ÜBERSICHTSARBEIT

Magnetic particle imaging: Introduction to imaging andhardware realization

Thorsten M. Buzuga,∗, Gael Bringouta, Marlitt Erbea, Ksenija Gräfea, Matthias Graesera, Mandy Grüttnera,

Aleksi Halkolaa, Timo F. Sattel a, Wiebke Tennera, Hanne Wojtczyka, Julian Haegeleb, Florian M. Vogtb,Jörg Barkhausenb, Kerstin Lüdtke-Buzuga

a Institute of Medical Engineering, University of Lübeck, Lübeck, Germanyb Clinic for Radiology and Nuclear Medicine, University Hospital Schleswig-Holstein, Lübeck, Germany

Received 1 March 2012; accepted 30 July 2012

Abstract

Magnetic Particle Imaging (MPI) is a recently inventedtomographic imaging method that quantitatively measuresthe spatial distribution of a tracer based on magneticnanoparticles. The new modality promises a high sensitiv-ity and high spatial as well as temporal resolution. Thereis a high potential of MPI to improve interventional andimage-guided surgical procedures because, today, estab-lished medical imaging modalities typically excel in onlyone or two of these important imaging properties. MPImakes use of the non-linear magnetization characteris-tics of the magnetic nanoparticles. For this purpose, twomagnetic fields are created and superimposed, a staticselection field and an oscillatory drive field. If superpara-magnetic iron-oxide nanoparticles (SPIOs) are subjectedto the oscillatory magnetic field, the particles will reactwith a non-linear magnetization response, which can bemeasured with an appropriate pick-up coil arrangement.Due to the non-linearity of the particle magnetization, thereceived signal consists of the fundamental excitation fre-quency as well as of harmonics. After separation of thefundamental signal, the nanoparticle concentration can bereconstructed quantitatively based on the harmonics. Thespatial coding is realized with the static selection field thatproduces a field-free point, which is moved through the fieldof view by the drive fields.

Magnetic particle imaging: Grundlagen derBildgebung und Hardware-Realisierung

Zusammenfassung

Magnetic Particle Imaging (MPI) ist ein neues tomo-graphisches Bildgebungsverfahren, mit dem sich dielokale Konzentration von magnetischen Nanopartikelnquantitativ sowohl mit hoher Empfindlichkeit als auchmit hervorragender räumlicher Auflösung in Echtzeitdarstellen lässt. Diese Vorteile gegenüber etabliertenVerfahren, die oft nur einen der Bereiche abdecken kön-nen oder nicht quantitativ sind, lassen ein hohes klini-sches Potenzial in vielen Anwendungen erwarten. DieGrundidee besteht in der Nutzung der nichtlinearen Mag-netisierungskurve der magnetischen Nanopartikel. DasVerfahren nutzt dazu zwei überlagernde Magnetfelder,zum einen ein statisches Selektionsfeld, zum anderen eindynamisches Wechselfeld. Werden die Nanopartikel in dasWechselfeld gebracht, ändert sich ihre Magnetisierungnichtlinear, was mit einer Empfangsspule gemessen werdenkann. Aufgrund der Nichtlinearität enthält das gemesseneSignal neben der Grundfrequenz des Wechselfelds auchHarmonische. Nach Separation der Harmonischen vondem eingespeisten Grundsignal kann die Konzentra-tion der Nanopartikel ermittelt werden. Eine örtliche

This article focuses on the frequency-based image recon-struction approach and the corresponding imaging devices

Kodierung wird durch das statische Selektionsfeld er-reicht, das einen feldfreien Punkt erzeugt. Die inhaltliche

∗ Corresponding author: Thorsten M. Buzug, Institute of Medical Engineering, University of Lübeck, Lübeck, Germany. Tel.: +49 451 500 5400;fax: +49 451 500 5403.

E-mail: buzug@imt.uni-luebeck.de (T.M. Buzug).

Z. Med. Phys. 22 (2012) 323–334http://dx.doi.org/10.1016/j.zemedi.2012.07.004http://journals.elsevier.de/zemedi

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while alternative concepts like x-space MPI and field-freeline imaging are described as well. The status quo in hard-ware realization is summarized in an overview of MPIscanners.

Keywords: Magnetic Particle Imaging,

Ausrichtung dieses Beitrages konzentriert sich auf dieBildrekonstruktion im Frequenzraum sowie die dazuge-hörigen Bildgebungssysteme und beschreibt kurz alterna-tive Konzepte, wie die Bildrekonstruktion im Zeitbereichund die Bildgebung mit einer feldfreien Linie. Zusammen-fassend wird ein Überblick über den gegenwärtigen Standvon MPI-Bildgebungssystemen gegeben.

Schlüsselwörter: Magnetic Particle Imaging,

Nanoparticles, SPIOs, Medical Imaging

1 Introduction

Magnetic particle imaging (MPI) is a new medical imag-ing method, first presented by Gleich and Weizenecker in2005 [1]. Applying static and oscillating magnetic fields, MPIimages the spatial distribution of superparamagnetic iron-oxide nanoparticles (SPIOs), which are deployed as tracermaterial. The advantage of this tracer type manifests in bio-compatibility and slow degradation by the iron metabolism. Incomparison to other medical imaging methods, MPI exhibitsa high sensitivity and a high spatial and temporal resolutionwithout the need for ionizing radiation (Table 1). Real-time3D imaging, which is one of the most important innovationsof MPI, makes it possible to visualize blood flow. Apart fromimaging of the vascular system, first clinical application sce-narios may include cancer detection and staging (cf. Section5).

The possibility to employ 3D real-time imaging is of partic-ular interest for cardiac imaging. In 2009, Weizenecker et al.presented first in vivo 3D real-time images of a beating mouseheart [3], which have been acquired by a previously introducedMPI scanner featuring a cylindrical bore (cf. Figure 1(a)).A single-sided MPI scanner (cf. Figure 1(b)), first presentedin 2009 by Sattel et al. [4], can be utilized for experimentalcancer staging in the case of the sentinel lymph node biopsy(SLNB), which is essential for the diagnosis and treatment ofbreast cancer [5].

Due to the excellent imaging properties of MPI (cf. Table 1),real-time tracking of interventional instruments is possiblewithin the field of view (FOV), e.g. balloon-catheters in car-diovascular procedures [6]. While most MPI scanner devices

Table 1Comparison of different medical imaging methods.

CT MRI PET MPI

Spatial resolution 0.5 mm 1 mm 4 mm < 1 mm*

Sensitivity low low high highMeasurement time 1 s 10 s - 30 min 1 min < 0.1 s**

Ionizing radiation yes no yes no

* Expectations based on calculations by Weizenecker et al. [2].** As measured by Weizenecker et al. [3].

Nanopartikel, SPIOs, Medizinische Bildgebung

are closed coil assemblies with a cylindrical bore (cf. Table 2),an open coil topology offering full patient access is prefer-able for interventional procedures and various other medicalapplications. With regard to the image guided interventionsin cardiovascular procedures, MPI has the potential to outper-form X-ray fluoroscopy and digital subtraction angiography(DSA), which nowadays are state of the art in clinical routine.

2 Methods and Materials

In MPI different aspects play a significant role for imagequality. It is of importance to develop and optimize SPIOsfor the MPI imaging process. Additionally, the basic princi-ple can be used in several ways to produce images. In thefollowing section the SPIO characteristics together with themain principle of MPI are introduced. An overview of differ-ent techniques to image the behavior of SPIOs in case of MPIis presented.

2.1 Superparamagnetic Nanoparticles

During the last decades, nanoparticles have been provento be interesting materials for a number of applications intechnology and life sciences. Particularly, applications inbiotechnology and medicine rose in importance [7]. Nanopar-ticles show very different behavior when compared to largerparticles of the same material. Especially, some physical andchemical properties are attractive for specific applications. Inmedicine, for instance, nanoparticles can be used as carriers toadminister chemo-therapeutic drugs at tumorous tissue, andmagnetic nanoparticles are used in thermo-therapeutic can-cer treatment [8]. In biotechnology, the magnetic propertiesare used in processes like cell separation and manipulation[9]. When magnetic iron-oxide based nanoparticles are smallenough that the magnetic core becomes a single domain, theparticles become superparamagnetic. SPIOs play a crucial rolein MPI. They show a relatively high saturation magnetizationMS (0.6 T/μ0 for magnetite particles - Fe3O4 [10]), but - in

the ideal case - do not have any hysteresis. This is the reasonwhy SPIOs constitute the perfect tracer material for imagingpurposes. Furthermore, they are non-toxic. SPIOs have beenused in MRI for years, and different commercially available

T.M. Buzug et al. / Z. Med. Phys. 22 (2012) 323–334 325

Figure 1. Schematic drawing of different MPI scanner topologies: An MPI scanner, where the field of view lies in the center of a cylindricalbore and a single-sided MPI scanner, where all coils lie on one side of the field of view.

Figure 2. SPIOs consist of a superparamagnetic iron-oxide core and a coating with a bio-molecule like dextran a). Often these particlesare organized as SPIO clusters b) as demonstrated in the transmission electron microscope (TEM) image c). The macroscopic magneticattraction of a nanoparticle suspension is demonstrated in d).

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gen

Figure 3. Signal

products are on the market (e.g. Resovist® (Bayer Scher-ing Pharma AG) [11], EndoremTM(Guerbet S.A.), Sinerem®(Guerbet S.A.) and Lumirem® (Guerbet S.A.)). The magneticcore of these products mainly consists of a mixture of two dif-ferent iron-oxide configurations, i.e. magnetite (Fe3O4) andmaghemite (Fe2O3). For the application in MPI, Resovistshows by far the best MPI performance [12] and is the workinghorse today. Unfortunately, Resovist has been withdrawn fromthe market. However, magnetic nanoparticles can easily besynthesized using the classical co-precipitation of iron-oxidein an alkaline solution in presence of dextran [13,7]. Dex-tran is used as coating material to prevent the particles fromagglomeration (cf. Figure 2). Typically, a broad distributionof particle sizes is produced in this way. Therefore, for sometime research groups have been making significantly greaterefforts to develop separation strategies [14]. Simulations havepredicted that a mono-modal suspension of particles with amagnetic core of approx. 30 nm will perform best in MPI.

2.2 Basic Principle of MPI

MPI takes advantage of the non-linear magnetizationbehavior of SPIOs used as tracer material, to detect theirspatial and temporal distribution within a patient. The mag-netization behavior of these particles can be approximated bythe Langevin function [15] (cf. Figure 3(a), black curve)

MD(t) = msc

(coth(ξ) − 1

ξ

). (1)

The magnetization of a distribution of particles of diame-ter D is described by MD, while ms = 1/6πD3Ms denotes themagnetic moment at saturation. The saturation magnetizationMs is a material constant. The particle concentration is givenby c, and the Langevin parameter reads

ξ = msμ0H(t)

kBTP, (2)

eration in MPI.

where H(t) is the external magnetic field, kB is the Boltz-mann constant, TP is the temperature of the particles, and μ0gives the permeability of vacuum [16]. Applying a sinusoidalexternal magnetic field, called drive field HD, with frequencyf0 (cf. Figure 3(a), magenta curve), a non-sinusoidal oscilla-tion of the particle magnetization M is induced (cf. Figure 3(a),green curve) due to the non-linearity of the Langevin function.In Fourier space, this deformation can be detected as higherharmonic frequency components, which are again illustratedin Figure 3(a) and constitute a fingerprint of the tracer material.To achieve spatial encoding, a static magnetic gradient field,called selection field, is superimposed to saturate all particlesexcept those located in the vicinity of a field-free region, i.e. a field-free point (FFP) or a field-free line (FFL). Hence,particles outside this region will not contribute to the signalas illustrated in Figure 3(b).

2.3 Imaging in Magnetic Particle Imaging

The basic physical concept of MPI allows measuring thechange of particle magnetization as a voltage signal usingparticular receive coils. To reconstruct the spatial distributionof the tracer a connection to the received signal has to beintroduced.

With the invention of MPI a calibration procedure wasdeveloped that generates a system matrix by placing a deltasample of the applied tracer at each position of the voxel gridand measuring the corresponding frequency spectrum [1,10].Therefore, the system matrix gives the connection between thespatial distribution of particles and the corresponding mea-sured, Fourier transformed voltage signal. This approach iscalled frequency space reconstruction and will be presentedin detail in Section 3.3.

Alternatively, Goodwill et al. introduced a reconstructionprinciple in the time domain, called x-space MPI [17,18].

Under the assumption of homogenous magnetic fields, i.e.assuming a linear shift-invariant system, and based on theLangevin theory of paramagnetism a correlation betweenFFP position and induced voltage signal can be established

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T.M. Buzug et al. / Z. Med.

and direct reconstruction becomes possible. The most sig-nificant advantage of x-space MPI is the omitted systemmatrix such that a scanner dependent calibration process isno longer necessary. Although deconvolution is not essen-tial it most likely improves image quality. A summarizedoverview of x-space MPI was published by Goodwill et al.in 2012 [19].

Besides FFP imaging, Weizenecker et al. introduced a coilarrangement to generate an FFL [20] that promises a highersensitivity due to particle contribution along a line. Initially,the setup consisted of 32 coils and was unfeasible to realize. In2010, Knopp et al. picked up the idea, developed techniques togenerate an FFL with just eight coils [21–23] and presentedan efficient FFL reconstruction based on the Fourier SliceTheorem [24].

Continuously, new MPI approaches are being presentedthat are related to frequency space and x-space MPI, suchas narrowband MPI [25] and traveling wave MPI [26].

3 Implementation of MPI UsingFrequency-Based Reconstruction

3.1 Signal Transmission and Reception

In MPI electromagnetic coils are employed for magneticfield generation as well as for particle signal reception. Forthe field generation, two different types of electromagneticfields are needed. First, time varying and spatially homoge-neous drive fields are applied to steer the FFP through theFOV and excite the tracer material at the same time. To imagea 3D distribution of SPIO particles within a patient, threedrive field coil pairs are needed carrying alternating currents.Furthermore, a static magnetic gradient field, which is calledselection field, needs to be generated providing the FFP usedfor spatial encoding. It is realized by coils carrying oppos-ing currents and may be supported by additional permanentmagnets.

The spatial resolution increases with a steeper particle mag-netization curve and a stronger magnetic field gradient, whichtypically is a few T/(mμ0) in actual systems (cf. Table 2). Sofar, a spatial resolution of about 1 mm has been realized, whileresolution in the sub-millimeter range seems to be feasible byimproving the field gradient strength, the signal-to-noise ratio,and the particle properties.

The three different types of electromagnetic coils – i.e. theselection field coils, the drive field coils and the receive coils– can be realized as dedicated or shared coils. In the initiallyintroduced coil topology (cf. Figure 1(a)), the static selectionfield is generated using a coil pair in Maxwell configura-tion. For the generation of the time-dependent magnetic fields

and signal reception with different orientation, coil pairs inHelmholtz configuration and solenoid coils are used. Apply-ing sinusoidal excitation fields of about 25 kHz, drives theFFP through space on a Lissajous trajectory with a frame rate

ys. 22 (2012) 323–334 327

of 46 volumes per second, i.e. a repetition time of 21.5 ms[3,27]. While other trajectories are also possible Lissajoustrajectories have been shown to be most suitable in a simula-tion study [27] and are so far mainly used for frequency-basedreconstruction. Applying drive field strengths in the order ofseveral 10 mT/μ0, a FOV with edge lengths in the order ofseveral 10 mm is covered. The widest bore realized so far ina pre-clinical small-animal scanner has a diameter of 120 mm[28].

The initial design provides good efficiency regarding elec-trical power loss and good field quality in terms of fieldhomogeneity and gradient linearity. However, both the boresize and thus, the access to the animal to be imaged islimited. A single-sided scanner design, which, in principle,permits arbitrarily large patient sizes and full patient access,was introduced by Sattel et al. in 2009 [4]. The conceptis shown in Figure 1(b). For selection field generation, itapplies currents of opposite direction to two concentricallymounted circular coils. While signal transmission and sig-nal reception for the axial direction is realized by circularcoils, D-shaped coil pairs could be employed for lateral fieldcomponents to enable multi-dimensional single-sided MPI[29]. However, compared to the initial scanner design, thesingle-sided coil topology exhibits a strongly inhomogeneousspatial resolution, which decreases with increasing distance tothe scanner.

The basic setup introduced so far can be extended by focus-field coils aiming at spatially shifting the FOV. To enlarge theFOV, a focus field is superimposed to the other fields in order toslowly move the FFP in space and thus avoid to exceed safetylimitations (such as specific absorption rate and peripheralnerve stimulation). Focus-field coils are technically similar todrive field coils but differ concerning the applied currents. Theimaging volume can be moved either continuously to follow,for example, a tracer bolus administered in the blood stream,or stepwise to image a larger volume [30–32].

3.2 Signal chain of an MPI device

A typical signal chain of an MPI device is shown in Figure 4.The unit for selection field generation is implemented once,while the other parts are required to be realized once for eachspatial dimension to be imaged. The fact that the drive fieldsignal directly couples into the receive coils poses two prob-lems. First, the transmit signal needs to be of high spectralpurity. Second, a part of the receive signal content has to bediscarded.

The drive field signal is generated digitally on a PC. Afterdigital-to-analog conversion, the signal passes a power ampli-fier for appropriate field generation. Due to the fact that even

high linear amplifiers generate harmonic distortions, a bandpass filter is used to keep the signal on the coils clean. Forthis purpose, a third order Butterworth or Chebycheff II filtermay be applied. To obtain a purely sinusoidal signal the filter

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of

Figure 4. Signal chain

needs to be of high quality. The magnetic field generated canbe described as

H = hI (3)

where h is the sensitivity profile of the magnetic fielddefined by the coil geometry and I is the current. To achievea high magnetic field strength, an impedance matching andan oscillating circuit in resonance is needed to generatehigh currents through the coil. Since the drive field signalcouples into the selection field coils, band stop filters areapplied to protect the DC source against the induced ACvoltage.

The particle magnetization changes depending on the actualresulting magnetic field, which induces a voltage signal in areceive coil. This particle signal has to be amplified to matchthe dynamic range of the data acquisition hardware to achievethe highest possible resolution. The essential specificationsof this amplifier are to achieve a high signal-to-noise ratio(SNR) and to damp the fundamental frequency, which directlycouples into the receive coil. This is achieved by an analogband stop filter and a low noise amplifier (LNA). It has tobe ensured that the signal does not exceed the linear rangeof the LNA. The LNA has to amplify especially the higherfrequencies so that as many harmonics as possible can beseparated from the system noise and no harmonics get lost inthe discretization noise [33,34]. The count of harmonics andthe SNR are directly linked to the achievable resolution asshowed in [35].

3.3 Image Reconstruction

A fundamental part of the MPI method is to reconstructthe unknown spatially dependent tracer concentration c fromthe received Fourier transformed voltage signal u. These are

a typical MPI device.

linked to each other by the system function S, forming a linearsystem of equations

Sc = u (4)

with S ∈ CR×dK, c ∈ RR, and u ∈ CdK. Here, R gives thenumber of spatial positions, d gives the number of imagingdimensions and K gives the number of frequencies used forreconstruction. The reconstruction step is to solve (4) forc. Alternatively, the reconstruction can be performed in thetime domain [17,18], which is not considered further here.The system function can either be measured using a deltasample [1] or modeled according to the particle characteris-tics and the scanner properties [36,37]. The former gives themost accurate results, since all particle properties and sys-tem imperfections are included. Recently, a hybrid approachto determine the system function was introduced [38] thatshows promising potential towards image reconstruction [39].Another possibility to speed up the system function acqui-sition is a system calibration unit (SCU), where instead ofmoving a delta sample within the FOV, the FOV is moved byadditional focus-fields [40] relative to the stationary sample.

Figure 5 shows the relation of S and the received signal u

and illustrates the reconstruction process and its challenges.Realistic scenarios additionally deal with noise and undeter-

mined systems of equations where solving the reconstructiontask is a delicate problem. To ensure a robust solution, theweighted least squares approach can be used to find the bestapproximation (compare eq. 5). A suitable weighting matrixW normalizes the energy at all frequencies to enhance imagereconstruction results [41].

∥∥∥Sc − u

∥∥∥2

W=

∥∥∥W12 (Sc − u)

∥∥∥2

2

c−→min (5)

T.M. Buzug et al. / Z. Med. Phys. 22 (2012) 323–334 329

Figure 5. Visualization of the reconstruction process: The unknown tracer concentration c gives the correspondence between the systemˆ ple

nt tion

function S (containing the frequency response (red) for a delta sam(green). The result of the backprojection c gives the spatial-dependeu (Forward projection). Here: light blue corresponds to a concentrat

Aiming for 3D real-time imaging with high spatial res-olution and a large FOV, the number of equations growsrapidly and especially the handling of the system functionbecomes challenging. Particularly, it is not possible to holdthe whole system function in the main memory. Therefore,the application of iterative solvers is an important and indis-pensable step. Different approaches were analyzed concerningreconstruction results, number of needed iterations and over-all reconstruction time [41]. Currently, the Kaczmarz method(called algebraic reconstruction techniques (ART) in com-puted tomography) is a widely used approach to reconstructMPI images. Although this method speeds up reconstructiontime drastically compared to singular value decomposition[41], real-time reconstruction for large three-dimensionalFOVs with adequate resolution is still a challenging problem.Recently, a method to speed up reconstruction was published[42], where data compression based on orthogonal transformsis used to extract the most significant data.

4 Hardware Realization

Although MPI is still a young modality scanners with differ-ent coil topologies and geometries as well as imaging concepts

at each position r) and the measured Fourier transformed signal u

racer concentration which equals the weighted contribution of S tofactor of 0.5 and dark blue to 1.0 at the corresponding position.

have already been implemented (Table 2). The first MPI scan-ner introduced by Gleich et al. in 2005 features a coil designwith a cylindrical bore (cf. Figure 1(a)) in combination withpermanent magnets and images are reconstructed in the fre-quency domain [1,43]. Using this device, a beating mouseheart (FOV 20.4 × 12 × 16.8 mm3) was imaged with a tem-poral resolution of 21.5 ms and a spatial resolution sufficientfor the identification of different structures in the heart (esti-mated to be 1 to 1.5 mm in anterior–posterior direction and2 to 3 mm in the orthogonal directions) [3]. In this study,concentrations of Resovist (undiluted: 500 mmol(Fe)/l) werevaried between the standard dosage of 8 μmol(Fe)/kg used inMRI scans and a dosage of 45 μmol(Fe)/kg, which is slightlyabove the safe dosage of 40 μmol(Fe)/kg for human applica-tions [44]. An advanced system with a larger bore (120 mm)was presented by Gleich et al. in 2010 [28]. This scanner addi-tionally introduces focus-field coils, which can be employedto image a large region of interest. In a multi-station approachwith an FFP volume coverage of 34.5 × 24.3 × 17.0 mm3 and

an acquisition time of 517 ms, several boli of Resovist cor-responding to a dosage of 280 μmol(Fe)/kg were imaged inthe heart and liver of a rat [45,30]. Similar MPI scanners werebuilt by Wawrzik et al. [46–49]. A novel approach for spatial

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Table 2Overview of MPI scanners.

Institution/Scanner FFP/ FFL 1D/2D/3D Strongest Gradient Free Bore Size Status Quo/References

Philips/Fast MPIDemonstrator

FFP 3D 5.5 T μ−10 m−1 32 mm Introduction of scanner and phantom

experiments [1,43], in vivo mouse (heart)[3], in vivo mouse (cerebral blood flow)[64]

Philips/Fast MPIDemonstrator withenlarged FOV

FFP 3D 2.5 T μ−10 m−1 120 mm (optional:

65 mm using an insertRx coil)

Introduction of scanner [28], phantomexperiments and in vivo rat (heart/liver)[45,30,65,32]

TU Braunschweig/2D MPI FFP 2D 3.5 T μ−10 m−1 10 × 15 mm2 [66] Introduction of scanner and phantom

experiments [46,47]TU Braunschweig/3D MPI FFP 3D 6.5 T μ−1

0 m−1 [66] 30 mm Introduction of scanner and 2D phantomexperiments [48,49]

U Würzburg/Traveling WaveMPI

FFP 3D 3.5 T μ−10 m−1 29 mm [67] Introduction of scanner and 2D phantom

experiments [26,50–53]UC Berkeley/Narrowband

MPIFFP 3D 4.5 T μ−1

0 m−1 38 mm Introduction of scanner, phantom andtissue experiments [25]

UC Berkeley/NarrowbandMPI with stronger gradient

FFP 3D 6.5 T μ−10 m−1 40 mm [68] Introduction of scanner, phantom

experiments and in vitro mouse(intestine) [54,55]

UC Berkeley/3D x-space MPI FFP 3D 6 T μ−10 m−1 40 mm [68] Introduction of scanner and phantom

experiments [18,56,69]UC Berkeley/3D x-space MPI

(mouse/rat)FFP 3D 7 T μ−1

0 m−1 57 to 70 mmdepending on insert[68]

Introduction of scanner [57]

UC Berkeley/Projection(reconstruction) x-spaceMPI

FFL 2D/3D 2.4 T μ−10 m−1 40 mm depending on

insert [68]Introduction of projection scanner, 2Dphantom experiments and post mortemmouse [70], introduction of projectionreconstruction scanner, 3D phantomexperiments and post mortem mouse[71,59]

U Lübeck/FFL FFL 2D (so far) 1.5 T μ−10 m−1 30 mm Scanner is currently under construction

[60,61]U Lübeck/Single-sided MPI

1DFFP 1D 1.3 T μ−1

0 m−1 n/a Introduction of scanner and phantomexperiments [4,72,73,35]

U Lübeck/Single-sided MPImultidimensional

FFP 2D (so far) n.s. n/a Scanner is currently under construction[62,63]

Figure 6. Series of reconstructed 1D images of two 2-hole phantoms (aResovist; left: with 4 mm gap, right: with 1 mm gap). The phantom pos

crylic glass that features holes with a diameter of 1 mm filled withition x increases consecutively by 2/3 mm.

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encoding in MPI is being pursued by Vogel et al. [50–53],who utilize a linear gradient array in a closed coil designto generate a traveling wave with two FFPs (of which onlyone is located within the FOV at each point in time). In2009, Goodwill et al. demonstrated two narrowband MPIscanners capable of 3D imaging [25,54,55]. They went on topresent several generations of x-space scanners, where imagereconstruction is performed in time domain [18,56,57]. A 2Dphantom consisting of 400 μm inner diameter tubing filledwith undiluted Resovist was imaged with a FOV of 40 × 20mm2 in a total imaging time of 28 s not including robotmovement [18]. Goodwill et al. also built the first projec-tion x-space MPI scanner [58]. 2D phantom measurements(FOV of 100 × 50 mm2) with an experimental resolution of3.8 × 8.4 mm2 were acquired in 4 s using diluted Resovist (onepart Resovist, nine parts deionized water). Recently, Konkleet al. implemented experimental 3D x-space MPI using pro-jection reconstruction, which requires a mechanical rotation ofthe sample [59]. Another MPI scanner using an FFL insteadof an FFP is being developed by Erbe et al. [60,61]. Thisdevice will rotate the FFL electronically and thus do withouta mechanical rotation of the sample, which is a prerequisitefor in vivo measurements. In 2009, the first single-sided MPIscanner (cf. Figure 1(b)), which allows for unrestricted patientaccess, was introduced by Sattel et al. [4]. Measurements oftwo phantoms, by which the dependence of imaging qual-ity on the distance to the scanner front was investigated, aredepicted in Figure 6. With the experimental setup, measure-ment time was 51.2 ms for each of the 1D images. The systemfunction used for reconstruction was obtained by similar mea-surements using a delta-like phantom with only one bore filledwith Resovist. To reduce noise contained in the system func-tion, which influences the reconstruction results, measurementtime was 256 ms for each point in space. For both phantoms,the dots could be resolved close to the scanner front. As thedistance increases, the gradient of the selection field and theSNR decrease, which results in worse resolution in distantregions. In [35], the resolution achieved by the single-sidedsystem has been determined to range from approximately 1.1to 2.7 mm within the FOV. The phantom dots in the recon-structed images disappeared at about x = 15 mm (cf. Figure 6),which illustrates that the penetration depth of the scanner setupis limited. Currently, a single-sided MPI scanner capable ofmultidimensional imaging is being developed by Sattel, Gräfeand co-workers [62,63].

5 Applications

As mentioned in the introduction, cardiovascular radiol-ogy, especially cardiovascular intervention is an applicationthat could benefit substantially from MPI. Until now, fluo-

roscopy including intraarterial digital subtraction angiography(DSA) is the gold standard for cardiovascular interventionalprocedures, interventional computed tomography (CT) andmagnetic resonance imaging (MRI) are rather experimental

ys. 22 (2012) 323–334 331

methods. DSA is not able to provide three-dimensional infor-mation and, as does CT even more, burdens patient andphysician with considerable doses of ionizing radiation. MRIsupplies three-dimensional information without use of ioniz-ing radiation, but temporal and spatial resolution is lower thanin DSA and CT [75–77]. MPI has the potential to combine theadvantages of those methods by providing three-dimensional,high resolution real-time imaging without ionizing radiation.The vision is to translate this technology into clinical practice.Then the physician could not only visualize the vasculatureand its pathologies like stenosis and occlusions, but wouldbe able to quantify these pathologies as well. Furthermore,the high temporal resolution would also allow real-time per-fusion imaging. If this application of MPI can be realized,it would allow real-time quantitative and qualitative evalua-tion of vascular pathologies and their systemic impact. Beforetreatment this would aid the choice of the individually idealtherapy and, during interventions, it would provide real-timeinformation regarding the procedure’s progress and successand afterwards detailed assessment of the further developmentwould be possible as well. Additionally, the three-dimensionalimage information as could be yielded by MPI has the poten-tial to facilitate the navigation of instruments considerably.Weizenecker et al. could already visualize the beating heartof a mouse using an experimental MPI scanner and Resovistas a tracer with high spatial and temporal resolution [3]. Still,for use in humans dedicated interventional instruments withrespect to visualization using MPI are a prerequisite (Figure 7)[6].

SPIOs are in general collected by cells of the mononu-clear phagocyte system and accumulate primarily in liver andspleen. Smaller SPIOs, in general referred to as ultrasmallSPIOs (uSPIOs) if their hydrodynamic diameter is smallerthan 50 nm, are not cleared by the liver and spleen as fast aslarger ones. uSPIOs can leave the vessel system into the con-nective tissue or into other organs. Here, they are collectedby cells of the mononuclear phagocyte system as well andare then carried to lymph nodes, were they accumulated. Thischaracteristic has been already used in lymph node staging ofe.g. pelvic tumors using MRI [79,80]. Presumably, the highersensitivity of MPI could enhance the accuracy of this methodas well. Gleich and Weizenecker have estimated the possiblesensitivity of MPI to be as high as 20 nmol(Fe)/l [1]. Labelingof lymph nodes using SPIOs can also be a promising tool forthe sentinel lymph node biopsy (SLNB) in breast cancer stag-ing. SLNB is a more gentle method for assessment of axillarlymph nodes opposed to radical axillary lymph node dissec-tion, which is accompanied by larger surgery and a highermorbidity [81]. For SLNB, dyes and radionuclides are used astracer. The tracer, which will be injected into the tumor region,reaches the sentinel lymph node via the lymphatic system and

allows the specific localization and subsequent explanationand histological assessment. The vision is that a particularsingle-sided MPI scanner can be manufactured [82,5], muchlike an ultrasound probe (Figure 8). This technique would

332 T.M. Buzug et al. / Z. Med. Phys. 22 (2012) 323–334

Figure 7. Three-dimensional visualization of a balloon-catheter for cardiovascular interventions using a luminal loading with diluted Resovisttheh of

(1:20, 25 mmol(Fe)/l). The left image shows the axial, the middle34 × 34 × 20 mm3, the balloon has a diameter of 10 mm and a lengt

permit sentinel lymph node detection using SPIOs as a tracer,thus without the use of a radionuclide and exposition of patientand physician to ionizing radiation.

Another application very likely to benefit from MPI ismolecular imaging. Molecular imaging includes the visu-alization of small structures like cells, receptors or evenpharmaceutical agents. It is an important method in e.g. oncol-ogy research, but has the potential to be a diagnostic toolas well. A wide variety of dedicated SPIOs are already usedfor imaging using active or passive targeting and other meth-ods like drug delivery [83–85]. But an important limitationof SPIO-based molecular imaging is the rather low sensitivityof MRI. As SPIOs are, especially regarding their versatilityand good biocompatibility, one of the most important tracers

for in vivo molecular imaging, a suitable method of visualiza-tion is essential [86]. MPI, especially with its possibly highsensitivity and spatial resolution could be a solution for this

Figure 8. Sentinel lymph node detection – one clinical applicationof single-sided MPI.

sagittal and the right image the coronal plane. The field of view is30 mm.

problem. Bulte et al. could already demonstrate the applica-bility of cellular MPI [87].

In general, all existing procedures using SPIOs are potentialapplications as well. In theory, MPI may improve, e.g., imag-ing of inflammation [88,89], neurological disorders [90,91]and high risk (vulnerable) plaques in arteriosclerosis [92,93]considerably. One very important step towards these scenar-ios is to merge the detailed knowledge of SPIO synthesis fordedicated applications, i.e. specific modification of the coat-ing, and the knowledge concerning ideal SPIOs for MPI. Theresult should be MPI-optimized particles, tailored to the needof the individual application.

6 Conclusion

In order to make the exciting performance of MPI avail-able for interventional and functional imaging, many differentscanners are currently under development. The differencesbetween those scanner types are mainly due to the large num-ber of geometrical and electrical parameters that can be chosenin particular realizations. At the same time, much effort is putinto the development of optimized contrast agents. Develop-ing and upscaling this technology to human sized scannersrequires to address issues such as power dissipation, imagereconstruction time and contrast agent production. Thus, MPIpromises to offer possibilities to acquire volumetric imagesof tracer distribution in a more sensitive, faster and safer wayas any existing contrast agent based imaging technique.

Acknowledgments

The authors gratefully acknowledge the financial supportof the German Federal Ministry of Education and Research(BMBF) under grant numbers 01EZ0912, 13N11086 and

13N11090, of the European Union and the State Schleswig-Holstein (Programme for the Future – Economy) under grantnumber 122-10-004 and of Germany’s Excellence Initiative[DFG GSC 235/1]. We would also like to express our gratitude

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towards S. Becker, Institute of Physical Chemistry, Univer-sity of Hamburg, Center for Applied Nanotechnology (CAN)Hamburg for the TEM image and J. Rahmer, Philips Technolo-gie GmbH Innovative Technologies, Hamburg for the supportof acquiring the balloon-catheter images.

References

[1] Gleich B, Weizenecker J. Nature 2005;435:1214–7.[2] Weizenecker J, Borgert J, Gleich B. Physics in Medicine and Biology

2007;52:6363.[3] Weizenecker J, Gleich B, Rahmer J, Dahnke H, Borgert J. Physics in

Medicine and Biology 2009;54:L1–10.[4] Sattel TF, Knopp T, Biederer S, Gleich B, Weizenecker J, Borgert J,

et al. Journal of Physics D: Applied Physics 2009;42:1–5.[5] Ruhland B, Baumann K, Knopp T, Sattel T, Biederer S, Luedtke-Buzug

K, et al. Geburtshilfe und Frauenheilkunde 2009;69:758.[6] Haegele J, Rahmer J, Gleich B, Borgert J, Wojtczyk H, Panagiotopoulos

N, et al., Radiology (in press).[7] Lüdtke-Buzug K. Chemie in unserer Zeit 2012;46:32–9.[8] Alexiou C. Nanomedicine - Basic and Clinical Applications in Diag-

nostics and Therapy. Karger; 2011.[9] Antonelli A, Sfara C, Mosca L, Manuali E, Magnani M. Journal of

Nanoscience and Nanotechnology 2008;8:2270–8.10] Rahmer J, Weizenecker J, Gleich B, Borgert J. BMC Medical Imaging

2009;9.11] Lawaczeck R, Bauer H, Frenzel T, Hasegawa M, Ito Y, Kito K, et al.

Acta Radiologica 1997;38:584–97.12] Biederer S, Sattel T, Knopp T, Erbe M, Lüdtke-Buzug K, Vogt F,

Barkhausen J, Buzug T. Magnetic Nanoparticles: Particle Science, Imag-ing Technology, and Clinical Applications 2010;1:60–5.

13] Khallafalla SE, Reimers GW. IEEE Transactions on Magnetics1980;16/2:178–83.

14] J. Lohrke, Herstellung und Charakterisierung neuer nanopartikulärerSPIO-Kontrastmittel für die Magnetresonanztomographie, Ph.D. thesis,University of Halle, Fakulty of Natural Science, 2010.

15] Chikazumi S, Charap S. Physics of Magnetism. New York: Wiley; 1964.16] Biederer S, Knopp T, Sattel TF, Lüdtke-Buzug K, Gleich B, Weizenecker

J, et al. Journal of Physics D: Applied Physics 2009;42:7pp.17] Goodwill PW, Conolly SM. IEEE Transactions on Medical Imaging

2010;29:1851–9.18] Goodwill PW, Conolly SM. IEEE Transactions on Medical Imaging

2011;30:1581–90.19] Goodwill PW, Saritas EU, Croft LR, Kim TN, Krishnan KM, Schaffer

DV, Conolly SM. Advanced Materials 2012.20] Weizenecker J, Gleich B, Borgert J. Journal of Physics D: Applied

Physics 2008;41:3pp.21] Knopp T, Erbe M, Biederer S, Sattel TF, Buzug TM. Medical Physics

2010;37:3538–40.22] Knopp T, Erbe M, Sattel TF, Biederer S, Buzug TM. Applied Physics

Letters 2010;97:092505-1–3.23] Erbe M, Knopp T, Sattel TF, Biederer S, Buzug TM. Medical Physics

2011;38:5200–7.24] Knopp T. Effiziente Rekonstruktion und alterntive Spulentopologien für

Magnetic-Particle-Imaging. Vieweg+Teubner; 2011.25] Goodwill PW, Scott GC, Stang PP, Conolly SM. IEEE Transactions on

Medical Imaging 2009;28:1231–7.26] Klauer P, Rückert MA, Vogel P, Kullmann WH, Jakob PM, Behr VC.

Proceedings of the International Society for Magnetic Resonance inMedicine 2011;19:3783.

27] Knopp T, Biederer S, Sattel T, Weizenecker J, Gleich B, Borgert J, et al.

Physics in Medicine and Biology 2009;54:385–97.

28] Gleich B, Weizenecker J, Timminger H, Bontus C, Schmale I, RahmerJ, Schmidt J, Kanzenbach J, Borgert J. Proceedings of the InternationalSociety for Magnetic Resonance in Medicine 2010;18:218.

[

[

ys. 22 (2012) 323–334 333

29] Sattel TF, Biederer S, Gleich B, Weizenecker J, Borgert J, Buzug TM.Proceedings of the International Society for Magnetic Resonance inMedicine 2010;18:3297.

30] Rahmer J, Gleich B, Bontus C, Schmale I, Schmidt J, Kanzenbach J,et al. Proceedings of the International Society for Magnetic Resonancein Medicine 2011;19:3285.

31] Grüttner M, Sattel TF, Graeser M, Wojtczyk H, Bringout G, Tenner W,et al. Springer Proceedings in Physics 2012;140:249–53.

32] Rahmer J, Gleich B, Schmidt J, Bontus C, Schmale I, Kanzenbach J,et al. Springer Proceedings in Physics 2012;140:255–9.

33] Schmale I, Weizenecker J. Magnetic Nanoparticles: Particle Science,Imaging Technology, and Clinical Applications 2010;1:148–53.

34] Schmale I, Weizenecker J. Magnetic Nanoparticles: Particle Science,Imaging Technology, and Clinical Applications 2010;1:154–61.

35] Knopp T, Biederer S, Sattel TF, Erbe M, Buzug TM. IEEE Transactionson Medical Imaging 2011;30:1284–92.

36] Knopp T, Sattel TF, Biederer S, Rahmer J, Weizenecker J, Gleich B,et al. IEEE Transactions on Medical Imaging 2010;29:12–8.

37] Knopp T, Biederer S, Sattel TF, Rahmer J, Weizenecker J, Gleich B,et al. Medical Physics 2010;37:485–91.

38] Gräser M, Biederer S, Grüttner M, Wojtczyk H, Tenner W, Sattel TF,et al. Biomedical Technology 2011;56.

39] Grüttner M, Gräser M, Biederer S, Sattel TF, Wojtczyk H, Tenner W,et al. Proceedings IEEE Nuclear Science Symposium and Medical Imag-ing Conference 2011:2545–8.

40] Halkola A, Buzug TM, Rahmer J, Gleich B, Bontus C. Springer Pro-ceedings in Physics 2012;140:27–31.

41] Knopp T, Rahmer J, Sattel TF, Biederer S, Weizenecker J, Gleich B,et al. Physics in Medicine and Biology 2010;55:1577–89.

42] Lampe J, Bassoy C, Rahmer J, Weizenecker J, Voss H, Gleich B, et al.Physics in Medicine and Biology 2012;57:1113–34.

43] Gleich B, Weizenecker J, Borgert J. Physics in Medicine and Biology2008;53:N81–4.

44] Patient information leaflet for Resovist, 2004.45] Schmale I, Rahmer J, Gleich B, Schmidt JKJ, Bontus C, Woywode O,

et al. SPIE Symposium on Medical Imaging: Biomedical Applicationsin Molecular, Structural, and Functional Imaging 2011.

46] Wawrzik T, Ludwig F, Schilling M. International Federation for Medicaland Biological Engineering Proceedings 2009;25:898–900.

47] Wawrzik T, Ludwig F, Schilling M. Magnetic Nanoparticles: Parti-cle Science, Imaging Technology, and Clinical Applications 2010;1:100–5.

48] Wawrzik T, Ludwig F, Schilling M. Biomedical Technology 2011;56.49] Wawrzik T, Ludwig F, Schilling M. Springer Proceedings in Physics

2012;140:21–5.50] Vogel P, Rückert MA, Klauer P, Kullmann WH, Jakob PM, Behr

VC. Proceedings of the European Society for Magnetic Resonance inMedicine and Biology 2011, abstract no. 78.

51] Vogel P, Rückert MA, Klauer P, Kullmann WH, Jakob PM, BehrVC. Proceedings of the European Society for Magnetic Resonance inMedicine and Biology 2011, e-Poster no. 78.

52] Vogel P, Rückert MA, Klauer P, Kullmann WH, Jakob PM, Behr VC.Springer Proceedings in Physics 2012;140:231–5.

53] Vogel P, Rückert MA, Klauer P, Kullmann WH, Jakob PM, Behr VC.Proceedings of the International Society for Magnetic Resonance inMedicine 2012;20:2742.

54] Goodwill P, Scott G, Stang P, Lee GC, Morris D, Conolly S. Proceed-ings of the International Society for Magnetic Resonance in Medicine2009;17:596.

55] Goodwill P, Conolly S. World Molecular Imaging Congress 2009:0222.56] Goodwill P, Croft LR, Konkle JJ, Zheng B, Lu K, Saritas EU, Conolly

S. World Molecular Imaging Congress 2011:T161.

57] Goodwill P, Croft L, Konkle J, Lu K, Saritas E, Zheng B, Conolly S.

Springer Proceedings in Physics 2012;140:261–5.58] Goodwill P, Konkle J, Zheng B, Saritas E, Conolly S. IEEE Transactions

on Medical Imaging 2012;31:1076–85.

ed

[

[

[

[

[

[

[

[[[[

[

[

[

[

[

[

[

[

[

[[

[

[

[

[[

[

[

[

[

334 T.M. Buzug et al. / Z. M

59] Konkle J, Goodwill P, Carrasco-Zevallos O, Conolly S. Springer Pro-ceedings in Physics 2012;140:243–7.

60] Erbe M, Sattel TF, Knopp T, Biederer S, Buzug TM. Biomedical Tech-nology 2011;56.

61] Erbe M, Knopp T, Sattel TF, Buzug TM. Springer Proceedings in Physics2012;140:225–9.

62] Sattel T, Erbe M, Biederer S, Knopp T, Finas D, Diedrich K, et al.SPIE Symposium on Medical Imaging: Biomedical Applications inMolecular, Structural, and Functional Imaging 2012.

63] Gräfe K, Sattel T, Lüdtke-Buzug K, Finas D, Borgert J, Buzug T.Springer Proceedings in Physics 2012;140:237–41.

64] Rahmer J, Gleich B, Weizenecker J, Borgert J. Proceedings of the Inter-national Society for Magnetic Resonance in Medicine 2010;18:714.

65] Rahmer J, Gleich B, Bontus C, Schmale I, Schmidt J, Kanzenbach J,et al. Proceedings of the International Society for Magnetic Resonancein Medicine 2011;19:629.

66] Thilo Wawrzik, Personal Communication, 2012.67] Patrick Vogel, Personal Communication, 2012.68] Patrick Goodwill, Personal Communication, 2012.69] Goodwill PW, Lu K, Zheng B, Conolly SM. Review of Scientific Instru-

ments 2012;3:033708.70] Goodwill P, Konkle J, Zheng B, Conolly ESS. IEEE Transactions on

Medical Imaging 2012;31:1076–85.71] Goodwill P, Konkle J, Zheng B, Conolly S. Springer Proceedings in

Physics 2012;140:267–71.72] Sattel TF, Biederer S, Knopp T, Lüdtke-Buzug K, Gleich B, Weize-

necker J, et al. World Congress on Medical Physics and BiomedicalEngineering, Springer IFMBE Series 2009;25(VII):281–4.

73] Sattel T, Knopp T, Biederer S, Erbe M, Lüdtke-Buzug K, Buzug T. Mag-

netic Nanoparticles: Particle Science, Imaging Technology, and ClinicalApplications 2010;1:106–12.

75] Nordeck P, Quick HH, Ladd ME, Ritter O. Heart Rhythm 2011 [Epubahead of print].

[

[

Available online at www

. Phys. 22 (2012) 323–334

76] Saeed M, Hetts S, English J, Wilson M. The International Journal ofCardiovascular Imaging 2012;28:117–37.

77] Kos S, Huegli R, Hofmann E, Quick HH, Kuehl H, Aker S, et al.Cardiovascular and Interventional Radiology 2009;32:514–21.

79] Heesakkers RA, Hövels AM, Jager GJ, van den Bosch HC, Witjes JA,Raat HP, et al. The Lancet Oncology 2008;9:850–6.

80] Harisinghani MG, Barentsz J, Hahn PF, Deserno WM, Tabatabaei S, vande Kaa CH, et al. New England Journal of Medicine 2003;348:2491–9.

81] Giuliano AE, Han SH. Advances in Surgery 2011;45:101–16.82] Sattel TF, Biederer S, Knopp T, Lüdtke-Buzug K, Gleich B, Borgert J,

et al. Suppl Mol Imaging Biol 2009:J521.83] Barreto JA, O’Malley W, Kubeil M, Graham B, Stephan H, Spiccia L.

Advanced Materials 2011;23:H18–40.84] Lee JH, Huh YM, Jun YW, Seo JW, Jang JT, Song HT, et al. Nature

Medicine 2007;13:95–9.85] Sun C, Lee JS, Zhang M. Advanced Drug Delivery Reviews

2008;60:1252–65.86] Higgins LJ, Pomper MG. Seminars in Oncology 2011;38:3–15.87] Bulte JW, Gleich B, Weizenecker J, Bernhard S, Walczak P, Markov DE,

Aerts HC, Borgert J, Boeve H. Proceedings of the International Societyfor Magnetic Resonance in Medicine 2008;16:1675.

88] Lefevre S, Ruimy D, Jehl F, Neuville A, Robert P, Sordet C, et al.Radiology 2011;258:722–8.

89] Lutz AM, Weishaupt D, Persohn E, Goepfert K, Froehlich J, Sasse B,et al. Radiology 2005;234:765–75.

90] Fleige G, Nolte C, Synowitz M, Seeberger F, Kettenmann H, ZimmerC. Neoplasia 2001;3:489–99.

91] Tysiak E, Asbach P, Aktas O, Waiczies H, Smyth M, Schnorr J, et al.Journal of Neuroinflammation 2009;6:20.

92] Sigovan M, Boussel L, Sulaiman A, Sappey-Marinier D, Alsaid H,Desbleds-Mansard C, et al. Radiology 2009;252:401–9.

93] Herborn CU, Vogt FM, Lauenstein TC, Dirsch O, Corot C, Robert P,Ruehm SG. Journal of Magnetic Resonance Imaging 2006;24:388–93.

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