List of modifications and replies
to referee comments
We are very grateful for your concern and highly valuable comments and advice. The
following are our responses (blue text) to the comments of referee 3 (black text). All
indications are identified by appending consecutive numbers.
The modifications and additions have been indicated in blue font in the revised
manuscript.
Responses to Referee 3
3-1
First, apparently, no core size distribution was implemented in the analysis. Second, from the
papers by Eberbeck and Yoshida et al., it is known that there is a bimodal distribution of
magnetic moments and effective core diameters, respectively. As can be seen from Fig. 4, the fit
of the measured quasi-static magnetization curves with the Langevin functions is not perfect,
and consequently provides a very rough guess for the effective core diameter. The obtained
sample parameters are summarized in Table 1. Here it does not get clear how the individual
numbers were determined. In comparing the magnetic susceptibility values, did the authors
make sure that all samples have the same iron oxide content?
The physical properties of the magnetic nanoparticle within the ferucarbotran’s
fractionation sample were evaluated in detail by D. Eberbeck and your group, as you pointed
out, and the knowledge obtained by those studies greatly contributed to MPI. In contrast, the
descriptions provided in our paper were insufficient. Therefore, we provided explanations by
suitably quoting these other studies (P.6 in the 2nd revised manuscript).
In addition, because the explanation of Da and Dv in Table 1 was insufficient, details of the
valuation method were added (P.11 in the 2nd revised manuscript).
In response to your final question, we have already indicated that the Fe concentration of
each sample, as well as that of the Resovist sample, was adjusted to 28 [mg/mL].
3-2
The comparison of their correlation-based reconstruction algorithms with the fundamental one
(which is applied my most other groups working on MPI) suffers from two points: First, in
contrast to the original version of the manuscript, the description of the fundamental mode was
completely omitted. To compare both reconstruction methods, some description of the
fundamental approach is necessary. Second, the description of the authors’ time-correlation
method has been published in detail elsewhere, i.e., it is not new.
Because our redundant description was already pointed out by the previous two referees, the
explanation of the image reconstruction method based on a fundamental method was deleted
(although when we asked the Editorial Board how we should correspond when the 3rd referee’s
comment differed from the previous referees’ directions for our “revised manuscript,” there was
no reply from the Editorial Board)*.
The principle of the time-correlation method and the results of a numerical simulation have
already been published, as you pointed out. In addition, if a nanoparticle with a large diameter is
used, the image resolution is also expected to improve. However, it was important to determine
the influence of the difference in particle diameter on the reconstructed images by the
time-correlation method, and the characteristics using an experiment with a prototype system
have not been clarified previously. In addition, because it was thought that the point regarding
the relation with the particle diameter of magnetic nanoparticles and the hardware ability
evaluated from these reconstructed images had novelty, the article was changed to emphasize
these points (P.6 in the 2nd revised manuscript).
*Although we genuinely express our gratitude for your polite refereeing, there are many
questions about this peer review process. Based on the previous two referees' comments, we
corrected our manuscript faithfully and submitted it on November 10, 2012. After that, the
manuscript was referred to you as the 3rd reviewer, and we received these refereeing results on
April 26, 2013. During this period, we asked the Editorial Board why the 3rd reviewer was
requested after the revised version was submitted. Usually, in the peer review process for an
academic journal, if the opinions of two referees differ, an editor would ask a 3rd reviewer for
another opinion before sending all of the referees’ comments to the author. However, such a
procedure was not followed this time (The Editorial Board also admitted that this process
differed from usual.). It is unsuitable to add directions for corrections from a different reviewer's
viewpoint to an already corrected manuscript, and it must be said that fairness was missing.
We asked for information about the delay in the review process, and the reason why the 3rd
referee was needed. However, the Editorial Board has not provided any details except to say that
the 2nd referee has given up refereeing. If the Editorial Board allows such a situation, it will
become difficult for the authors and the referee to discuss MPI in the same study field in the
future because this journal reveals the referee's name to the authors.
3-3
Summarizing the first two points, neither the facts that there are certain fractions from Resovist
having a better MPI performance than Resovist and that magnetic nanoparticles having a steeper
M-H curve allow one to achieve a better spatial resolution, nor the application of the proposed
time-correlation reconstruction algorithm are new. Their conclusion (p. 16 last paragraph) that
magnetic tracers with steeper M-H curves relax the requirements on the magnetic field gradient
while having the same spatial resolution is trivial and ignores the important issue or particle
dynamics: As shown in the papers by Yoshida and Ludwig (see above) the requirement of marge
magnetic moments, i.e., steep M-H curves is not sufficient for getting a good MPI performance.
The only new contribution of the paper is that they directly demonstrate - applying their
reconstruction technique - that the spatial resolution of sample 3 is indeed better than that
achievable with Resovist using the same hardware.
As you pointed out, only the particle diameter had no effect on the image resolution. We
believe that the influence of the factor that your group is evaluating on the reconstructed images
by the time-correlation method should be considered in the future. For this reason, an
explanation of that point was added, quoting your studies (P.18 in the 2nd revised manuscript).
3-4
p. 4, 4th line: The authors say that “clinical trials (of cancer treatment) have now started”. The
referenced paper, however, is from 2001.
We changed this expression to indicate that clinical trials are continuing (P.4 in 2nd revised
manuscript).
3-5
p. 10: Equations (2) and (3) are not clear, presumably a formatting problem. Please check!
The signal observed as a time function at each FFP scanned in two-dimensional space is
expressed by the one-dimensional sequence of numbers. Because this is an expression
commonly used in the field of signal and image processing, we did not change it.
3-6
p. 12, last paragraph and p. 13, last two paragraphs: First they say that a gradient field of 1.5
T/m at the center was used. On the next page, they quote a value of 1.9 T/m. Why did the
authors use a different value in the numerical analysis?
Because the experimental condition differed from the conditions of the numerical analysis,
an unsuitable expression was deleted (P.12 in the 2nd revised manuscript).
*Although it is necessary to perform the experiment under essentially the same conditions,
our research-and-development organization has been changed after submitting our revised
manuscript, and we have not been able to carry out further experiments under the same
conditions.
3-7
P. 14, middle paragraph: The authors say that “magnetization curves were normalized by the
maximum magnetization”. However, for the investigated field range, there is no maximum.
Please correct!
Because the ranges in consideration of normalization used different theoretical and
measurement values, we standardized the definitions of normalization (Figure 4 in the 2nd
revised manuscript).
3-8
p. 15, 1st paragraph: The authors conclude that the saturation magnetization of the MNP
accompanies an increase in particle diameter. First, this is against the general tendency for
magnetite MNP reported in numerous papers. Second, the referee cannot follow the authors’
argumentation. They say that the induced EMF for sample 3 was about a factor of 3 higher than
that of pure Resovist. The induced EMF depends on a number of points: on the mean magnetic
moment of the MNP, on the iron oxide content of the given sample, of the percentage of MNP
with large moments etc. Thus, their argumentation should be a more detailed.
Although we are concerned about the possibility of not understanding your suggestions
correctly, because the saturation magnetization becomes large when the diameters of the
particles that compose a magnetic fluid become large, we believe that there was no error from
the perspective of physical properties in our experimental findings.
3-9
p. 15, middle: Please specify the location of the MNP sample!
Because the magnetic nanoparticle was arranged at the central pixel of the image, we
specified it in each figure (Figures 5 and 7, and P.15 in the 2nd revised manuscript).
3-10
In the title and in the conclusions, the authors stress the excellent biocompatibility of their tracer
materials. However, there is no obvious own contribution to improve the biocompatibility. The
statement is just based on the biocompatibility of the coating of Resovist.
As you pointed out, the biocompatibility of the ferucarbotran samples was restricted to the
range guaranteed by the drug trial data for Resovist. For example, because the nanoparticles
with large diameters in internal organs might differ in behavior from Resovist, we added a note
about that point (title and P.18 in the 2nd revised manuscript).
3-11
Captions of Figs. 5, 6, and 7: It should be explicitly said that (a) refers to fundamental and (b) to
correlation-based reconstruction.
We added a caption to the figure as requested (Figures 5 and 7 in the 2nd revised manuscript).
3-12
p. 17, first paragraph: The positions of L20, C and R20 are not totally clear. Do these numbers
refer to the z axis position?
In the caption, we added text stating that those symbols indicated the distance in the z-axial
direction (P.17 and 23 in the 2nd revised manuscript).
3-13
Fig. (c): A log axis for S would be helpful to make differences clearer.
We changed it to the log scale as suggested (Figure 8 in the 2nd revised manuscript).