Magnetic Resonance Imaging 24 (2006) 195 – 200

Blackberry (Rubus spp.): a pH-dependent oral contrast medium for

gastrointestinal tract images by magnetic resonance imaging
Marı́a G. Espinosaa, Modesto Sosab,4, Luis M. De León-Rodrı́guezc,
Teodoro Córdovad, Jesús Bernal-Alvaradob, Mario Avila-Rodrı́guezc,
José A. Reyes-Aguilerac, Juan J. Ortı́ze, Fernando A. Barriose
a
Facultad de Fı́sica e Inteligencia Artificial, Universidad Veracruzana, 91090 Xalapa, Ver., México
b
Instituto de Fı́sica, Universidad de Guanajuato, Apartado Postal E-143, 37000 León, Gto., México
c
Instituto de Investigaciones Cientı́ficas, Universidad de Guanajuato, Apartado Postal E-143, 36000 Guanajuato, Gto., México
d
Department of Physics, Vanderbilt University, Stevenson Center, Nashville, TN 37235, USA
e
Instituto de Neurobiologı́a, Universidad Nacional Autónoma de México, Apartado Postal 1-1141, 76001 Queretaro, Qro., México
Received 14 September 2005; revised 16 October 2005; accepted 16 October 2005

Abstract
In this study, seven fruits have been tested on their magnetic properties, paramagnetic metal content and contrast enhancement in magnetic
resonance imaging (MRI) of phantom and in vivo. Magnetic susceptibility was determined for the fruit pulps, as well as the contents of
paramagnetic metals; iron, manganese and copper. The total content of these metals was 4.3, 8.6, 11.1, 10.9, 12.3, 8.3 and 29.3 mg/kg of fruit
for plum, blueberry, apple (red), pineapple, beet, grape, blackberry, respectively, and with magnetic susceptibility of 2.29F0.07,
2.43F0.07, 2.13F0.07, 1.84F0.02, 1.75F0.01, 1.78F0.06, 2.18F0.07 SI, respectively. T1- and T2-weighted MR images were
performed for the seven fruits and water (v = 9.9810 3 SI) and in one subject. While there was no correlation between the magnetic
susceptibility and contrast enhancement, there is a correlation with the total paramagnetic metal content determined with contrast
enhancement in MRI. Thus, blackberry (Rubus spp.) contrast enhancement was the highest among the fruits in T1-weighted images.
Furthermore, this fruit’s contrast enhancement shows to be pH-dependent. These characteristics and the wide availability of the Rubus spp.
suggest that it should be implemented as an oral contrast agent in images by MR to assess the function of the gastric section of the GI tract.
Furthermore, it has the advantage of being a natural meal, so that it can be well tolerated by the patients and use as much as it is needed
without side effects.
D 2006 Elsevier Inc. All rights reserved.
Keywords: Oral contrast agent; Gastrointestinal imaging; MRI; Stomach; Magnetic susceptibility; T1- and T2-weighed images; Atomic absorption spectroscopy

1. Introduction resolution and have extended the role of MRI in the

evaluation of abdominopelvic disease and gastrointestinal
Magnetic resonance imaging (MRI) is a powerful
(GI) tract functions [5– 8]. Furthermore, with the develop-
imaging tool in soft tissue contrast [1,2]. It is an expensive
ment of parallel imaging [9] and multielement SENSE coils
yet risk-free procedure that provides high-quality images in
speed and quality of body MRI has capitalized from SENSE
any plane. Nevertheless, the application of MRI in
acceleration factors.
abdominal imaging is still limited by problems such as
The images generated by MR technique are made up of
peristaltic, respiratory, cardiac and pulsatile flow motion.
voxels (three-dimensional pixels), and the brightness of
Fortunately, recent advance in rapid imaging techniques
each voxel is dependent on the intensity of the magnetic
[3,4] and implementation of torso phase array coils are
nuclear signal [10], which in medical images is produced by
allowing high-quality breath-hold imaging with spatial
the density of hydrogenous atoms localized in each section
4 Corresponding author. Tel.: +52 477 788 5100; fax: +52 477
under study [2,6]. Hence, an MR image is essentially a map
788 5100. of water distribution, although the water density varies
E-mail address: modesto@fisica.ugto.mx (M. Sosa). relatively little in between the human tissues [1,6,10].
0730-725X/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.mri.2005.10.026
196 M.G. Espinosa et al. / Magnetic Resonance Imaging 24 (2006) 195 – 200

Table 1 Table 2
Magnetic susceptibilities measured for all of the fruit pulps Microwave mineralization conditions for the dry fruit samples
4
Fruit sample Magnetic susceptibility (v) (10 SI) Stage Pressure (psi) Temperature (8C) Time (min)
Plum 2.29F0.07 1 70 200 8.30
Blueberry 2.43F0.07 2 120 200 8.30
Apple 2.13F0.07 3 195 210 9
Pineapple 1.84F0.02 4* 255 220 12
Beet 1.75F0.01
A mixture of HNO3 (8 mL), HF (0.4 mL) and water (2.6 mL) was added to
Grape 1.78F0.06
0.5 g of dry fruit sample in a close vessel and then the mixture was
Blackberry 2.18F0.07
submitted to a mineralization microwave program. This program was
Magnetic susceptibilities measured for all of the fruit pulps in a 10-ml optimized as a function of the changes of pressure and temperature.
sample using a susceptibility balance. Just as a reference, pure water has a
magnetic susceptibility (v) of 9.9810 3 SI [21].
The outcome suggest that although the Rubus spp. is not
Nevertheless, MRI has become an important technique in the more paramagnetic fruit, it has an excellent contrast
clinical medicine; because of its major strength is the ability enhancement as a positive oral contrast agent for images
to manipulate the image contrast [1 –3]. of the GI by MRI given the highest content of paramag-
The signal intensity of the tissue visualized depends on netic metals.
several factors, which include the number of protons or spin
density, relaxation time T 1 and T 2, chemical shift, flow 2. Material and methods
perfusion, as well as technical parameters related mainly to
the sequences, echo and repetition time and the magnetic 2.1. Magnetic characterization
field intensity used [1,2,10]. Measurements of the volumetric magnetic susceptibilities
When the contrast manipulations mentioned above are were carried out in seven different kinds of fruit: plum,
not enough to attain the needed contrast, exogenous contrast blueberry, apple, pineapple, beet, grape and blackberry (see
agents are used to highlight some particular structures of Table 1). Samples (10 mL) of the pulp of these fruits were
interest [2,10]. They are usually based on metallic ions used, and the process of the susceptibility balance described
[2,4,6,10] with large magnetic moments to have drastic in Ref. [29] was followed to determine this magnetic
effects on the relaxation properties of the water protons parameter. The balance used was an Explorer OHAUS,
and hence on the signal characteristic, relaxation times T 1
and T 2. Gadolinium Gd3+ [4,11–13] is the element more
commonly used in elaboration of exogenous contrast agents,
and its application is mainly by intravenous injection of an
appropriate inert complex chelate of the metal, so that it is
distributed to all of the body through the blood flow.
Oral contrast agents are another modality to highlight
particular structures of the GI tract by MR studies
[1,2,10,12]. Two modalities are identified in this kind of
oral contrast agents: artificial and natural [10]; (1) the first is
made mainly of macroscopic magnetic particles, and targeted
agents which have potential to enhance signal from specific
tissues [13 –20], while (2) the second one is a juice or pulp of
any fruit, water, or tea [21 –28]. They are swallowed and
used to enhance different sections of the GI tract.
Frequently, artificial oral contrasts are not tolerated by
the patient, because they induce side effects as nausea,
vomit, diarrhea and dysentery [1,2]. On the other hand, the
side effects described above are not presented when natural
oral contrast agents (dessert, meal, water, or tea) are used
[21,22,24 – 26]. One limitation of these contrast agents is
probably that they are not widely available, considering that
some are grown in particular regions or during a specific
period of the year [21,28].
The characterization of magnetic properties, percentage
Fig. 1. (A) Metal contents in fruits. Paramagnetic metals such as iron,
determination of three metals and the accomplishment of manganese and copper were performed by using absorption atomic
T1- and T2-weighted MR images of a phantom and a spectroscopy. (B) Total metal content in fruits (iron plus manganese
subject is presented in this work for seven different fruits. plus copper).
 M.G. Espinosa et al. / Magnetic Resonance Imaging 24 (2006) 195 – 200 197

Fig. 2. T1-weighted images: (A) water, (B) plum, (C) blueberry, (D) apple, (E) pineapple, (F) beet, (G) grape and (H) blackberry. (1) Sample without acid,
(2) sample after 5 min of HCl addition and (3) sample after 25 minutes of HCl addition.

which has a precision of 0.1 mg, while the magnet was a
NdFeB cylinder whose magnetic moment (m) is 0.58F
0.04 A m2; the magnetic interaction between the specific
sample under study and a particular magnet is measured.
2.2. Spectroscopic characterization
Atomic absorption spectroscopy (AAS) was performed
to quantify the paramagnetic metals, iron, manganese and
copper in each fruit, which underwent the following stages:
(1) drying, (2) powdering, (3) microwave digestion and
(4) metal analysis by flame or graphite furnace AAS in a
Perkin-Elmer 3110 equipment. In addition, samples diges-
tion was carried out in a MARS 5 microwave apparatus
from CEM with close vessels. To achieve full sample
mineralization, a mixture of HNO3 (8 ml), HF (0.4 ml), and
water (2.6 ml) were added to 0.5 g of dry fruit sample in a
close vessel, and then the mixture was submitted to a
mineralization microwave program, see Table 2. This
program was optimized as a function of the changes of
pressure and temperature.
2.3. Imaging acquisition
Several image sequences were performed from phantoms
and one subject with a whole-body MRI scanner, Philips
Intera 1.0 T (Best, The Netherlands). The phantoms image
acquisitions were conducted with different spin-echo and
field-echo pulse sequences and two element SENSE-flex-m
reception coils, which were also used for the in vivo data
acquisitions. To have identical image sequences. Turbo
spin-echo, fast inversion recovery and fast field-echo
sequences were acquired in all the sessions with identical
parameters and SENSE factors [9].
After giving his informed consent, one female adult
healthy subject participated in the study; she participated in
six imaging sessions during six different days following the
same image protocol, which demanded 4 h of fasting and no
water consumption in the previous hour to the image study.
Furthermore, the subject was deprived of caffeine and
tobacco during the study days.
All imaging was conducted using the breathing sensor to
monitor the breath-hold of the subject. The T2-weighted
turbo spin-echo protocol includes the following: TR =
1600 ms and TE = 100 ms over an FOV=375 mm and
RFOV of the 85%, with slice thickness/gap of 6/4 mm,
using three acquisitions in a maximum of 5 slices per
breath-hold, respiratory compensation on and SENSE factor
of 2, while T1-weighted turbo spin-echo imaging was
acquired with TR = 525 ms and TE = 13 ms over an
FOV=375 mm and RFOV of 85%, with slice thickness/
gap of 6/4 mm using four acquisitions in 5 slices per
breath-hold, respiratory compensation and SENSE factor of
2. On the other hand, the parameters for the T2-weighted
FLAIR imaging were the following: TR = 600 ms, TE =
100 ms and IR delay of 2000 ms over an FOV= 350 mm and
RFOV of 85%, with slice thickness/gap of 6/4 mm in 5 slices
per breath-hold, respiratory compensation on and SENSE
factor of 2, while the T2-weighted fast field-echo parameters
were the following: TR = 150 ms, TE = 13.81 ms, 608 flip
angle over FOV=375 mm and RFOV of 85%, with slice
thickness/gap of 6/4 mm using four acquisitions in 5 slices

Fig. 3. T2-weighted images: (A) water, (B) plum, (C) blueberry, (D) apple, (E) pineapple, (F) beet, (G) grape and (H) blackberry. (1) Sample without acid, (2)
sample after 5 min of HCl addition.
198 M.G. Espinosa et al. / Magnetic Resonance Imaging 24 (2006) 195 – 200

Fig. 4. T1-weighted images: (A) empty stomach, (B) stomach after ingesting water, (C) after 5 minutes of ingesting 200 g of blended plum, (D) after 5 minutes
of ingesting 200 g of blended blackberry, (E) after 12 minutes of ingesting 200 g of blended blackberry, (F) after 22 minutes of ingesting 200 g of blended
blackberry and (G) after 30 minutes of ingesting 200 g of blended blackberry.

per breath hold and SMART and respiratory compensation
on. All images were transferred to off line workstations using
the Philips (Clinical Science Software) exporting image tool
and the MRIcro public domain program (Chris Rorden,
http://www.psychology.nottingham.ac.uk/staff/cr1/).
3. Results and discussion
The magnetic susceptibilities measured are showed in
Table 1, where the net diamagnetic behavior of the seven
fruits is constituted by a large percentage of water in each of
them. Pure water has a magnetic susceptibility (v) of
9.9810 3 SI [21]. Nevertheless, when increasing the
paramagnetic elements in aqueous solution, its susceptibility
is increased, which explains the final magnetic susceptibility
values exhibited in Table 1.
The contents of paramagnetic metals (Fe, Mn and Cu)
were determined in the fruit samples (Fig. 1A). In general, it
was found that iron content is higher than manganese and
copper for all these samples. While pineapple has the most
manganese content, the blackberry fruit has the highest
iron content. The amount of copper is approximately similar
(5 ppm) for all the samples.
The assumption was that by determining the concentra-
tion of paramagnetic elements in the fruits, it would be
possible to find which sample will be a promising contrast
agent in MRI.
On the other hand, T1-weighted images of the fruits were
obtained to determine the feasibility of using them as gastric
contrast agents. All fruits were blended (seeds removed), and
the blend was poured in glass vials (5 cm long and 2.5 cm
diameter). T1-weighted images of the blend were obtained
(Fig. 2 row 1), and image contrast was compared to a water
blank (Column A). It is clear that of all the samples
blackberry was the only fruit that showed a positive contrast,
which agrees with the fact that this fruit has the highest total
amount of paramagnetic metals (Fig. 1B) as well as iron,
followed by beet. Furthermore, it has to be considered that
the fruit will be acidified and diluted due to gastric juices
inside of the stomach, which are composed mainly of HCl
and pepsin. Therefore, to simulate stomach conditions, the
same fruit samples imaged were mixed and diluted with
0.15 M HCl, and T1-weighted images were obtained after
5 and 25 min from the time of acid addition as shown in
Fig. 2, rows 2 and 3, respectively. It can be observed that after
5 min of acid addition, beet shows a contrast increase
disappearing after 25 min. On the other hand, the blackberry
reached maximum contrast intensity after 5 min of acid
addition, followed by a total lack of contrast after 25 min.
The dependence on the pH contrast observed can be
attributed to changes on the chemical species of the different
paramagnetic metals, such as changes on the amounts of free
metal ions [30] and metal bound to macromolecules (e.g.,
proteins, carbohydrates, etc.) and/or oxidation states. pH

Fig. 5. T2-weighted images: (A) empty stomach, (B) stomach after ingesting water, (C) after 5 minutes of ingesting 200 g of blended plum and (D) after
5 minutes of ingesting 200 g of blended blackberry.
 M.G. Espinosa et al. / Magnetic Resonance Imaging 24 (2006) 195 – 200
contrast dependence has been previously reported in the
literature for Gd based contrast agents [31].
Similar T2-weighted images of the fruits were obtained
(see Fig. 3). Blackberry shows the highest negative contrast
among the fruits. However, this contrast decreases upon HCl
addition. Hence, the blackberry was selected as a potential
gastric contrast agent, which allowed time dependence
monitoring of the stomach activity.
Images from the stomach of a healthy fast volunteer were
acquired to asses the feasibility of using the blackberry as a
gastric contrast agent. Fig. 4 shows T1-weighted images of
an empty stomach (Fig. 4A), the stomach after drinking
300 ml of water (Fig. 4B) and the same stomach after
ingesting 200 g of blended plum (Fig. 4C). The latter case
was used as a reference since plum is one of the fruits that
did not show a positive contrast increase although it still
contains the paramagnetic metals. In the empty stomach,
there is not clear definition of the gastric volume. However,
once the water or plum was ingested, the expansion of the
stomach volume is clearly detected as a dark region. A
positive contrast is evident after 5 min of the blackberry
ingestion. Furthermore, this contrast decreases as time
progresses (Fig. 4D – G), which is in agreement to what is
observed with the fruit (see Fig. 2).
Similarly T2-weighted images were obtained for the same
individual as shown in Fig. 5. However, negative contrast is
minimal when the blackberry was ingested.
4. Conclusion
The T1-weighted MR images have shown contrast
enhancement with the blackberry and the gastric lumen,
which was better than that between the other six fruits and
the gastric lumen; therefore, blackberry should be consid-
ered as a potential oral contrast agent when images of the
gastric section of the GI tract are performed by MR. Since
blackberry enhancement is better in gastric conditions, it
gives a time dependence on the contrast because of changes
on pH into the stomach related to gastric activity, which can
give valuable information of stomach activity and behavior
of the meal.
An important characteristic is that contrast efficiency of
the fruits is correlated to the content of paramagnetic metals
in the sample, but not to magnetic susceptibilities. This
could be attributed to the actual chemical species of the
metal present in the fruits. For future works on finding
natural contrast agents, monitoring the amounts of para-
magnetic metals is needed.
Acknowledgments
The authors acknowledge the financial support of
CONACyT under grant number 38749-E. Support for MR
resources came from The Gonzalo Rio Arronte Foundation.
FAB acknowledges the financial support of PAPIIT-DGAPA
199
IN214304. The authors also thank D. Pless, who helped us
to improve the writing of the manuscript.
References
[1] Paley MR, Ros PR. MRI of the gastrointestinal tract. Eur Radiol
1997;7:1387 – 97.
[2] Giovagnoni A, Fabbri A, Maccioni F. Oral contrast agents in MRI of
the gastrointestinal tract. Abdom Imaging 2002;27(4):365 – 7.
[3] Unterweger M, Marincek B, Gottstein-Aalame N, et al. Ultrafast MR
imaging of the pelvic floor. AJR Am J Roentgenol 2001;176(4):
959 – 63.
[4] Luboldt W, Bauerfeind P, Wildermuth S, Debatin JF. Contrast
optimization for assessment of the colonic wall and lumen in MR
colonography. J Magn Reson Imaging 1999;9(5):745 – 50.
[5] Keogan MT, Edelman RR. Technological advances in abdominal MR
imaging. Radiology 2001;220:310 – 20.
[6] Patak MA, Weishaupt D, Frohlich JM, Debatin JF. Sequential fast 3D
MRI following oral ingestion of Gd-DOTA: a new means to assess
intestinal transit time. J Magn Reson Imaging 1999;10(3):474 – 6.
[7] Debatin JF, Patak MA. MRI of the small and large bowel. Eur Radiol
1999;9(8):1523 – 34.
[8] Furukawa A, Saotome T, Yamasaki M, et al. Cross-sectional imaging
in Crohn disease. Radiographics 2004;24(3):689 – 702.
[9] Pruessmann KP, Weiger M, Scheidegger MB, Boesinger P. SENSE:
sensitivity encoding for fast MRI. Magn Reson Med 1999;42:952 – 62.
[10] Keevil SF. Magnetic resonance imaging in medicine. Phys Educ
2001;36:476 – 84.
[11] Goyen M, Herborn CU, Vogt FM, et al. Using a 1 M Gd-chelate
(gadobutrol) for total body three-dimensional MR angiography:
preliminary experience. J Magn Reson Imaging 2003;17(5):565 – 71.
[12] Lauenstein TC, Schneemann H, Vogt FM, Herborn CU, Ruhm SG,
Debatin JF. Optimization of oral contrast agents for MR imaging of
the small bowel. Radiology 2003;228(1):279 – 83.
[13] Laghi A, Carbone I, Catalano C, et al. Polyethylene glycol solution
as an oral contrast agent for MR imaging of the small bowel. AJR Am
J Roentgenol 2001;177:1333 – 4.
[14] Jacobsen TF, Laniado M, VanBeers BE, et al. Oral magnetic particles
(ferristene) as a contrast medium in abdominal magnetic resonance
imaging. Acad Radiol 1996;3(7):571 – 80.
[15] Kaminsky S, Laniado M, Gogoll M, Clauss W, Langer M.
Comparison of positive and negative enteral contrast agents for
MR-imaging of the abdomen. Fortschr Geb Roentgenstrahlen Neuen
Bildgeb Verfahr 1994;161(3):220 – 5.
[16] Duda Sh, Laniado M, Kopp Af, et al. Superparamagnetic iron-oxide-
detection of focal liver-lesions at high-field-strength MR-imaging.
J Magn Reson Imaging 1994;4:309 – 14.
[17] Rubin DL, Falk KL, Sperling MJ, et al. A multicenter clinical trial of
gadolite oral suspension as a contrast agent for MRI. J Magn Reson
Imaging 1997;7(5):865 – 72.
[18] Kivelitz D, Gehl HB, Heuck A, Krahe T, Taupitz M, Lodemann KP.
Ferric ammonium citrate as a positive bowel contrast agent for MR
imaging of the upper abdomen — safety and diagnostic efficacy. Acta
Radiol 1999;40(4):429 – 35.
[19] Bisset GS, Emery KH, Meza MP, Rollins NK, Don S, Shorr JS.
Perflubron as a gastrointestinal MR imaging contrast agent in the
pediatric population. Pediatr Radiol 1996;26(6):409 – 15.
[20] Bachgansmo T. Ferrimagnetic susceptibility contrast agents. Acta
Radiol 1993;34:1 – 6.
[21] Cordova-Fraga T, De Araujo DB, Sanchez TA, et al. Euterpe olerácea
(Açaı́) as an alternative oral contrast agent in MRI of the
gastrointestinal system: preliminary results. Magn Reson Imaging
2004;22:389 – 93.
[22] Hiraishi K, Narabayashi I, Fujita O, et al. Blueberry juice: preliminary
evaluation as an oral contrast agent in gastrointestinal MR imaging.
Radiology 1995;194(1):119 – 23.
200 M.G. Espinosa et al. / Magnetic Resonance Imaging 24 (2006) 195 – 200
[23] Mirowitz S, Susman N. Use of nutritional support formula as a
gastrointestinal contrast agent for MRI. J Comput Assist Tomogr
1992;16(6):908 – 15.
[24] Sato S. A study of green tea for a positive gastrointestinal MR
imaging enhancing agent. Nippon Igaku Hoshasen Gakkai Zasshi
1994;54(9):876 – 85.
[25] Hasegawa M, Kubota H, Kitanosono T, Ri K, Munechika H. New
oral contrast material for gastrointestinal MR examination — green tea
mixed with sodium alginate]. Nippon Igaku Hoshasen Gakkai Zasshi
1990;50(1):79 – 80 [in Japanese].
[26] Karantanas AH, Papanikolaou N, Kalef-Ezra J, Challa A,
Gourtsoyiannis N. Blueberry juice used in upper abdominal MR
imaging: composition and initial clinical data. Eur Radiol 2000;10(6):
909 – 13.
[27] Balzarini L, Aime S, Barbero L, et al. Magnetic resonance imaging of
the gastrointestinal tract: investigation of baby milk as a low cost
contrast medium. Eur J Radiol 1992;15(2):171 – 4.
[28] Hung YC, Sava VM, Juang CL, Yeh T, Shen WC, Huang GS.
Gastrointestinal enhancement of MRI with melanin derived from
tea leaves (Thea sinensis Linn.). J Ethnopharmacol 2002;79(1):
75 – 9.
[29] Carneiro AAO, Touso AT, Baffa O. Avaliação da susceptibilidade
magnetica usando uma balança analı́tica. Quı́m Nova 2003;26:
952 – 6.
[30] Evans S, Hall L. Evaluation of a range of MRI-active pH indicators
using a multiple sample method. AIChe 2005;51:1541 – 7.
[31] Zhang S, Kuangcong W, Sherry AD. A novel pH-sensitive MRI
contrast agent. Angew Chem Int Ed 1999;38(21):3192 – 4.