementation. The fast convergence is
33 due to the MPI system matrix rows being close to orthogonal (Knopp et al. 2010h).
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35 6.3. Matrix Compression
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37 One limitation for algebraic image reconstruction are the memory requirements of the
38 system matrix S red , which has to fit into memory for fast reconstruction. Consider for
39 instance a 3D MPI system matrix containing measurements for 323 spatial positions.
40 In this case the size of the system matrix is about 20 GB in single precision considering
41 all measured frequency components.
42 A method to circumvent the problems related to the processing of huge amounts of
43 data has been proposed by Lampe et al. (2012). The key idea is to represent the MPI
44 system matrix in a different basis with only few coefficients significantly divergent
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45 from zero. Such a sparse matrix needs significantly less memory if a dedicated
46 dataformat such as CRS (compressed row storage) is used. Mathematically the matrix
47 compression method can be derived by introducing a unitary basis transformation
48 matrix B into (38) yielding
49
50 u = S red BB c
51 = Ŝ red ĉ (45)
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53 with Ŝ red = S red B and ĉ = B c. By storing only the significant entries of the sparse
54 matrix Ŝ red one can invert (45) very quickly in the transformed domain. To obtain c
55 from ĉ one simply uses the unitary of B to calculate c = Bĉ.
56 While Lampe et al. (2012) used a global threshold for sparsification, Knopp &
57 Weber (2015) have shown that it is much more effective to apply a local threshold to
58 each matrix row. Recently Maass et al. (2016) used a symmetry-preserving secondary
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31 Figure 20. Overview of the real-time data pipeline proposed by Knopp & Hofmann
32 (2016). Raw data is continuously measured and appended to a measurement file. The online
33 reconstruction process grabs a certain amount of frames, averages them and then performs
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34 the data reconstruction. Finally the reconstructed particle concentration is visualized using a
suitable 3D display. The figure is reproduced from (Knopp & Hofmann 2016).
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37 6.4. Online Reconstruction
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39 MPI by design has the potential to be a fast imaging method that allows for near
40 real-time imaging of the tracer distribution. Naturally, a fast raw data acquisition
41 is mandatory. Moreover, since raw data is not suitable for visualization, it is
42 important that the data reconstruction is on a par or faster than the data acquisition
43 process. Knopp & Hofmann (2016) introduced the first online reconstruction
44 framework capable of near real-time visualization. It used a simple Kaczmarz-based
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45 reconstruction approach in combination with a high SNR threshold and a low number
46 of Kaczmarz iterations reaching frame rates ranging between 0.3 and 10 frames per
47 second.
48 The key proposal is the implementation of an adaptive reconstruction process to
49 minimize the latency of the online reconstruction framework. Instead of reconstructing
50 each frame, the adaptive reconstruction process uses the latest data from the receive
51 chain for reconstruction. If the reconstruction process is slower than the acquisition
52 process, the framework combines several measurements in an optional averaging
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53 step. This ensures that no measurements are dropped by the online reconstruction
54 framework. A sketch of the proposed online data processing framework is given in
55 figure 20.
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10 7. Anatomical Background
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12 One of the advantages of MPI is the positive contrast solely generated by MNPs, while
13 the object under investigation does not generate background signal. This discriminates
MR and MP imaging using MNPs. In MRI, signal is generated by the tissue of the
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15 patient and the MNPs influence the T∗2 relaxation time of the tissue. Depending on the
16 particle concentration, the T∗2 time is considerably shortened resulting in a negative
17 contrast (i.e. black spots) in locations with significant concentration of MNPs.
18 On the other hand, the positive contrast and the lack of background information
19 is also a major challenge in practical in-vivo imaging using MPI. In particular two
20 issues have to be solved:
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22 (ii) the registration of MPI signal and animal anatomy.
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Before tracer injection, no MPI signal is generated from the object and the obtained
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25 image only contains background noise, which is why the relative position and the
26 orientation of the imaging volume and the object has to be determined. After image
acquisition a positive contrast is generated in locations with significant concentration
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of tracer material. Prior knowledge about the typical distribution of the specific MNPs
in the body is required to interpret the MPI signal.
For these reasons, MPI usually requires an additional imaging modality providing
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31 an anatomical reference and a basis for geometry planning. Here, MRI is the natural
32 choice since it is radiation free and provides an outstanding soft-tissue contrast. In
33 the following subsections we will discuss approaches providing such a reference.
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35 7.1. Fiducial Markers
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In figure 21 the basic workflow of a preclinical MPI experiment as proposed by Kaul
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et al. (2015) is sketched. An animal is first anesthetized and then placed in a special
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39 bed that fits into the MRI and MPI without changes in the animal position. Then the
40 MRI scan of the desired body region is performed. For imaging of body regions prone
41 to motion, gating techniques are used to mitigate motion artifacts. Scan planning in
42 the MRI can be easily performed based on scout scans that are performed prior to
43 the actual high resolution MRI measurement. Then, the animal bed is moved to the
44 MPI scanner, geometry planning is performed, and finally in a post-processing step
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45 the MRI and MPI datasets are overlayed using appropriate fusion techniques.
46 For the MPI geometry planning and the final image fusion it is essential to
47 precisely know the coordinate transform between the MRI and the MPI coordinate
48 system. As it has been shown by Werner et al. (2016) this can be done using fiducial
49 markers that are positioned in the vicinity of the imaged animal. It is important to
50 use a marker that is visible in the MRI as well as in the MPI. Werner et al. (2016)
51 constructed a bimodal marker consisting of a MNP rod surrounded with a Gadolinium
52 based contrast agent. The MNP rod provides an MPI signal, while Gadolinium
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53 provides positive contrast in MRI. In figure 22 the bimodal fiducial marker is shown.
54 Three of these markers were arranged in such a way that the position and orientation
55 in space can be precisely determined. The mapping between MRI and MPI coordinates
56 is then done using classical rigid body image registration algorithms based on the MRI
57 scan and a fiducial scan performed before tracer injection.
58 The coordinate transform obtained by image registration of the fiducial scan and
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59 the MRI scan can later be used to fuse MRI and MPI datasets. As has been discussed
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10 avoid loss of contrast in the imaging area. If a marker with high tracer concentration is
11 too close to the imaged area there is the risk that the fiducial shadows the actual MPI
12 signal since the dynamic range that can be measured with MPI is limited (Gdaniec
13 et al. 2016). For this reason it has been proposed by Werner et al. (2016) to place the
marker sufficiently apart from the targeted FOV and measure the fiducial signal in a
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15 dedicated scan by shifting the FOV to the marker position.
16
17 7.2. Hybrid Imaging
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19 The workflow described so far assumed that the anatomical reference and the MPI
20 measurement are obtained in two dedicated devices and that the imaged object is
21 transferred between the two. In terms of workflow and total measurement time it
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22 would be even better if MRI and MPI measurements could be performed within the
23 same device.
24 Since both MRI and MPI rely on the application of magnetic fields a combination
25 of both scanner types in a hybrid scanner seems to be an option. The main difference
26 between MRI and MPI is that the former requires a static homogeneous magnetic B0
field while the latter requires a static gradient field. Both magnetic field topologies can
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be realized with a single coil pair aligned along the scanner tube. For a homogeneous
magnetic field the coils are driven by currents flowing in the same direction, while a
gradient field is generated by currents flowing in opposed direction. Thus, the same
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31 hardware components can be used for the different topologies, conserving the limited
32 space around the patient.
33 Apart from the homogeneous B0 field in MRI and the selection field in MPI, MRI
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34 requires gradient fields and MPI requires homogeneous drive fields. Using components
35 that can generate either of these are in principle feasible, but very challenging in
36 practice. The reason being that MPI drive-fields are usually driven by harmonic
37 currents requiring dedicated filter stages that would have to be bypassed for static or
38 non-harmonic MRI gradients.
39 Vogel et al. (2014a) developed the first experimental hybrid MRI/MPI scanner.
40 The authors designed a MRI/MPI system using exclusively electrically generated
41 magnetic fields and a common receive coil for signal detection. The first integrated
42 system was published by Franke et al. (2016), where the MRI/MPI scanner shared
43 the same coils for generating the MRI B0 field and the MPI selection field. Both
44
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systems allowed for an overlay of MPI and MRI data without usage of co-registration
45 algorithms for post-measurement alignment. Apart from a hardware characterization
46 Franke et al. (2016) studied workflow and MPI FOV planning using their MPI/MRI
47 hybrid system.
48 While these first hybrid MRI/MPI scanners provide a proof of principle, upscaling
49 to human size has yet to be investigated. It might further be possible to build
50 MRI/MPI shuttle systems as has been done for PET/CT and PET/MRI. In these
51 cases, the two imaging modalities are located in the same room directly next to
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each other. They share the same patient bed, that directly transfers the patient
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without repositioning from one scanner to the other. While we discussed hybrid
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MRI/MPI systems to gain an anatomical reference it is worth mentioning that also
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other combinations as e.g. with ultrasound are possible.
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10 8. Multi-spectral MPI
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12 The main assumption made in MPI is that the relation between the measured signal
13 and the particle concentration is linear (see section 6). This assumption depends
on a number of parameters, which might change during the imaging process and
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15 therefore limit the applications of MPI. The three most prominent parameters are
16 the viscosity of the particle environment, the particle temperature, and the particle
17 binding state. Any spatial or temporal dependence of these parameters will affect the
18 relaxation dynamics and therefore the relation between the measured signal and the
19 particle concentration. Note that apart from external parameters also the particle
20 core diameter and other material properties such as the particle anisotropy affect the
21 particle dynamics (Schmale et al. 2010).
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22 However, these limitations are not of principle nature. On the contrary, changes
23 in the relaxation dynamics can be used to actually determine temperature, viscosity,
24 and/or molecular binding and the bound fraction. Initial prove of concepts were given
25 for temperature (Weaver et al. 2009), viscosity (Rauwerdink & Weaver 2010), and
26 bound fraction (Rauwerdink & Weaver 2009) using magnetic particle spectroscopy. In
all cases the ratio of the fifth and third harmonic of the particle magnetization was used
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to estimate the additional parameter from the MPS measurements. The accuracy of
the temperature estimation in (Weaver et al. 2009) was 0.3 K between 20 ◦ C and 50 ◦ C.
30 The accuracy of the viscosity estimation was in the order of 0.05 cP. The incorporation
31 of these techniques into an imaging systems was discussed by Rauwerdink & Weaver
32 (2009).
33 These findings show that the MPI signal carries functional information about the
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34 nanoparticles, which can be extracted. One of the first instances, where imaging of
35 functional parameters succeeded using MPI were the particle mobility during blood
36 coagulation (Murase et al. 2014) and the particle temperature during heating (Murase
37 et al. 2015). In both studies the authors investigated the MPI signal, which is
38 proportional to the iron concentration. Though this concentration was static in both
39 experiments the MPI signal did change due to the blood coagulation and heating
40 process. In the later experiments the authors found significant correlations between
41 the MPI signal and the temperature indicating feasibility of functional MPI.
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8.1. Mobility MPI
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45 One important mechanism of the magnetic particle response to a changing external

46 field is the Brownian relaxation. It describes the mechanical rotation of a particle if
47 the magnetization aligns with the applied field. The particle binding state and the
48 viscosity of the surrounding medium determines if and how well particles can relax via
49 this mechanism. The aim of mobility MPI is to extract qualitative and quantitative
50 information about the Brownian relaxation of the nanoparticles. This in turn allows
51 to estimate their binding state and the viscosity of the surrounding medium.
52 Due to the complex relaxation dynamics most studies performed in this field have
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53 been using 1D sinusoidal drive-field excitations. Wawrzik et al. (2013) and Muslu et al.
54 (2016) developed methods to estimate the mobility or binding state of an MPI tracer
55 from the MPI signal. Han et al. (2014) and Hensley et al. (2015) proposed methods
56 to generate Brownian and Neel MPI images, where pure Neel particles would have
57 high signal in the Neel image and little signal in the Brownian image and Brownian
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10 image.
11 A method to obtain mobility information of particles subjected to Lissajous type
12 excitation trajectories has been introduced by Rahmer et al. (2015). The authors
13 generalized the algebraic reconstruction method discussed in section 6.2 to take
multiple system matrices into account. Using calibration measurements of a particle
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15 powder with immobilized particles and a solution with mobile particles they were
16 able to discriminate these two in later measurements. Recent studies indicate that
17 the same methods can be used to discriminate different viscous particle environments
18 using just two calibration measurements of nanoparticles in the least and most viscous
19 environment (Hofmann et al. 2016).
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overlay reconstructed channels

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26 measure û
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37 Figure 23. A short summary of the algebraic multi-spectral reconstruction is given. In this
38 example two samples containing a fixed iron concentration ferucarbotran tracer in a low (green
dot) and high (red dot) viscous solution are measured (1st box). For both the low and high
39 viscous sample system matrices are obtained using calibration measurements (2nd box). These
40 are used to invert the algebraic multi-spectral image equation (3rd box). Each channel is then
41 individually normalized and converted to an RGB image. The separation of the two samples
42 is very good but not perfect as can be seen in channel c1 . In a last step both channels are
combined into a single image.
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46 introduced by Rahmer et al. (2015) is given in the following. Consider a number
47 of Θ ∈ N calibration samples and let S i , i = 1, 2, . . . , Θ be the system matrix
48 acquired using the i-th sample. Given a measurement u the algebraic multi-spectral
49 reconstruction is formulated by the linear equation
50

Θ
51 S i ci = û, (46)
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54 where ci is the (color) channel corresponding to the i-th sample. This equation can
55 be brought into the form of equation (34) by concatenation of the system matrices S i
56 and the channels ci . Let
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22 This multi-spectral imaging equation can be solved using the algebraic techniques
23 discussed in section 6.2. The different channels ci can either be displayed separately
24 or they can be combined into a color-coded image. To this end each channels is
25 assigned to a different color channel. For instance in case of Θ = 3 one can assign the
26 three channels to red, green, and blue yielding an RGB image with distinct colors. A
short summary of the method can be found in figure 23.
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29
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In addition to different binding states Rahmer et al. (2015) could also discriminate
different particle types in the same measurement. Recently, Stehning et al. (2016a)
performed initial experiments on temperature imaging using the algebraic multi-
30
31 spectral reconstruction. For the latter, a tracer sample at two fixed temperatures was
32 used to obtain the reference system matrices. Measurements during the cool down of a
33 heated sample showed a significant signal shift from the warm channel at the beginning
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34 of the measurement to the cold one at the end. Although no quantitative information
35 was obtained both experiments provide a proof of principle that spatially resolved
36 functional information affecting the magnetic particle dynamics can be obtained from
37 MPI measurements.
38
39 9. Force Application using MPI
40
41 In its original form MPI has been developed primary as an imaging technique. Beside
42 its imaging abilities, an MPI scanner is a flexible magnetic field generator. The
43 generated fields can be used to apply forces for pulling, pushing, bending, and twisting
44
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magnetic objects. These possibilities are of special relevance for interventional MPI
45 where forces can be used to fully automatic steer a catheter through the vascular
46 tree. This is already done using hard-magnetic tips in X-ray interventional imaging
47 (Armacost et al. 2007) and for catheter steering in MRI (Roberts et al. 2002, Wilson
48 et al. 2013). While additional equipment is required in both imaging modalities to
49 apply magnetic forces, the intrinsic magnetic fields used in MPI are sufficient for force
50 applications going much beyond the capabilities of previous approaches.
51 The imaging process in MPI is based on the superposition of spatially
52
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homogeneous magnetic fields and magnetic gradient fields. In a magnetic field with
53
flux density B a force
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55 F = ∇(m · B), (50)
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57 is acting on a magnetic dipole with the magnetic moment m. The direction of the force
58 depends on the magnetic material. For ferromagnetic material m and B are parallel
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59 and the force is thus directed towards higher field strength, i.e. away from the field-free
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24 Figure 24. The magnetic forces acting on the ferromagnetic material at the tip (red) of
each device bends the device towards higher field strengths. Except for the second device,
25 where the tip is located at the FFP. The strength of the magnetic gradient field is indicated
26 in the background with a gray colormap. The direction and strength of the force acting on
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27 ferromagnetic material at a certain position is visualized by arrows.
28
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30 region (FFR) in an MPI scanner (Nothnagel et al. 2013, Nothnagel et al. 2016). An
31 illustration of the basic principle of force application in MPI can be found in figure 24.
32 In a comprehensive paper Nothnagel et al. (2016) have recently shown that a
33 regular MPI scanner equipped with focus fields can be used to apply forces of arbitrary
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34 strength and direction. The force can be used to move small magnetic objects and
35 perform imaging at the same time. In their experiments the authors used a phantom
36 consisting of six nearly MPI-silent tempered soft-magnetic spheres for steering and
37 two soft-magnetic needles for imaging. The position of the object was adjusted with
38 the help of a control loop determining the position of the object from the MPI image
39 in real-time. The required force to steer the object in the desired direction is then
40 applied by placing the FFR to an adequate position relative to the object driven by
41 the control loop. Using this procedure, the phantom was steered in a fully automatic
42 way to a target position using the MPI scanner.
43 It was shown in a simulation study by Mahmood et al. (2015) and later in
44 an experimental study (Zhang et al. 2017, Zhang et al. 2016) that manipulation
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45 of magnetic nanoparticles can be performed in a scanner geometry specifically

46 designed for force application. The 1D imaging and manipulation are performed
47 in an interleaved fashion with a repetition time of 0.5 s for both scanner modes.
48 Mode switching is performed periodically with a short pause interval accounting for
49 relaxation effects. In (Zhang et al. 2017, Zhang et al. 2016) movement of undiluted
50 Resovist from one end of a tube to the other by application of magnetic fields was
51 shown. The movement was captured with a camera and with 1D MPI imaging.
52 Furthermore, it was shown by Wirtz et al. (2016) that the force can be used
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53 to steer a catheter intended for interventions through a vascular phantom with

54 bifurcations. Branches that are difficult to reach can be made easily accessible by
55 applying transversal forces that can not be induced by pulling and pushing of the
56 catheter.
57 It is a challenging task to determine the magnetic moment for objects of arbitrary
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10 generated by permanent magnets was presented by Weller et al. (2016). The force
11 is determined with an external device consisting of a seesaw with the test object
12 (steel beads of different size) attached to it and an analytical balance. The difference
13 in weight force is analyzed with the balance. The magnetic field strength of the
permanent magnets was determined with a 3-axis Hall probe. It was shown that
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15 the force increases with increasing distance from the FFR and with the diameter of
16 the beads. Due to the remanence of the steel beads, a premagnetization (parallel
17 or antiparallel to magnetic gradient field) influences the strength of the force. A
18 premagnetization antiparallel to the magnetic gradient field results in a reduced force
19 on the ferromagnetic material.
20 Apart from force a magnetic moment experiences a torque
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It was shown by Stehning et al. (2016b) that torque can be applied to an appropriately
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magnetized object using an MPI scanner. In particular the authors use the moment
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to turn a magnetic screw through a gelatine sample or a cut of meat.
26 an
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28 10. Potential Medical Applications
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30 During the first years after MPI was invented the development was focused on technical
31 improvements leading to better performance of MPI in terms of spatio-temporal
32 resolution and sensitivity. Furthermore, the upscaling of scanner components to
33 human size was and is an ongoing research field. During this time the number of
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34 available and functional MPI scanners was quite small, which is why research on
35 medical applications was limited. With the availability of the first two different
36 commercial MPI systems (Bruker Biospin MRI GmbH 2014, Magnetic Insight,
37 Inc. 2017) and an increasing number of research systems MPI currently enters the
38 preclinical research phase. It can be expected that this will shift the focus of future
39 MPI related studies to the exploration of potential medical applications.
40 Within this section we will discuss potential medical applications and review the
41 main results of application orientated MPI research during the last 12 years. We
42 will start to review vascular and device imaging, which are historically the earliest
43 MPI related applications which were investigated and close the section with a short
44 discussion on targeted imaging and magnetic hyperthermia.
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46 10.1. Vascular Imaging
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48 The current clinical standard for vascular imaging are conventional X-ray angiography,
49 digital subtraction angiography (DSA), computed tomography angiography (CTA),
50 and magnet resonance angiography (MRA). Since diagnostic imaging requires
51 tomographic information, CTA and MRA are usually used for this purpose. For
52 interventional applications DSA is the clinical gold standard.
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53 The X-ray based methods (CTA, DSA) have the drawback that they require
54 ionizing radiation. While CTA is usually limited to static imaging due to restrictions in
55 the applied X-ray dose, DSA has an excellent spatio-temporal resolution but provides
56 only 2D projection images during an intervention.
57 MPI is suitable for vascular imaging as well by using blood pool MPI tracers.
58 Long-circulating tracers can be used to visualize blood vessels over a long time window
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59 of several hours (Khandhar et al. 2016). Due to the ability to quantify the tracer
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28 Figure 25. The first in-vivo measurements published by Weizenecker et al. (2009)
29 (supplementary material: figure 1). Shown are time profiles for selected voxels that are located
30 in different structures of the mouse heart. It can be concluded from the arrival times of the
31 bolus that the tracer enters the heart through the vena cava end fills first the right atrium and
then the right ventricle. After passing through the lungs the tracer enters the left atrium and
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35 concentration in MPI, it might be possible to diagnose pathologies like stenosis,
36 vascular occlusions, internal bleedings, aneurysms, and determine information on
37 organ perfusion. Utilizing the high imaging speed of MPI and taking the blood
38 pulsation into account even blood flow measurements are possible.
39 The first in-vivo experiments using a healthy mouse were published by
40 Weizenecker et al. (2009). They show a Resovist bolus injected intravenously passing
41 through the mouse heart revealing structures such as the left/right atrium, the left and
42 right ventricle, and the pulmonary veins. A selected subset of the in-vivo MPI data
43 is reproduced in figure 25. The applied tracer dosage in (Weizenecker et al. 2009)
44
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was already in the range of clinically allowed dosages for iron-oxide based tracers
45 (40 μmol(Fe) kg−1 ).
46 The ferucarbotran tracer used by Weizenecker et al. (2009) is known to have a very
47 short blood half-life time of only few minutes. It is rapidly uptaken by Kupffer cells
48 in the liver and limits vascular imaging to a short time frame. In order to increase the
49 blood half-life times, the ferucarbotran tracer was loaded into red blood cells (RBC)
50 by Rahmer et al. (2013) which have typical life time of 30 days in humans. These
51 loaded RBC enabled vascular imaging even 24 hours after the initial tracer application,
52
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which is a huge advantage in particular in comparison to the iodine tracers used in

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CTA and DSA. Iodine has a blood half-life time of only some seconds and therefore
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has to be regularly reinjected during an interventional procedure. Long circulating
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tracers would further enable long time monitoring applications such as regular bleeding
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diagnoses after stroke treatment, which nowadays is done irregularly due to the dose
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20 Figure 26. Left: 3D printed aneurysm model. Right: A ferucarbotran bolus (MM4) passing
through the aneurysm model. Shown are consecutive MPI images obtained with a frame rate of
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46 frames per second. “Photo of the aneurysm model” (left) and an image section of “Multiple
22 frames of dynamic MRI, MPI, and DSA measurements during the passage of a local maximum
23 of contrast agent concentration” (right) from (Sedlacik et al. 2016) licensed under CC BY 4.0
24 (https://creativecommons.org/licenses/by/4.0/).
25
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tracers that do not use red blood cells as carriers. Instead of using a Dextran or
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Carboxydextran coating, the tracer LS-008 is coated by PEG providing very high
colloidal stability and persistent intravascular MPI signal over several hours. The
blood half-life time reported by Khandhar et al. (2016) was 105 minutes in mice. The
30
31 LS-008 tracer does additionally provide a very strong MPI signal being about a factor
32 of 4 stronger than the signal of the initially used ferucarbotran tracer Resovist.
33 In (Sedlacik et al. 2016) it was shown that MPI can be used for high temporal
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34 resolution assessment of aneurysm hemodynamics using a 3D printed in-vitro model
35 of a human aneurysm. The model and measured MPI tomograms with a temporal
36 resolution of 46 frames per second are shown in figure 26. As can be seen, MPI is
37 capable of visualizing the passage of a bolus through the aneurysm under pulsated
38 flow conditions. Within the aneurysm the tracer lasts a little bit longer due to the
39 flow dynamics inside the aneurysm.
40
41 10.2. Device Imaging
42
43 Apart from the visualization of the vascular tree, DSA is also able to visualize medical
44 devices such as guide wires and PTA catheters during an intervention. For better
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45 localization and enhanced image contrast some of the devices are even equipped with
46 X-ray markers. In principle MPI offers similar capabilities, i.e. a tomographic imaging
47 method able to visualize parts of the vascular tree and marked instruments in real time
48 at high frame rates.
49 Interventional imaging using MPI has been first discussed by Haegele et al. (2012)
50 where the suitability of medical devices for MPI imaging was investigated. Different
51 available catheters and guide wires were tested with respect to their MPI compatibility.
52 On one hand, the instruments were tested with regards to heat generation caused by
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53 eddy currents that would occur in conducting materials. On the other hand, the
54 imaging process was investigated for any unwanted signals or artifacts caused by the
55 medical devices. For MR compatible instruments that are usually made of polymers
56 neither heating nor signal distortion was observed. The initial investigations of Haegele
57 et al. (2012) were later continued by Duschka et al. (2014).
58 Following the initial safety tests, Haegele et al. (2013) visualized interventional
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59 instruments using MPI. To this end, the authors filled a balloon catheter with
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10 10.3. Targeted Imaging
11 Aside vascular applications MPI has great potential to be a suitable imaging modality
12 for targeted imaging. Targeted imaging in general uses specialized markers to target
13 specific cell types and molecules. These markers are then imaged using a suitable
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14 imaging modality. In the imaging of cancer for example targeting allows to differentiate
15 the healthy tissue from cancer tissue, which is challenging for non-targeted diagnostic
16 imaging techniques. The clinical gold standard for targeted imaging are PET/SPECT
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offering an outstanding sensitivity at the cost of using radioactive tracers requiring
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nuclear diagnostic infrastructure.
19
MNPs have a long history of being suitable for targeted imaging (McCarthy &
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Weissleder 2008, Veiseh et al. 2010). Recent advances allow to design and fabricate
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magnetic nanoparticles for cellular-specific targeting. Even though these image agents
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were originally developed for MRI, the nanoparticles can be altered to generate an MPI
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24 signal. In contrast to MRI, MPI generates a positive contrast and an image signal
25 intrinsically quantifying the tracer concentration. On the down side MPI imaging
26 systems have yet to reach their full potential in terms of sensitivity to be able to
image tracer concentrations down to the pico molar level. Despite this current short
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coming several researchers have reported experiments of successful targeted MPI.
One very promising way to do targeted MNP imaging is to embed the
nanoparticles into mesenchymal stem cells (MSCs) that can be found in many tissue
30
31 types and can be used for therapy of various diseases such as stroke, myocardial
32 infarction, traumatic brain injury, and cancer. The first in-vivo imaging of loaded
33 stem cells in a rat model have been performed by Zheng et al. (2015) and Zheng et al.
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34 (2016). The authors imaged and quantified neural progenitor cells (NPCs) that were
35 implanted in the forebrain of immunosuppressed rats over a time period of more than
36 80 days.
37 Bulte et al. (2015) implanted MNP loaded stem cells in mouse brains in both
38 hemispheres using a different number of cells. After taking tomographic images with
39 a preclinical MPI scanner it was possible to quantify the difference in the MPI signal
40 that corresponded to the difference in implanted cells. Depending on the iron load of
41 each cell and the used MPI hardware the detection limit varied in different publications
42 from 200 (Zheng et al. 2015) to 50,000 cells (Bulte et al. 2015).
43 Them et al. (2016b) analyzed the reconstruction of MNP labeled stem cells in
44 more detail. For system matrix based reconstruction it was found that it is highly
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45 important to match the mobility of the nanoparticles used for the system calibration
46 to the imaged sample. In the case of stem cells the mobility of the nanoparticles is
47 restricted and therefore, it is advantageous to use a delta sample with MNPs mixed
48 with gel. It was shown by Them et al. (2016b) that a mismatch of the system matrix
49 lowers the detection limit due to an increased level of image artifacts.
50 A further interesting application for MPI is the sentinal lymph node biopsy. For
51 women suffering from breast cancer, the sentinal lymph node is the node most likely
52 spread with cancer cells from a primary tumor. Goal of the sentinal lymph node
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53 biopsy is to identify only the sentinal lymph nodes. These are then resected while
54 the non-sentinal lymph nodes remain in the patient. Using MNPs it is possible to
55 target the sentinal lymph node (Finas et al. 2015) which can then be imaged using
56 MPI (Finas et al. 2012). Since the lymph nodes are located surface near in the axilla
57 it may be advantageous to use single-sided MPI scanner that may be implemented as
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10 Tomitaka et al. (2015) have developed a concept for tumor targeting alternative
11 to cell labeling. They synthesized MNPs and conjugated their surface with lactoferrin
12 converting the non-functional MNPs into agents that specifically targeted brain
13 glioma.
While the applications discussed until now would administer the MNPs into the
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15 blood stream or lymph, there are some applications that would benefit from providing
16 the MNPs in nebulized form ready for inhalation. In this way imaging of lung
17 ventilation would be possible. First in-vivo experiments of this concept have been
18 successfully performed by Nishimoto et al. (2015).
19
20 10.4. Magnetic Hyperthermia
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22 MPI also seems to be a promising candidate for hyperthermia treatment as magnetic
23 particles can be heated with an alternating magnetic field (Rosensweig 2002, Thiesen
24 & Jordan 2008, Jordan et al. 2009). The usage of magnetic nanoparticles has the
25 advantage that the particles can be delivered to a target tissue. Selective heating of
26 these particles can be performed without damaging normal tissues as shown by Petryk
et al. (2013) for tumor cells. Conventional methods used radio frequency to heat the
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particles through relaxational and hysteresis loss (Kumar & Mohammad 2011).
Apart from heating, one may use the magnetic nanoparticles for imaging. Murase
et al. (2015) showed that MPI is indeed useful for predicting the therapeutic effect
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31 of magnetic hyperthermia treatment as the MPI value has a significant correlation
32 with the temperature rise inside tumor tissue. These initial findings were extended by
33 Kuboyabu et al. (2016) and Ohki et al. (2016). Kuboyabu et al. (2016) have shown
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34 that MPI can be used to quantitatively evaluate the tumor early response to magnetic
35 hyperthermia treatment combined with vascular disrupting agents. Ohki et al. (2016)
36 evaluated the usefulness of MPI for quantitatively evaluating the tumor response to
37 magnetic hyperthermia treatment with or without additional radiation therapy.
38 Recent developments like new high-performance iron oxide nanoparticles for MPI
39 guided hyperthermia (Bauer et al. 2016), temperature imaging using multi-spectral
40 MPI (Stehning et al. 2016a), and localized nanoparticle heating (Hensley et al. 2016)
41 suggest that MPI guided magnetic hyperthermia treatment has the potential to
42 become a major player of MPI related medical applications.
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11. MPI Data Format

45
46 MPI is an interdisciplinary research field that involves researchers ranging from physi-
47 cists, mathematicians, and engineers to chemists, biologist, and physicians. With the
48
availability of different scanner types it becomes increasingly important to find ways
49
of exchanging data between different research groups. For this reason, a group of re-
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searchers from different research facilities proposed a standardized format describing
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MPI raw data (Knopp et al. 2016). The development of the format is done in an open
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55 https://github.com/MagneticParticleImaging/MDF
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57 and open to any researcher from the MPI community to participate and enhance the
58 data format.
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10 sensitivity (Gleich & Weizenecker 2005). From today’s perspective MPI has definitely
11 fulfilled the expectation with regards to temporal resolution, whereas it still lacks
12 behind nuclear diagnostic imaging techniques with regards to sensitivity. The spatial
13 resolution is one of the major challenges of MPI. While submillimeter resolution was
expected most works report resolutions in between 1–5 mm.
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15 Although the basic principle of MPI is very simple there exist various different
16 imaging sequences, each with its advantages and technical limitations. However there
17 is not yet any consensus in the MPI community which sequence is best suited for
18 which application and it is likely that many imaging sequences end up in coexistence.
19 Lissajous type imaging sequences are known for its rapid imaging speed, whereas
20 Cartesian sequences are known for its simplicity enabling x space reconstruction.
21 One of the main foci of the MPI community has been the development and
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22 improvement of image reconstruction algorithms. Current reconstruction methods
23 are quite successful in inverting the MPI imaging equation and new methods are
24 emerging, which include prior knowledge such as image sparsity. Still, in the field of
25 image reconstruction one main challenge remains: A complete understanding of the
26 complex magnetization dynamics during imaging, which would allow for an accurate
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27 modeling of the MPI forward operator. Such a model could deepen our understanding
28 of the imaging process and provide analytical tools for the design of scanner hardware,
29 imaging sequences, MPI tracer particles, and reconstruction algorithms.
30 One of the most fundamental prerequisites for medical imaging using MPI turned
31 out to be the possibility of correlating MPI images with an anatomical background.
32 To guarantee a reliable and reproducible workflow for medical experts, marker based
33
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image registration techniques and new hybrid MPI/MRI scanner designs have been
34 developed. The registration methods implemented so far use static background
35 information for correlation with the MPI data. However, if MPI is operated with high
36 temporal resolutions respiration and heart beat become an issue as static background
37 images merely approximate the real background. The challenge will in turn be to
38 develop registration methods and measurement protocols that take the movement of
39
the MPI data on top of the MRI background data into account.
40
Beyond imaging the distribution of magnetic nanoparticles MPI can potentially
41
be used to extract functional information, such as the particles temperature, the
42
particle mobility and the binding state. Initial results indicate that qualitative
43
differences can be visualized (Rahmer et al. 2015). It still remains an open question,
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46 their functional parameters are mutual exclusive. Nonetheless these new multi-spectral
47 imaging methods are likely to give new impulses to MPI tracer development and the
48 research of potential medical applications.
49 Beyond imaging the static and dynamic fields of MPI field generators can be used
50 to apply forces to magnetic materials. These forces can be used for pulling, pushing,
51 bending, and twisting of magnetic objects. These possibilities could lead to completely
52 new applications like the actuation of magnetic micro machines or the navigation of
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53 medical devices (Rahmer et al. 2017).

54 Indispensable for the study of potential medical applications was the introduction
55 of first commercial MPI systems providing access to this new technology for a wide
56 range of medical experts. From there on a close collaboration of application experts
57 and MPI experts will be crucial to prepare the route of MPI into the clinical routine.
58 From a medical point of view it will be crucial to find clinical applications for MPI
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10 to established methods. From a technical perspective the upscaling from preclinical
11 systems to human size will be the major challenge for the upcoming years. Here, it
12 will be crucial to minimize the technical effort while still preserving good imaging
13 performance in terms of sensitivity and spatiotemporal resolution.
An issue underrated throughout early development have been safety limits.
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15 Initially it was assumed that 20 mT drive field amplitude would be feasible in human
16 applications. While this is true from the perspective of tissue heating the real issue
17 turned out to be peripheral nerve stimulation, which is why the frequency of the drive
18 field was increased from 25 kHz to 150 kHz during the development of the first clinical
19 MPI scanner at Philips research allowing for larger drive field amplitudes that still
20 will be below 10 mT (Schmale et al. 2013).
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22 Acknowledgment
23
24 The authors thank the anonymous reviewers for careful reading of our manuscript.
25 Their suggestions were very helpful and improved the paper substantially. The authors
26 thankfully acknowledge the financial support by the German Research Foundation
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27 (DFG, grant numbers AD 125/5-1 and KN 1108/2-1) and the Federal Ministry of
28 Education and Research (BMBF, grant number 05M16GKA).
29
30
References
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Magnetic particle imaging: from proof of principle to preclinical applications

Manuscript version: Accepted Manuscript

4.1 Particle Magnetization . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

53 imaging modality determining the spatial distribution of magnetic nanoparticles.

3   

=    5  %

in an external magnetic ﬁeld is discussed.

is the particle core volume derived from the core diameter

59 H D (t) = −AD cos(2πf D t)eD , (7)

59 Langevin particles is excited by this ﬁeld it generates the signal

excitation as illustrated by ﬁgure 4. The signal then reads

53 the net magnetization generated by the magnetic nanoparticles.

59 u(t) = − B(r, t) dS, (13)

45 last will be subject of section 5. The FFP velocity is determined by

45 instrumentation and the particle performance.

53 movements (also called focus-ﬁeld shifts),

for instance in the scanner developed by Weizenecker et al. (2009).

harmonics and therefore requires a broadband receive chain. It is unavoidable that

53 sharper in direction of the FFP movement compared to orthogonal directions.

the object) or electromagnetically by applying focus ﬁelds. In order to achieve 3D

45 frequencies can for instance be obtained for

stepped focus-ﬁeld sequence can be found in ﬁgure 12.

59 individually and merges the reconstruction results in a post-processing step. In the

53 Tomographic imaging using an FFL is technically much more challenging since it

59 following three steps:

45 the gridding step of x-space reconstruction.

53 It remains an open question if it is feasible to reconstruct Lissajous type data

53 and 30 × 30 × 30 positions to be measured in a 3D volume, the required calibration

59 an increase of calibration time. The outstanding advantage of the calibration method

53 S red c = ured . (38)

similar to Tikhonov regularization, which will be discussed in section 6.2.5.

53 respect to visual inspection of the reconstructed images. Automatic determination of

59 the reconstructed particle concentration vector c contains negative entries or entries

59 orthogonal transform to improve the compression rates even further.

45 One important mechanism of the magnetic particle response to a changing external

overlay reconstructed channels

A detailed description of the algebraic multi-spectral reconstruction method

45 of magnetic nanoparticles can be performed in a scanner geometry speciﬁcally

53 to steer a catheter intended for interventions through a vascular phantom with

shape in a gradient ﬁeld. An experimental determination of the magnetic force

which is a huge advantage in particular in comparison to the iodine tracers used in

59 Khandhar et al. (2016) developed an alternative concept for long circulating

hand-held devices (Sattel et al. 2009a).

11. MPI Data Format

source fashion. The project is hosted at the public Github repository

if qualitative imaging is possible and if imaging of the nanoparticle distribution and

53 medical devices (Rahmer et al. 2017).

59 which oﬀer an additional value in the diagnosis or treatment of disease compared

Haegele J, Panagiotopoulos N, Cremers S, Rahmer J, Franke J, Duschka R L, Vaalma S, Heidenreich

53 of Medical Imaging 6(01), 1.

Optics and Photonics pp. 79652I–79652I.

53 Saritas E U, Goodwill P W & Conolly S M 2015 Medical physics 42(6), 3005–3012.

Physics D: Applied Physics 42(1), 1–5.

Weaver J, Rauwerdink A & Hansen E 2009 Medical Physics 36(5), 1822–1829.

24(6), 885 – 891.

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