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Evaluation of magnetic nanoparticle samples made from biocompatible ferucarbotran by time-correlation magnetic particle imaging reconstruction method

Evaluation of magnetic nanoparticle samples made from biocompatible ferucarbotran by... Background: Molecular imaging using magnetic nanoparticles (MNPs)—magnetic particle imaging (MPI)—has attracted interest for the early diagnosis of cancer and cardiovascular disease. However, because a steep local magnetic field distribution is required to obtain a defined image, sophisticated hardware is required. Therefore, it is desirable to realize excellent image quality even with low-performance hardware. In this study, the spatial resolution of MPI was evaluated using an image reconstruction method based on the correlation information of the magnetization signal in a time domain and by applying MNP samples made from biocompatible ferucarbotran that have adjusted particle diameters. Methods: The magnetization characteristics and particle diameters of four types of MNP samples made from ferucarbotran were evaluated. A numerical analysis based on our proposed method that calculates the image intensity from correlation information between the magnetization signal generated from MNPs and the system function was attempted, and the obtained image quality was compared with that using the prototype in terms of image resolution and image artifacts. Results: MNP samples obtained by adjusting ferucarbotran showed superior properties to conventional ferucarbotran samples, and numerical analysis showed that the same image quality could be obtained using a gradient magnetic field generator with 0.6 times the performance. However, because image blurring was included theoretically by the proposed method, an algorithm will be required to improve performance. Conclusions: MNP samples obtained by adjusting ferucarbotran showed magnetizing properties superior to conventional ferucarbotran samples, and by using such samples, comparable image quality (spatial resolution) could be obtained with a lower gradient magnetic field intensity. Keywords: Magnetic particle imaging, MPI, Nanoparticle, Ferucarbotran, Resovist, Image reconstruction, Time correlation * Correspondence: y_ishr@meiji.ac.jp Equal contributors School of Science and Technology, Meiji University, Higashimita Tama, Kawasaki, Kanagawa, Japan Full list of author information is available at the end of the article © 2013 Ishihara et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 2 of 10 http://www.biomedcentral.com/1471-2342/13/15 Background the distribution of MNPs accumulated in the cancer cell. Developments in nanotechnology have been exploited to Owing to its various advantages, MPI has attracted con- realize innovative techniques for the diagnosis and treat- siderable research attention as a new diagnostic imaging ment of diseases in the field of medicine. In particular, modality. nanotechnology has been applied to drug delivery sys- The possibility of in-vivo real time imaging has already tems (DDSs) in which a nanoparticle, the surface of been demonstrated in a mouse [8]. However, a clinical which is functionalized with various antibodies, is used MPI system for humans will require a large magnetic to attack cancer cells; furthermore, cellular imaging field generator to realize a magnetic field distribution using the light scattered by a nanoparticle has been ac- with a steep slope, which is advantageous in identifying tively studied [1]. Cancer treatment has also been the position of an MNP and in obtaining a high- attempted using nanoparticles with high sensitivity to resolution image in MPI. To avoid this problem, the seg- light or heat [2,3]. Similarly, the use of magnetic mentation scanning of the objective region has been nanoparticles (MNPs) has also been investigated. For ex- proposed as a workaround [9]. ample, in the thermal treatment of cancer, MNPs are In order to realize a feasible clinical system, since used as heating elements to selectively heat a cancer cell 2007, we have focused our attention on developing a [4]; in fact, clinical trials of this technique are now un- high-resolution MPI imaging system that does not derway [5]. Gleich et al. reported magnetic particle im- require special, high-performance hardware. As a candi- aging (MPI), a technique in which MNPs are applied to date procedure, we have proposed an image reconstruc- medical imaging [6,7]. MPI uses the harmonic compo- tion method to improve the spatial resolution by nents of the magnetization signal produced by the inter- reducing the interference signal produced around the action between the nonlinear magnetizing properties of target region [10]. Through the use of this method, local an MNP and the alternative magnetic field around the image artifacts and blurring could be suppressed. More- target body. In this technique, MNPs play the role of a over, we reported that the components of image blurring contrast medium in blood vessels for the diagnosis of and artifacts could be suppressed based on the difference cardiovascular diseases and that of a tracer that images of the “saturation time” between the ideal magnetization Figure 1 Concept of image reconstruction by time-correlation method. (a) The waveforms of the induced electromotive force produced by the MNPs arranged at each point are observed by scanning the FFP, and the signal sequences that connect them to the time axis are defined as the system function. (b) The signal detected from an unknown MNP distribution at each FFP is connected to a time axis and defined as an observation signal sequence. (c) The intensity of a reconstruction image is determined by calculating the time correlation between a system function and an observation signal sequence. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 3 of 10 http://www.biomedcentral.com/1471-2342/13/15 signal (corresponding to an impulse response or a point spread function (PSF) of the MPI system), which arises from an isolated MNP and the observed magnetization signal [11]. However, when MNPs are distributed con- tinuously, it becomes difficult to obtain an accurate image of MNPs because of the enhancement of the image edge part, as noted previously. Therefore, we have proposed a new image reconstruction method and eval- uated its validity [12]. In this method, the observed magnetization signal produced around a target region is extracted based on the correlation with a system func- tion, and it can be reflected by the intensity of the reconstruction image. However, because the image re- construction is performed based on a simple correlation, it tends to expand the image blurring theoretically. Therefore, it is necessary to remove the image blurring actively, and we are currently attempting to design an ef- fective algorithm for this purpose [13]. Meanwhile, to improve the image resolution without requiring high-performance hardware, the characteristics of an MNP should be improved in parallel to the image quality improvement by such an image reconstruction method because the spatial broadening of the observed magnetization signal is approximated by the differenti- ation of the Langevin function [14]. Therefore, high spatial resolution is expected when the particle diameter Figure 2 Outside view of phantom and MPI prototype system. of an MNP is large because the full width at half max- (a) Each MNP sample was placed in an acrylic cylindrical container. imum (FWHM) of this differentiated waveform narrows (b) The receiver coil was coaxially arranged on a cylindrical container with an increase in the particle diameter [15]. placed in the MNP sample. (c) The prototype system was built to collect one-dimensional MPI data. Currently, the ferucarbotran (a drug substances of Resovist; supplied only by Meito Sangyo Co., Ltd.) used as a contrast medium for magnetic resonance imaging and it is expected that obtaining such information will re- (MRI) is being used in MPI. However, because the par- quire considerable effort and time. On the other hand, ticle diameters of the MNPs contained in ferucarbotran some studies have shown that the signal detection sensi- differ, as already pointed out, it is not an optimal con- tivity in magnetic particle spectroscopy (MPS) can be en- trast medium for demonstrating the performance of hanced by using fractionation samples of ferucarbotran MPI. Generally, if the influence of the relaxation time for [18] or FeraSpin (Miltenyi Biotec GmbH) [19]. the magnetization response is ignored, the magnetization In this study, MNP samples adjusted to some particle properties of an MNP with large particle diameter are ad- diameters are prepared by using ferucarbotran, which vantageous for MPI [16]. Therefore, a trial in which MNPs has already been approved for clinical use, as a base ma- with large particle diameters are compounded efficiently terial. In particular, this study aims at estimating the using an organic solvent is performed [17]. However, suffi- influence of the characteristics of the MNPs based on the difference in particle diameter on the images cient information regarding the biocompatibility of most particles compounded by such processes is not available, reconstructed using our proposed method in the Table 1 Characteristics of each sample based on ferucarbotran -2 -1 -1 -1 No. D [nm] PI D [nm] Magnetic susceptibility [erg � gauss � g]T relaxivity [mM � s ] D [nm] a v 2 1 55 0.28 30-110 0.0315 186 15 2 59 0.24 30-120 0.0387 268 18 3 86 0.19 50-200 0.0399 494 20 4 56 0.26 35-110 0.0354 274 17 D Average diameter including coating layer. D Particle size distribution of average diameter including coating layer. D Particle diameter of experimentally evaluated MNP. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 4 of 10 http://www.biomedcentral.com/1471-2342/13/15 Figure 3 Signal detected with each sample. (a.1), (b.1) Waveform of induced electromotive force. (a.2), (b.2) Magnetization response waveform. numerical simulation and the experiments using a a similar manner, with the position of an MNP being prototype. In addition, the relation between the charac- changed and the series G and G being created, re- i=2 i=3 teristics of the MNP and the hardware ability is spectively (Figure 1(a)). Next, the induced EMF gener- discussed based on the results of such reconstructed ated from the unknown MNPs’ distribution is observed images. at each FFP (x=1,2,3),anditis consideredasthe series V connected to the time-axis as well as the Principle abovementioned system function. Here, the observed Time-correlation MPI reconstruction method signal V shown in Figure 1(b) reflects the outline form In consideration of the abovementioned problems, we of the signal series obtained when the MNP is arranged have proposed an image reconstruction method based at the left end matrix as an example. Then, the correl- on the correlation information between an observed sig- ation information of this observed signal and each sys- nal (induced electromotive force: induced EMF) and a tem function is calculated (Figure 1(c)). It is expected system function without depending on inverse matrix that only the magnetization signal generated from a tar- operations [12]. The conceptual diagram of this tech- get region is emphasized and reflected as the image nique is shown in Figure 1. Here, for simplification, the intensity by such correlation processing. In contrast, an analyzed matrix is assumed to include three points. interference signal is difficult to reflect as the re- First, a system function is defined. When an MNP is constructed image intensity because the correlation arranged as a delta function at the left end matrix point between the observed waveform of the induced EMF (i = 1), a field free point (FFP) [6,7] where the local mag- and the system function is small. In the case of a general netic field strength is almost zero is scanned in order two-dimensional image, the image intensity F(i, j)inthe (x = 1, 2, 3) while applying an alternative magnetic field proposed method can be expressed by the following at each FFP. Here, although such a procedure may be equation: classified under the category of narrow band MPI [20], the FFP scanned by our method is encoded intermit- FiðÞ ; j ¼ ∫V ðÞ t G ðÞ t dt ð1Þ x;z i;j;x;z tently as in robot position movement [7]. Consequently, aseries (G )thatcombinesthree waveformsofthe Here, x and z express the scanning position of FFP, i=1 induced EMF observed at each FFP is created. The sys- V expresses an observed signal, and G expresses x,z x,z tem function at each matrix point (i = 2, 3) is defined in the system function as follows [12]. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 5 of 10 http://www.biomedcentral.com/1471-2342/13/15 x ¼ 1; 2; ⋯; X The average particle diameter of each sample was G ðÞ t ¼ G½ xt þXzðÞ −1 ; ð2Þ i;j;x;z i;j z ¼ 1; 2; ⋯; Z computed by approximating the magnetization curve obtained in the abovementioned experiment with a Langevin function. x ¼ 1; 2; ⋯; X V ðÞ t ≡Vx½ t þXzðÞ −1 ; ð3Þ x;z Evaluation of image reconstruction method by numerical z ¼ 1; 2; ⋯; Z analysis A gradient magnetic field intensity of 1.5 [T/m] at the cen- Methods ter of a Maxwell pair coil and an alternating magnetic field Evaluation of magnetizing properties of MNP intensity of 32.0 [mT] were used. The FOV was set as 40 In this study, four types of samples (including [mm] × 40 [mm], and the matrix size was set as 21 × 21. ferucarbotran), as listed in Table 1, with ferucarbotran as The system function was analytically computed in each the base material and adjusted particle diameters were matrix point of this FOV based on the Langevin function used. These samples were respectively prepared by mag- approximated using the particle diameter of each MNP as netic separation, centrifugal separation, and gel filtration. evaluated by the abovementioned procedure. The Fe concentration of each sample as well as the Then, based on equations (1), (2) and (3) and Figure 1, Resovist sample was adjusted to 28 [mg/mL]. The average image reconstruction was performed for the signal series diameter including the coating layer (Da) and the particle that connected the induced EMF observed at the FFP size distribution of the average diameter including the scanned by each matrix point. coating layer (Dv) were evaluated using a photon correl- ation spectrometer, the susceptibility was measured using the magnetic balance method, and the T relaxation time was evaluated using 0.47 [T] NMR equipment. The poly- dispersity index (PI) was evaluated using the light scatter- ing method. A vibrating sample magnetometer (VSM) is commonly used for evaluating the magnetization proper- ties; however, in this case, these properties were evaluated using our MPI prototype because the detection sensitivity in MPI was also evaluated. Each sample was sealed her- metically in 0.7 [cc] cylindrical containers (∅5 [mm], ap- proximately 12 [mm] in length) made from acrylics, and a solenoid coil of 19 [mm] diameter and with 350 turns was arranged as a receiver coil on the outer circumference (Figure 2). They were installed centered on the gap (50 [mm]) of a customized Maxwell pair coil (Toyojiki In- dustry Co., Ltd., Niiza, Japan) with an iron core, 180 [mm] diameter, and 285 turns for each coil. An alterna- tive magnetic field with an amplitude of approximately 65 [mT] was generated at the center of those coils by ap- plying an alternative current with an amplitude of 12.0 [A] and frequency of 33.0 [Hz] to each coil in the same direction. To distinguish between the magnetization components (harmonics) generated from an MNP and the primary magnetic field components applied from the outside, the induced EMF to a coil without a sample was observed previously, and it was defined as the raw flux density ap- plied to an MNP. Then, an induced EMF was generated when an MNP was arranged, and the actual induced EMF generated from the MNP was determined from the difference between this observed signal and the above- described raw flux density. In this case, the absolute value of flux density was corrected using a gauss meter Figure 4 Magnetization curve of each sample. (Model 460; Lakeshore Cryotronics Inc., OH, USA). Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 6 of 10 http://www.biomedcentral.com/1471-2342/13/15 Figure 5 Reconstructed image for each sample by numerical analysis. (a.1), (a.2) Images by fundamental and proposed reconstruction methods in the case of sample 1, respectively. (b.1), (b.2) Images by fundamental and proposed reconstruction methods in the case of sample 3, respectively. Figure 6 Image profiles of reconstructed images by numerical analysis. (a.1), (a.2) Image profiles at z = 0 in the case of sample 1, respectively. (b.1), (b.2) Image profiles at z = 0 in the case of sample 3, respectively. (a. 2), (b. 2) Individual theoretical point spread functions indicated by red lines. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 7 of 10 http://www.biomedcentral.com/1471-2342/13/15 Evaluation of one-dimensional reconstructed image using In a preliminary experiment, the electric current re- prototype quired to move the FFP by a unit length (this corre- Both an alternative magnetic field and an FFP were gen- sponds to the spatial resolution) was evaluated; based on erated using the abovementioned one-axis Maxwell pair this, the scanning of the FFP was controlled by the func- coil. The coil current was supplied from a bipolar power tion generator. In addition, a ±20-mm region from the supply (BP30-30; Heiwa Electric Co., Ltd., Kashiwa, Maxwell pair coil’s center was set as the FOV, and the Japan) in constant current mode, and the current wave matrix that divides the inside of this FOV into 21 points for scanning the FFP was controlled by a function gener- was made into each measuring point (FFP). ator (AFG3252; Tektronix, Inc., OR, USA). After the in- To detect only the induced EMF generated from an duced EMF was detected using the receiver coil MNP in consideration of the frequency purity of the al- (diameter 19 [mm], 350 turns) and passed through the ternative magnetic field due to the imperfection of the programmable filter (3628, NF Corporation, Yokohama, power supply and the coil, difference processing with Japan), it was supplied to a 14-bit AD converter the induced EMF and without a sample was carried out. (M2i4031; Spectrum Systementwicklung Microelectronic GmbH, Grosshansdorf, Germany). The detected signal Results and discussion was sampled with a sampling frequency of 20 [kHz] and Magnetization property of each MNP sample was sent to a personal computer (dc7800 MT/CT; The induced EMF from the samples made with Hewlett–Packard Co., CA, USA). ferucarbotran as the base material to the external alter- As a result of arranging each abovementioned sample at native magnetic field and the magnetization response the center of the gap of a Maxwell pair coil and applying obtained from the integration operation of EMF are the alternative current with an amplitude of 6.0 [A] and shown in Figure 3 (in what follows, only the results of frequency of 39.0 [Hz] in the same direction, the MNPs in sample 1 (ferucarbotran) and sample 3, which show the each sample were subjected to an alternative magnetic characteristic tendency, were displayed.). In addition, the field of approximately 30 [mT]. Under such device condi- average particle diameter of each sample was evaluated tions, a gradient magnetic field of 1.9 [T/m] was generated by comparing the observed magnetization properties by applying an offset current of 12.0 [A] simultaneously to with the magnetization curve of the MNP as indicated by the opposite direction of each coil, and an FFP was formed Langevin’s approximate expression (Figure 4). These at the center of the Maxwell pair coil. magnetization curves were normalized by the maximum Figure 7 Reconstructed image with numerical analysis for each sample at gradient field of 2.5 T/m. (a.1), (a.2) Images by fundamental and proposed reconstruction methods in the case of sample 1, respectively. (b.1), (b.2) Images by fundamental and proposed reconstruction methods in the case of sample 3, respectively. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 8 of 10 http://www.biomedcentral.com/1471-2342/13/15 magnetization of each case. The results are summarized the system function [22]. The PSF of this image recon- in Table 1. struction method was expected as an autocorrelation dis- It was estimated that the average particle diameter D tribution of the system function, and it was superimposed of sample 1 (ferucarbotran), which has been clinically in Figure 6 for MNPs of each particle diameter. Therefore, approved, was 15 [nm]. That of sample 3 was 20 [nm], it is possible to newly propose the following iterative esti- which is the largest among all samples, and it was shown mation of the distribution of MNPs in order to improve that sample 3 is the most suitable because a sample with the image resolution [13]. large particle diameter is advantageous for MPI. Here, the difference between the obtained magnetization prop- (1)The position at which the correlation with an erties and the approximated curve reflected the variation observed signal and a system function is the maximum in the particle size distribution of the MNPs in a sample, in the FOV is detected. and it was suggested that the particle diameter of sample 3 was adjusted satisfactorily. This result was also sup- ported by the evaluation results obtained by PI and D , shown in Table 1. Because the particle size distribution follows a logarithmic normal distribution [21], it was considered important to adjust the particle diameter in a sample uniformly in order to improve the image reso- lution in MPI. Moreover, the induced EMF detected from sample 3 was approximately 3 times that from ferucarbotran, indicating that sample 3 also contributes greatly to the improvement of SNR. This is based on the increase in the saturation magnetization of the MNP ac- companying the increase in the particle diameter [15]. From the physical properties obtained by this eva- luation, as listed in Table 1, it was confirmed that the particle diameter of MNPs was also related to the sus- ceptibility and T relaxation time. Numerical analysis of time-correlation MPI image reconstruction Next, the image reconstruction results of the numerical simulation based on the characteristics of sample 1 (ferucarbotran) and sample 3, which were chosen from among all samples as discussed above, are described. The images reconstructed by the fundamental image re- construction method based on an imaging principle (an alternative magnetic field was applied at each FFP that was scanned for every encoded position [7]) and our proposed time-correlation method for a sample arranged at the center pixel of the FOV are shown in Figure 5. In addition, the profiles at z = 0 of these reconstruction im- ages are shown in Figure 6. It was confirmed that the image artifact observed in the upper and lower sides of the actual MNP by the fundamental image reconstruc- tion method was suppressed by the proposed method. However, the image resolution of the proposed method (~12 mm) was slightly degraded compared to that of the fundamental method (~8 mm) using the FWHM for sample 1. Then, it was shown that the image blurring in- Figure 8 Signal detected using prototype. (a) Waveform of induced electromotive force. (b) Magnetization response waveform. creased. This is because theoretically, the distribution of (c) Fourier components of magnetization response waveform. Here, correlation between the observed signal and the system only the waveforms obtained by scanning the FFP at −20 [mm] function at every FFP position (Figure 1) was given as (L20), 0 [mm] (C), and 20 [mm] (R20) along the z-axis were indicated. the image intensity with nearly two times the FWHM of Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 9 of 10 http://www.biomedcentral.com/1471-2342/13/15 (2)At this position (image matrix), the amount of magnetization response are shown in Figure 8. Here, when correlation is given as the reconstructed image the center coordinate of the FOV was set to 0, only the intensity. wave obtained by scanning the FFP at −20 [mm], 0 [mm], (3)The distribution of a corresponding system function and 20 [mm] along the z-axis was indicated in the figure is subtracted from the observed signal at this position. (this corresponds to the sign L20, C, and R20, respect- ively.). It was confirmed that the difference of the induced Then, the candidate of the processing position is moved EMF’s waveform in an experiment appeared depending on to the next FFP and the abovementioned process is re- the position of the FFP. In other words, because it would peated until the residual of the subtraction signal at every reflect that the position of the MNP was indistinguishable FFP becomes small. It is considered that a deconvolution when the correlation with an observed signal was evalu- with a system function can be carried out equivalently by ated with a system function, the validity of our proposed such processing; therefore, the image blurring can be re- method based on time-correlation information was also duced effectively without inverse matrix operations. confirmed by experimental data. With regard to sample 1 An evaluation of the profile at z = 0 (Figure 6) showed (ferucarbotran) and sample 3, the one-dimensional images that the spatial resolution of sample 3 was approximately obtained using the fundamental image reconstruction 1.3 times better than that of sample 1. This corresponded method and the proposed method are shown in Figure 9. to the fact that the spatial resolution obtained by a gradi- In these reconstructed images, although the precise sys- ent magnetic field strength of 2.5 [T/m] for sample 1 was tem function should ideally be measured from the signal achieved by a gradient magnetic field strength of approxi- observed when the MNPs are arranged in a shape like a mately 1.5 [T/m] for sample 3 (Figure 7). In other words, delta function at each analyzed point in the reconstructed it was shown that the dependence on hardware require- image, the analytically calculated system function corre- ments was reduced by 0.6 times under such conditions sponding to each particle diameter at every image matrix and that the spatial resolution could be improved by sim- point was used. This is because considerable time is gener- ply adjusting the particle diameter. ally required for the measurement of a system function, and our system’s operation might become unstable over One-dimensional imaging experiment using prototype such a long time. It was found that sample 3 afforded an The waveform of the induced EMF obtained by scanning image resolution superior to that of sample 1 through the FFP, the magnetization response calculated from the both the experimental results as well as the numerical integration of the EMF, and the Fourier transform of this simulation. Figure 9 One-dimensional reconstructed images using prototype. (a.1), (a.2) Images by fundamental and proposed reconstruction methods in the case of sample 1, respectively. (b.1), (b.2) Images by fundamental and proposed reconstruction methods in the case of sample 3, respectively. In these cases, the calculated system function corresponding to each particle diameter was used. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 10 of 10 http://www.biomedcentral.com/1471-2342/13/15 Conclusions 3. El-Sayed IH, Huang X, El-Sayed MA: Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold In this study, to suppress image artifacts in MPI and im- nanoparticles. Cancer Lett 2006, 239:129–135. prove the spatial resolution without requiring high- 4. Hergt R, Hiergeist R, Zeisberger M, Schüler D, Heyen U, Hilger I, Kaiser WA: performance hardware, an image obtained using an Magnetic properties of bacterial magnetosomes as potential diagnostic and therapeutic tools. Journal of Magnetism and Magnetic Materials 2005, MNP sample made of biocompatible ferucarbotran as 293:80–86. the base material and a sample made by our proposed 5. Jordan A, Scholz R, Maier-Hauff K, Johannsen M, Wust P, Nadobny J, Schirra method were compared. It is essential to evaluate the H, Schmidt H, Deger S, Loening S, Lanksch W, Felix R: Presentation of a new magnetic field therapy system for the treatment of human solid biocompatibility because a large-diameter nanoparticle tumors with magnetic fluid hyperthermia. Journal of Magnetism and may behave differently in internal organs compared to Magnetic Materials 2001, 225:118–126. Resovist, which is approved for clinical use. Nonetheless, 6. Gleich B: Method for determining the spatial distribution of magnetic particles. DE 10151778(A1)05 2003, 05:08. some samples used for MPI were found to have magnet- 7. Gleich B, Weizenecker J: Tomographic imaging using the nonlinear izing properties superior to those of ferucarbotran. Con- response of magnetic nanoparticles. Nature 2005, 435:1214–1217. sequently, it was shown that an equivalent image quality 8. Weizenecker J, Gleich B, Rahmer J, Dahnke H, Borgert J: Three-dimensional real-time in vivo magnetic particle imaging. Phys Med Biol 2009, (spatial resolution) could be obtained with a smaller gra- 54:L1–L10. dient magnetic field strength compared to the case in 9. Schmale I, Rahmer J, Gleich B, Kanzenbach J, Schmidt JD, Bontus C, which ferucarbotran was used. Woywode O, Borgert J: First phantom and in vivo MPI images with an extended field of view. Florida: Proc. of SPIE Medical Imaging; 2011:796510.6. Therefore, if a method for preparing MNP samples 10. Kusayama Y, Ishihara Y: A preliminary study on the molecular imaging consisting of particles with large and equisized diameters device using magnetic nanoparticles. Technical Report of IEICE. MBE 2007, made from ferucarbotran as the base material is devel- 107:15–18. 11. Kusayama Y, Ishihara Y: High-resolution image reconstruction method on oped, the MPI image quality can be further improved, and the molecular imaging using magnetic nanoparticles. IEICE Trans. D 2009, the conditions imposed on hardware ability can be re- J92–D:1653–1662. duced. However, because our study was restricted to the 12. Ishihara Y, Kuwabara T, Honma T, Nakagawa Y: Correlation-based image reconstruction methods for magnetic particle imaging. IEICE Transactions use of an alternating magnetic field with relatively low fre- on Information and Systems 2012, E95-D:872–879. quency, evaluations in consideration of the dynamic char- 13. Honma T, Shimizu S, Ishihara Y: Correlation-based image reconstruction acteristic of the MNP [19,23] will be required when faster methods for magnetic particle imaging.In Proceedings of the Branch Conference of Japanese Society for Medical Biological Engineering 2012. Edited scanning of FFP is used. In addition, because a sufficiently by Kyoso M. Tokyo; 2012. 2012: C-1-04. high spatial resolution has not yet been achieved theoretic- 14. Goodwill PW, Conolly SM: The X-space formulation of the magnetic ally using the proposed time-correlation MPI reconstruc- particle imaging process: 1-D signal, resolution, bandwidth, SNR, SAR, and magnetostimulation. IEEE Trans Med Imaging 2010, 29:1851–1859. tion method, it is necessary to devise an algorithm that 15. Chikazumi S: In Physics of Magnetism. Edited by Charap SH. New York: John can use correlation information more effectively. Wiley and Sons; 1964. 16. Ferguson RM, Minard KR, Krishnan KM: Optimization of nanoparticle core Competing interests size for magnetic particle imaging. J. Magn. Magn. Mater. 2009, The authors have no competing interests to declare. 321:1548–1551. 17. Ferguson RM, Minard KR, Khandhar AP, Krishnan KM: Optimizing magnetite nanoparticles for mass sensitivity in magnetic particle imaging. Med Phys Authors’ contributions 2011, 38:1619–1626. YI conceived the study, built the algorithm, and drafted the manuscript. TH 18. Eberbeck D, Wiekhorst F, Wagner S, Trahms L: How the size distribution of implemented the algorithm in a program, developed the prototype system, magnetic nanoparticles determines their magnetic particle imaging performed data collection, and helped to draft the manuscript. SN prepared performance. Appl Phys Lett 2011, 98:182502.1–182502.3. the experimental MNP samples and helped to draft the manuscript. All 19. Ludwig F, Wawrzik T, Yoshida T, Gehrke N, Briel A, Eberbeck D, Schilling M: authors have read and approved the final manuscript. Optimization of magnetic nanoparticles for magnetic particle imaging. IEEE Transactions on Magnetics 2012, 48:3780–3783. Acknowledgements 20. Goodwill PW, Scott GC, Stang PP, Conolly SM: Narrowband magnetic This study was supported by a Grant-in-Aid for Scientific Research (B), particle imaging. IEEE Trans Med Imaging 2009, 28:1231–1237. 24300184, 2012, from the Japan Society for the Promotion of Science (JSPS). 21. Chantrell RW, Popplewell J, Charles SW: Measurements of particle size distribution parameters in ferrofluids. IEEE Transactions on Magnetics 1978, Author details 1 14:975–977. School of Science and Technology, Meiji University, Higashimita Tama, 2 22. Yarlagadda RKR: Analog and Digital Signals and Systems. New York: Springer Kawasaki, Kanagawa, Japan. Graduate School of Science and Technology, 3 Science + Business Media; 2010. Meiji University, Higashimita, Tama, Kawasaki, Kanagawa, Japan. The Nagoya 23. Yoshida T, Enpuku K, Ludwig F, Dieckhoff J, Wawrzik T, Lak A, Schilling M: Research Laboratory, Meito Sangyo Co., Ltd, Kaechi Nishibiwajima, Kiyosu, Characterization of Resovist® nanoparticles for magnetic particle Aichi, Japan. imaging. Springer Proceedings in Physics 2012, 140:3–7. Received: 24 August 2012 Accepted: 29 May 2013 doi:10.1186/1471-2342-13-15 Published: 5 June 2013 Cite this article as: Ishihara et al.: Evaluation of magnetic nanoparticle samples made from biocompatible ferucarbotran by time-correlation References magnetic particle imaging reconstruction method. BMC Medical Imaging 1. Huang X, Jain PK, El-Sayed H, El-Sayed MA: Gold nanoparticles: interesting 2013 13:15. optical properties and recent applications in cancer diagnostics and therapy. Nanomedicine 2007, 2:681–693. 2. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q: Photodynamic therapy. J Natl Cancer Inst 1998, 90:889–905. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Medical Imaging Springer Journals

Evaluation of magnetic nanoparticle samples made from biocompatible ferucarbotran by time-correlation magnetic particle imaging reconstruction method

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Copyright © 2013 by Ishihara et al.; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Imaging / Radiology
eISSN
1471-2342
DOI
10.1186/1471-2342-13-15
pmid
23734917
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Abstract

Background: Molecular imaging using magnetic nanoparticles (MNPs)—magnetic particle imaging (MPI)—has attracted interest for the early diagnosis of cancer and cardiovascular disease. However, because a steep local magnetic field distribution is required to obtain a defined image, sophisticated hardware is required. Therefore, it is desirable to realize excellent image quality even with low-performance hardware. In this study, the spatial resolution of MPI was evaluated using an image reconstruction method based on the correlation information of the magnetization signal in a time domain and by applying MNP samples made from biocompatible ferucarbotran that have adjusted particle diameters. Methods: The magnetization characteristics and particle diameters of four types of MNP samples made from ferucarbotran were evaluated. A numerical analysis based on our proposed method that calculates the image intensity from correlation information between the magnetization signal generated from MNPs and the system function was attempted, and the obtained image quality was compared with that using the prototype in terms of image resolution and image artifacts. Results: MNP samples obtained by adjusting ferucarbotran showed superior properties to conventional ferucarbotran samples, and numerical analysis showed that the same image quality could be obtained using a gradient magnetic field generator with 0.6 times the performance. However, because image blurring was included theoretically by the proposed method, an algorithm will be required to improve performance. Conclusions: MNP samples obtained by adjusting ferucarbotran showed magnetizing properties superior to conventional ferucarbotran samples, and by using such samples, comparable image quality (spatial resolution) could be obtained with a lower gradient magnetic field intensity. Keywords: Magnetic particle imaging, MPI, Nanoparticle, Ferucarbotran, Resovist, Image reconstruction, Time correlation * Correspondence: y_ishr@meiji.ac.jp Equal contributors School of Science and Technology, Meiji University, Higashimita Tama, Kawasaki, Kanagawa, Japan Full list of author information is available at the end of the article © 2013 Ishihara et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 2 of 10 http://www.biomedcentral.com/1471-2342/13/15 Background the distribution of MNPs accumulated in the cancer cell. Developments in nanotechnology have been exploited to Owing to its various advantages, MPI has attracted con- realize innovative techniques for the diagnosis and treat- siderable research attention as a new diagnostic imaging ment of diseases in the field of medicine. In particular, modality. nanotechnology has been applied to drug delivery sys- The possibility of in-vivo real time imaging has already tems (DDSs) in which a nanoparticle, the surface of been demonstrated in a mouse [8]. However, a clinical which is functionalized with various antibodies, is used MPI system for humans will require a large magnetic to attack cancer cells; furthermore, cellular imaging field generator to realize a magnetic field distribution using the light scattered by a nanoparticle has been ac- with a steep slope, which is advantageous in identifying tively studied [1]. Cancer treatment has also been the position of an MNP and in obtaining a high- attempted using nanoparticles with high sensitivity to resolution image in MPI. To avoid this problem, the seg- light or heat [2,3]. Similarly, the use of magnetic mentation scanning of the objective region has been nanoparticles (MNPs) has also been investigated. For ex- proposed as a workaround [9]. ample, in the thermal treatment of cancer, MNPs are In order to realize a feasible clinical system, since used as heating elements to selectively heat a cancer cell 2007, we have focused our attention on developing a [4]; in fact, clinical trials of this technique are now un- high-resolution MPI imaging system that does not derway [5]. Gleich et al. reported magnetic particle im- require special, high-performance hardware. As a candi- aging (MPI), a technique in which MNPs are applied to date procedure, we have proposed an image reconstruc- medical imaging [6,7]. MPI uses the harmonic compo- tion method to improve the spatial resolution by nents of the magnetization signal produced by the inter- reducing the interference signal produced around the action between the nonlinear magnetizing properties of target region [10]. Through the use of this method, local an MNP and the alternative magnetic field around the image artifacts and blurring could be suppressed. More- target body. In this technique, MNPs play the role of a over, we reported that the components of image blurring contrast medium in blood vessels for the diagnosis of and artifacts could be suppressed based on the difference cardiovascular diseases and that of a tracer that images of the “saturation time” between the ideal magnetization Figure 1 Concept of image reconstruction by time-correlation method. (a) The waveforms of the induced electromotive force produced by the MNPs arranged at each point are observed by scanning the FFP, and the signal sequences that connect them to the time axis are defined as the system function. (b) The signal detected from an unknown MNP distribution at each FFP is connected to a time axis and defined as an observation signal sequence. (c) The intensity of a reconstruction image is determined by calculating the time correlation between a system function and an observation signal sequence. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 3 of 10 http://www.biomedcentral.com/1471-2342/13/15 signal (corresponding to an impulse response or a point spread function (PSF) of the MPI system), which arises from an isolated MNP and the observed magnetization signal [11]. However, when MNPs are distributed con- tinuously, it becomes difficult to obtain an accurate image of MNPs because of the enhancement of the image edge part, as noted previously. Therefore, we have proposed a new image reconstruction method and eval- uated its validity [12]. In this method, the observed magnetization signal produced around a target region is extracted based on the correlation with a system func- tion, and it can be reflected by the intensity of the reconstruction image. However, because the image re- construction is performed based on a simple correlation, it tends to expand the image blurring theoretically. Therefore, it is necessary to remove the image blurring actively, and we are currently attempting to design an ef- fective algorithm for this purpose [13]. Meanwhile, to improve the image resolution without requiring high-performance hardware, the characteristics of an MNP should be improved in parallel to the image quality improvement by such an image reconstruction method because the spatial broadening of the observed magnetization signal is approximated by the differenti- ation of the Langevin function [14]. Therefore, high spatial resolution is expected when the particle diameter Figure 2 Outside view of phantom and MPI prototype system. of an MNP is large because the full width at half max- (a) Each MNP sample was placed in an acrylic cylindrical container. imum (FWHM) of this differentiated waveform narrows (b) The receiver coil was coaxially arranged on a cylindrical container with an increase in the particle diameter [15]. placed in the MNP sample. (c) The prototype system was built to collect one-dimensional MPI data. Currently, the ferucarbotran (a drug substances of Resovist; supplied only by Meito Sangyo Co., Ltd.) used as a contrast medium for magnetic resonance imaging and it is expected that obtaining such information will re- (MRI) is being used in MPI. However, because the par- quire considerable effort and time. On the other hand, ticle diameters of the MNPs contained in ferucarbotran some studies have shown that the signal detection sensi- differ, as already pointed out, it is not an optimal con- tivity in magnetic particle spectroscopy (MPS) can be en- trast medium for demonstrating the performance of hanced by using fractionation samples of ferucarbotran MPI. Generally, if the influence of the relaxation time for [18] or FeraSpin (Miltenyi Biotec GmbH) [19]. the magnetization response is ignored, the magnetization In this study, MNP samples adjusted to some particle properties of an MNP with large particle diameter are ad- diameters are prepared by using ferucarbotran, which vantageous for MPI [16]. Therefore, a trial in which MNPs has already been approved for clinical use, as a base ma- with large particle diameters are compounded efficiently terial. In particular, this study aims at estimating the using an organic solvent is performed [17]. However, suffi- influence of the characteristics of the MNPs based on the difference in particle diameter on the images cient information regarding the biocompatibility of most particles compounded by such processes is not available, reconstructed using our proposed method in the Table 1 Characteristics of each sample based on ferucarbotran -2 -1 -1 -1 No. D [nm] PI D [nm] Magnetic susceptibility [erg � gauss � g]T relaxivity [mM � s ] D [nm] a v 2 1 55 0.28 30-110 0.0315 186 15 2 59 0.24 30-120 0.0387 268 18 3 86 0.19 50-200 0.0399 494 20 4 56 0.26 35-110 0.0354 274 17 D Average diameter including coating layer. D Particle size distribution of average diameter including coating layer. D Particle diameter of experimentally evaluated MNP. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 4 of 10 http://www.biomedcentral.com/1471-2342/13/15 Figure 3 Signal detected with each sample. (a.1), (b.1) Waveform of induced electromotive force. (a.2), (b.2) Magnetization response waveform. numerical simulation and the experiments using a a similar manner, with the position of an MNP being prototype. In addition, the relation between the charac- changed and the series G and G being created, re- i=2 i=3 teristics of the MNP and the hardware ability is spectively (Figure 1(a)). Next, the induced EMF gener- discussed based on the results of such reconstructed ated from the unknown MNPs’ distribution is observed images. at each FFP (x=1,2,3),anditis consideredasthe series V connected to the time-axis as well as the Principle abovementioned system function. Here, the observed Time-correlation MPI reconstruction method signal V shown in Figure 1(b) reflects the outline form In consideration of the abovementioned problems, we of the signal series obtained when the MNP is arranged have proposed an image reconstruction method based at the left end matrix as an example. Then, the correl- on the correlation information between an observed sig- ation information of this observed signal and each sys- nal (induced electromotive force: induced EMF) and a tem function is calculated (Figure 1(c)). It is expected system function without depending on inverse matrix that only the magnetization signal generated from a tar- operations [12]. The conceptual diagram of this tech- get region is emphasized and reflected as the image nique is shown in Figure 1. Here, for simplification, the intensity by such correlation processing. In contrast, an analyzed matrix is assumed to include three points. interference signal is difficult to reflect as the re- First, a system function is defined. When an MNP is constructed image intensity because the correlation arranged as a delta function at the left end matrix point between the observed waveform of the induced EMF (i = 1), a field free point (FFP) [6,7] where the local mag- and the system function is small. In the case of a general netic field strength is almost zero is scanned in order two-dimensional image, the image intensity F(i, j)inthe (x = 1, 2, 3) while applying an alternative magnetic field proposed method can be expressed by the following at each FFP. Here, although such a procedure may be equation: classified under the category of narrow band MPI [20], the FFP scanned by our method is encoded intermit- FiðÞ ; j ¼ ∫V ðÞ t G ðÞ t dt ð1Þ x;z i;j;x;z tently as in robot position movement [7]. Consequently, aseries (G )thatcombinesthree waveformsofthe Here, x and z express the scanning position of FFP, i=1 induced EMF observed at each FFP is created. The sys- V expresses an observed signal, and G expresses x,z x,z tem function at each matrix point (i = 2, 3) is defined in the system function as follows [12]. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 5 of 10 http://www.biomedcentral.com/1471-2342/13/15 x ¼ 1; 2; ⋯; X The average particle diameter of each sample was G ðÞ t ¼ G½ xt þXzðÞ −1 ; ð2Þ i;j;x;z i;j z ¼ 1; 2; ⋯; Z computed by approximating the magnetization curve obtained in the abovementioned experiment with a Langevin function. x ¼ 1; 2; ⋯; X V ðÞ t ≡Vx½ t þXzðÞ −1 ; ð3Þ x;z Evaluation of image reconstruction method by numerical z ¼ 1; 2; ⋯; Z analysis A gradient magnetic field intensity of 1.5 [T/m] at the cen- Methods ter of a Maxwell pair coil and an alternating magnetic field Evaluation of magnetizing properties of MNP intensity of 32.0 [mT] were used. The FOV was set as 40 In this study, four types of samples (including [mm] × 40 [mm], and the matrix size was set as 21 × 21. ferucarbotran), as listed in Table 1, with ferucarbotran as The system function was analytically computed in each the base material and adjusted particle diameters were matrix point of this FOV based on the Langevin function used. These samples were respectively prepared by mag- approximated using the particle diameter of each MNP as netic separation, centrifugal separation, and gel filtration. evaluated by the abovementioned procedure. The Fe concentration of each sample as well as the Then, based on equations (1), (2) and (3) and Figure 1, Resovist sample was adjusted to 28 [mg/mL]. The average image reconstruction was performed for the signal series diameter including the coating layer (Da) and the particle that connected the induced EMF observed at the FFP size distribution of the average diameter including the scanned by each matrix point. coating layer (Dv) were evaluated using a photon correl- ation spectrometer, the susceptibility was measured using the magnetic balance method, and the T relaxation time was evaluated using 0.47 [T] NMR equipment. The poly- dispersity index (PI) was evaluated using the light scatter- ing method. A vibrating sample magnetometer (VSM) is commonly used for evaluating the magnetization proper- ties; however, in this case, these properties were evaluated using our MPI prototype because the detection sensitivity in MPI was also evaluated. Each sample was sealed her- metically in 0.7 [cc] cylindrical containers (∅5 [mm], ap- proximately 12 [mm] in length) made from acrylics, and a solenoid coil of 19 [mm] diameter and with 350 turns was arranged as a receiver coil on the outer circumference (Figure 2). They were installed centered on the gap (50 [mm]) of a customized Maxwell pair coil (Toyojiki In- dustry Co., Ltd., Niiza, Japan) with an iron core, 180 [mm] diameter, and 285 turns for each coil. An alterna- tive magnetic field with an amplitude of approximately 65 [mT] was generated at the center of those coils by ap- plying an alternative current with an amplitude of 12.0 [A] and frequency of 33.0 [Hz] to each coil in the same direction. To distinguish between the magnetization components (harmonics) generated from an MNP and the primary magnetic field components applied from the outside, the induced EMF to a coil without a sample was observed previously, and it was defined as the raw flux density ap- plied to an MNP. Then, an induced EMF was generated when an MNP was arranged, and the actual induced EMF generated from the MNP was determined from the difference between this observed signal and the above- described raw flux density. In this case, the absolute value of flux density was corrected using a gauss meter Figure 4 Magnetization curve of each sample. (Model 460; Lakeshore Cryotronics Inc., OH, USA). Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 6 of 10 http://www.biomedcentral.com/1471-2342/13/15 Figure 5 Reconstructed image for each sample by numerical analysis. (a.1), (a.2) Images by fundamental and proposed reconstruction methods in the case of sample 1, respectively. (b.1), (b.2) Images by fundamental and proposed reconstruction methods in the case of sample 3, respectively. Figure 6 Image profiles of reconstructed images by numerical analysis. (a.1), (a.2) Image profiles at z = 0 in the case of sample 1, respectively. (b.1), (b.2) Image profiles at z = 0 in the case of sample 3, respectively. (a. 2), (b. 2) Individual theoretical point spread functions indicated by red lines. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 7 of 10 http://www.biomedcentral.com/1471-2342/13/15 Evaluation of one-dimensional reconstructed image using In a preliminary experiment, the electric current re- prototype quired to move the FFP by a unit length (this corre- Both an alternative magnetic field and an FFP were gen- sponds to the spatial resolution) was evaluated; based on erated using the abovementioned one-axis Maxwell pair this, the scanning of the FFP was controlled by the func- coil. The coil current was supplied from a bipolar power tion generator. In addition, a ±20-mm region from the supply (BP30-30; Heiwa Electric Co., Ltd., Kashiwa, Maxwell pair coil’s center was set as the FOV, and the Japan) in constant current mode, and the current wave matrix that divides the inside of this FOV into 21 points for scanning the FFP was controlled by a function gener- was made into each measuring point (FFP). ator (AFG3252; Tektronix, Inc., OR, USA). After the in- To detect only the induced EMF generated from an duced EMF was detected using the receiver coil MNP in consideration of the frequency purity of the al- (diameter 19 [mm], 350 turns) and passed through the ternative magnetic field due to the imperfection of the programmable filter (3628, NF Corporation, Yokohama, power supply and the coil, difference processing with Japan), it was supplied to a 14-bit AD converter the induced EMF and without a sample was carried out. (M2i4031; Spectrum Systementwicklung Microelectronic GmbH, Grosshansdorf, Germany). The detected signal Results and discussion was sampled with a sampling frequency of 20 [kHz] and Magnetization property of each MNP sample was sent to a personal computer (dc7800 MT/CT; The induced EMF from the samples made with Hewlett–Packard Co., CA, USA). ferucarbotran as the base material to the external alter- As a result of arranging each abovementioned sample at native magnetic field and the magnetization response the center of the gap of a Maxwell pair coil and applying obtained from the integration operation of EMF are the alternative current with an amplitude of 6.0 [A] and shown in Figure 3 (in what follows, only the results of frequency of 39.0 [Hz] in the same direction, the MNPs in sample 1 (ferucarbotran) and sample 3, which show the each sample were subjected to an alternative magnetic characteristic tendency, were displayed.). In addition, the field of approximately 30 [mT]. Under such device condi- average particle diameter of each sample was evaluated tions, a gradient magnetic field of 1.9 [T/m] was generated by comparing the observed magnetization properties by applying an offset current of 12.0 [A] simultaneously to with the magnetization curve of the MNP as indicated by the opposite direction of each coil, and an FFP was formed Langevin’s approximate expression (Figure 4). These at the center of the Maxwell pair coil. magnetization curves were normalized by the maximum Figure 7 Reconstructed image with numerical analysis for each sample at gradient field of 2.5 T/m. (a.1), (a.2) Images by fundamental and proposed reconstruction methods in the case of sample 1, respectively. (b.1), (b.2) Images by fundamental and proposed reconstruction methods in the case of sample 3, respectively. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 8 of 10 http://www.biomedcentral.com/1471-2342/13/15 magnetization of each case. The results are summarized the system function [22]. The PSF of this image recon- in Table 1. struction method was expected as an autocorrelation dis- It was estimated that the average particle diameter D tribution of the system function, and it was superimposed of sample 1 (ferucarbotran), which has been clinically in Figure 6 for MNPs of each particle diameter. Therefore, approved, was 15 [nm]. That of sample 3 was 20 [nm], it is possible to newly propose the following iterative esti- which is the largest among all samples, and it was shown mation of the distribution of MNPs in order to improve that sample 3 is the most suitable because a sample with the image resolution [13]. large particle diameter is advantageous for MPI. Here, the difference between the obtained magnetization prop- (1)The position at which the correlation with an erties and the approximated curve reflected the variation observed signal and a system function is the maximum in the particle size distribution of the MNPs in a sample, in the FOV is detected. and it was suggested that the particle diameter of sample 3 was adjusted satisfactorily. This result was also sup- ported by the evaluation results obtained by PI and D , shown in Table 1. Because the particle size distribution follows a logarithmic normal distribution [21], it was considered important to adjust the particle diameter in a sample uniformly in order to improve the image reso- lution in MPI. Moreover, the induced EMF detected from sample 3 was approximately 3 times that from ferucarbotran, indicating that sample 3 also contributes greatly to the improvement of SNR. This is based on the increase in the saturation magnetization of the MNP ac- companying the increase in the particle diameter [15]. From the physical properties obtained by this eva- luation, as listed in Table 1, it was confirmed that the particle diameter of MNPs was also related to the sus- ceptibility and T relaxation time. Numerical analysis of time-correlation MPI image reconstruction Next, the image reconstruction results of the numerical simulation based on the characteristics of sample 1 (ferucarbotran) and sample 3, which were chosen from among all samples as discussed above, are described. The images reconstructed by the fundamental image re- construction method based on an imaging principle (an alternative magnetic field was applied at each FFP that was scanned for every encoded position [7]) and our proposed time-correlation method for a sample arranged at the center pixel of the FOV are shown in Figure 5. In addition, the profiles at z = 0 of these reconstruction im- ages are shown in Figure 6. It was confirmed that the image artifact observed in the upper and lower sides of the actual MNP by the fundamental image reconstruc- tion method was suppressed by the proposed method. However, the image resolution of the proposed method (~12 mm) was slightly degraded compared to that of the fundamental method (~8 mm) using the FWHM for sample 1. Then, it was shown that the image blurring in- Figure 8 Signal detected using prototype. (a) Waveform of induced electromotive force. (b) Magnetization response waveform. creased. This is because theoretically, the distribution of (c) Fourier components of magnetization response waveform. Here, correlation between the observed signal and the system only the waveforms obtained by scanning the FFP at −20 [mm] function at every FFP position (Figure 1) was given as (L20), 0 [mm] (C), and 20 [mm] (R20) along the z-axis were indicated. the image intensity with nearly two times the FWHM of Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 9 of 10 http://www.biomedcentral.com/1471-2342/13/15 (2)At this position (image matrix), the amount of magnetization response are shown in Figure 8. Here, when correlation is given as the reconstructed image the center coordinate of the FOV was set to 0, only the intensity. wave obtained by scanning the FFP at −20 [mm], 0 [mm], (3)The distribution of a corresponding system function and 20 [mm] along the z-axis was indicated in the figure is subtracted from the observed signal at this position. (this corresponds to the sign L20, C, and R20, respect- ively.). It was confirmed that the difference of the induced Then, the candidate of the processing position is moved EMF’s waveform in an experiment appeared depending on to the next FFP and the abovementioned process is re- the position of the FFP. In other words, because it would peated until the residual of the subtraction signal at every reflect that the position of the MNP was indistinguishable FFP becomes small. It is considered that a deconvolution when the correlation with an observed signal was evalu- with a system function can be carried out equivalently by ated with a system function, the validity of our proposed such processing; therefore, the image blurring can be re- method based on time-correlation information was also duced effectively without inverse matrix operations. confirmed by experimental data. With regard to sample 1 An evaluation of the profile at z = 0 (Figure 6) showed (ferucarbotran) and sample 3, the one-dimensional images that the spatial resolution of sample 3 was approximately obtained using the fundamental image reconstruction 1.3 times better than that of sample 1. This corresponded method and the proposed method are shown in Figure 9. to the fact that the spatial resolution obtained by a gradi- In these reconstructed images, although the precise sys- ent magnetic field strength of 2.5 [T/m] for sample 1 was tem function should ideally be measured from the signal achieved by a gradient magnetic field strength of approxi- observed when the MNPs are arranged in a shape like a mately 1.5 [T/m] for sample 3 (Figure 7). In other words, delta function at each analyzed point in the reconstructed it was shown that the dependence on hardware require- image, the analytically calculated system function corre- ments was reduced by 0.6 times under such conditions sponding to each particle diameter at every image matrix and that the spatial resolution could be improved by sim- point was used. This is because considerable time is gener- ply adjusting the particle diameter. ally required for the measurement of a system function, and our system’s operation might become unstable over One-dimensional imaging experiment using prototype such a long time. It was found that sample 3 afforded an The waveform of the induced EMF obtained by scanning image resolution superior to that of sample 1 through the FFP, the magnetization response calculated from the both the experimental results as well as the numerical integration of the EMF, and the Fourier transform of this simulation. Figure 9 One-dimensional reconstructed images using prototype. (a.1), (a.2) Images by fundamental and proposed reconstruction methods in the case of sample 1, respectively. (b.1), (b.2) Images by fundamental and proposed reconstruction methods in the case of sample 3, respectively. In these cases, the calculated system function corresponding to each particle diameter was used. Ishihara et al. BMC Medical Imaging 2013, 13:15 Page 10 of 10 http://www.biomedcentral.com/1471-2342/13/15 Conclusions 3. El-Sayed IH, Huang X, El-Sayed MA: Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold In this study, to suppress image artifacts in MPI and im- nanoparticles. Cancer Lett 2006, 239:129–135. prove the spatial resolution without requiring high- 4. Hergt R, Hiergeist R, Zeisberger M, Schüler D, Heyen U, Hilger I, Kaiser WA: performance hardware, an image obtained using an Magnetic properties of bacterial magnetosomes as potential diagnostic and therapeutic tools. Journal of Magnetism and Magnetic Materials 2005, MNP sample made of biocompatible ferucarbotran as 293:80–86. the base material and a sample made by our proposed 5. Jordan A, Scholz R, Maier-Hauff K, Johannsen M, Wust P, Nadobny J, Schirra method were compared. It is essential to evaluate the H, Schmidt H, Deger S, Loening S, Lanksch W, Felix R: Presentation of a new magnetic field therapy system for the treatment of human solid biocompatibility because a large-diameter nanoparticle tumors with magnetic fluid hyperthermia. Journal of Magnetism and may behave differently in internal organs compared to Magnetic Materials 2001, 225:118–126. Resovist, which is approved for clinical use. Nonetheless, 6. Gleich B: Method for determining the spatial distribution of magnetic particles. DE 10151778(A1)05 2003, 05:08. some samples used for MPI were found to have magnet- 7. Gleich B, Weizenecker J: Tomographic imaging using the nonlinear izing properties superior to those of ferucarbotran. Con- response of magnetic nanoparticles. Nature 2005, 435:1214–1217. sequently, it was shown that an equivalent image quality 8. Weizenecker J, Gleich B, Rahmer J, Dahnke H, Borgert J: Three-dimensional real-time in vivo magnetic particle imaging. Phys Med Biol 2009, (spatial resolution) could be obtained with a smaller gra- 54:L1–L10. dient magnetic field strength compared to the case in 9. Schmale I, Rahmer J, Gleich B, Kanzenbach J, Schmidt JD, Bontus C, which ferucarbotran was used. Woywode O, Borgert J: First phantom and in vivo MPI images with an extended field of view. Florida: Proc. of SPIE Medical Imaging; 2011:796510.6. Therefore, if a method for preparing MNP samples 10. Kusayama Y, Ishihara Y: A preliminary study on the molecular imaging consisting of particles with large and equisized diameters device using magnetic nanoparticles. Technical Report of IEICE. MBE 2007, made from ferucarbotran as the base material is devel- 107:15–18. 11. Kusayama Y, Ishihara Y: High-resolution image reconstruction method on oped, the MPI image quality can be further improved, and the molecular imaging using magnetic nanoparticles. IEICE Trans. D 2009, the conditions imposed on hardware ability can be re- J92–D:1653–1662. duced. However, because our study was restricted to the 12. Ishihara Y, Kuwabara T, Honma T, Nakagawa Y: Correlation-based image reconstruction methods for magnetic particle imaging. IEICE Transactions use of an alternating magnetic field with relatively low fre- on Information and Systems 2012, E95-D:872–879. quency, evaluations in consideration of the dynamic char- 13. Honma T, Shimizu S, Ishihara Y: Correlation-based image reconstruction acteristic of the MNP [19,23] will be required when faster methods for magnetic particle imaging.In Proceedings of the Branch Conference of Japanese Society for Medical Biological Engineering 2012. Edited scanning of FFP is used. In addition, because a sufficiently by Kyoso M. Tokyo; 2012. 2012: C-1-04. high spatial resolution has not yet been achieved theoretic- 14. Goodwill PW, Conolly SM: The X-space formulation of the magnetic ally using the proposed time-correlation MPI reconstruc- particle imaging process: 1-D signal, resolution, bandwidth, SNR, SAR, and magnetostimulation. IEEE Trans Med Imaging 2010, 29:1851–1859. tion method, it is necessary to devise an algorithm that 15. Chikazumi S: In Physics of Magnetism. Edited by Charap SH. New York: John can use correlation information more effectively. Wiley and Sons; 1964. 16. Ferguson RM, Minard KR, Krishnan KM: Optimization of nanoparticle core Competing interests size for magnetic particle imaging. J. Magn. Magn. Mater. 2009, The authors have no competing interests to declare. 321:1548–1551. 17. Ferguson RM, Minard KR, Khandhar AP, Krishnan KM: Optimizing magnetite nanoparticles for mass sensitivity in magnetic particle imaging. Med Phys Authors’ contributions 2011, 38:1619–1626. YI conceived the study, built the algorithm, and drafted the manuscript. TH 18. Eberbeck D, Wiekhorst F, Wagner S, Trahms L: How the size distribution of implemented the algorithm in a program, developed the prototype system, magnetic nanoparticles determines their magnetic particle imaging performed data collection, and helped to draft the manuscript. SN prepared performance. Appl Phys Lett 2011, 98:182502.1–182502.3. the experimental MNP samples and helped to draft the manuscript. All 19. Ludwig F, Wawrzik T, Yoshida T, Gehrke N, Briel A, Eberbeck D, Schilling M: authors have read and approved the final manuscript. Optimization of magnetic nanoparticles for magnetic particle imaging. IEEE Transactions on Magnetics 2012, 48:3780–3783. Acknowledgements 20. Goodwill PW, Scott GC, Stang PP, Conolly SM: Narrowband magnetic This study was supported by a Grant-in-Aid for Scientific Research (B), particle imaging. IEEE Trans Med Imaging 2009, 28:1231–1237. 24300184, 2012, from the Japan Society for the Promotion of Science (JSPS). 21. Chantrell RW, Popplewell J, Charles SW: Measurements of particle size distribution parameters in ferrofluids. IEEE Transactions on Magnetics 1978, Author details 1 14:975–977. School of Science and Technology, Meiji University, Higashimita Tama, 2 22. Yarlagadda RKR: Analog and Digital Signals and Systems. New York: Springer Kawasaki, Kanagawa, Japan. Graduate School of Science and Technology, 3 Science + Business Media; 2010. Meiji University, Higashimita, Tama, Kawasaki, Kanagawa, Japan. The Nagoya 23. Yoshida T, Enpuku K, Ludwig F, Dieckhoff J, Wawrzik T, Lak A, Schilling M: Research Laboratory, Meito Sangyo Co., Ltd, Kaechi Nishibiwajima, Kiyosu, Characterization of Resovist® nanoparticles for magnetic particle Aichi, Japan. imaging. Springer Proceedings in Physics 2012, 140:3–7. Received: 24 August 2012 Accepted: 29 May 2013 doi:10.1186/1471-2342-13-15 Published: 5 June 2013 Cite this article as: Ishihara et al.: Evaluation of magnetic nanoparticle samples made from biocompatible ferucarbotran by time-correlation References magnetic particle imaging reconstruction method. BMC Medical Imaging 1. Huang X, Jain PK, El-Sayed H, El-Sayed MA: Gold nanoparticles: interesting 2013 13:15. optical properties and recent applications in cancer diagnostics and therapy. Nanomedicine 2007, 2:681–693. 2. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q: Photodynamic therapy. J Natl Cancer Inst 1998, 90:889–905.

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