Fiber ATR infrared spectroscopy of kidney tissue during live surgery

Abstract

More than 90% of solid kidney tumors are cancerous and have to be treated by surgical resection where surgical outcomes and patient prognosis are dependent on the tumor discrimination. The development of alternative approaches based on a new generation of fiber attenuated total reflection (ATR) probes could aid tumor identification even under intra‐surgical conditions. Herein, fiber ATR IR spectroscopy is employed to distinguish normal and cancerous kidney tissues. Freshly resected tissue samples from thirty four patients are investigated under nearly native conditions. Spectral marker bands that allow a reliable discrimination between tumor and normal tissue is identified by a supervised classification algorithm. The absorbance values of the bands at 1025, 1155 and 1240 cm⁻¹ assigned to glycogen and fructose 1,6‐bisphosphatase are used as the clearest markers for the tissue discrimination. Absorbance threshold values for tumor and normal tissue are determined by discriminant analysis. This new approach allows the surgeon to make a clinical diagnosis.
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FULL ARTICLE
Fiber attenuated total reflection infrared spectroscopy of
kidney tissue during live surgery
Valdas Sablinskas
1
*| Rimante Bandzeviciute
1
| Martynas Velicka
1
|
Justinas Ceponkus
1
| Vidita Urboniene
1
| Feliksas Jankevicius
2,3
|
Arvydas Laurinavicˇius
4
| Darius Dasevicˇius
4
| Gerald Steiner
5
1
Institute of Chemical Physics, Vilnius
University, Vilnius, Lithuania
2
Faculty of Medicine, Vilnius University,
Vilnius, Lithuania
3
National Cancer Institute, Vilnius,
Lithuania
4
National Center of Pathology, Affiliate of
Vilnius University Hospital Santaros
Klinikos, Vilnius, Lithuania
5
Faculty of Medicine Carl Gustav Carus,
Clinical Sensoring and Monitoring,
Dresden University of Technology,
Dresden, Germany
*Correspondence
Valdas Sablinskas, Faculty of Medicine,
Vilnius University, Santariskiu str.
2, Vilnius, LT-08661, Lithuania.
Email: valdas.sablinskas@ff.vu.lt
Funding information
Research Council of Lithuania, Grant/
Award Number: SEN-16/2015
Abstract
More than 90% of solid kidney
tumors are cancerous and have to be
treated by surgical resection where
surgical outcomes and patient prog-
nosis are dependent on the tumor
discrimination. The development of alternative approaches based on a new
generation of fiber attenuated total reflection (ATR) probes could aid tumor
identification even under intrasurgical conditions. Herein, fiber ATR IR spec-
troscopy is employed to distinguish normal and cancerous kidney tissues.
Freshly resected tissue samples from 34 patients are investigated under nearly
native conditions. Spectral marker bands that allow a reliable discrimination
between tumor and normal tissue are identified by a supervised classification
algorithm. The absorbance values of the bands at 1025, 1155 and 1240 cm
−1
assigned to glycogen and fructose 1,6-bisphosphatase are used as the clearest
markers for the tissue discrimination. Absorbance threshold values for tumor
and normal tissue are determined by discriminant analysis. This new approach
allows the surgeon to make a clinical diagnosis.
KEYWORDS
ATR, fiber probe, FTIR, kidney cancer, resected tissue
1|INTRODUCTION
During the past decades, many efforts were made to char-
acterize and to distinguish tissue by vibrational spectros-
copy. Although a huge number of successful reports were
published dealing with this topic [1–3], the transfer into
clinic appears to be limited due to the lack of instruments
and systems that allow in situ measurements. While usu-
ally Raman spectroscopy is considered as method of
choice for an in situ characterization of tissue [4], infra-
red (IR) spectroscopy is often seen as laboratory testing
method. However, Raman spectroscopy requires often
few minutes measurement time to record qualitative
spectra and, more important, the question of photo toxic-
ity or photo damaging of the excitation laser is not
answered yet. Reasons why IR spectroscopy did not
found broad application for in situ diagnosis might be
among other things. The strong absorption bands of
Received: 17 January 2020 Revised: 6 March 2020 Accepted: 24 March 2020
DOI: 10.1002/jbio.202000018
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2020 The Authors. Journal of Biophotonics published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Biophotonics. 2020;e202000018. www.biophotonics-journal.org 1of7
https://doi.org/10.1002/jbio.202000018

water and the fact that IR light is difficult to “transport”
to the point of measurements. However, recent develop-
ments in IR fiber spectroscopy allow now quick and reli-
able spectroscopic measurements even of native tissue
and opens the door for in situ applications in the clinic.
This is mainly driven by the fact that there is big need for
surgeons to determine malignancy of tissue during the
surgical operation in order to make final decision about
exact place of the surgical cut. On the other hand, the
evaluation of spectra in regard to classify tissue as normal
or pathological is still a challenge.
IR absorption spectra of biological tissue are rather
complex and difficult to analyze; nevertheless, during the
last decades, there are many successful attempts to apply
IR spectroscopy for detection of tumorous tissue areas
[5–8], for elucidating structure of kidney, bladder or gall
stones [9–12], for analysis of sediments in various bodily
fluids [13–15]. Main drawback of this method is that sam-
pleforthestudieshastobetransferredfromthepatientto
the instrument. Using IR fibers in combination with an
attenuated total reflection (ATR) crystal may overcome the
time consuming ex vivo measurements. However, main
drawback of the ATR-FTIR method as a tool for detection
of tumorous tissue areas was a lack of suitable fiber probes
which provide quick and reliable measurements of native
tissue.TwotypesoffiberATRprobescouldbeused:ATR
crystal probe and loop probe. Generally, both types of probe
could be used for tissue examination, but an application of
fiber probes for tissue measurements is restricted by the
requirement to sterilize them after each use to avoid the
contamination of the tissue. This requirement restricts the
design of the probes to be easily changeable and sterilizable.
Therefore, the tip with ATR crystal is more appropriate for
the tissue examination. For this reason, this type of tips was
used in designing our fiber ATR FTIR system.
In order to use IR spectroscopy in operating room
(OR) there are some requirements concerning size of the
instrument and ability to do measurements in situ. There
is some choice of portable IR spectrometers in the mar-
ket, but they are not suitable for the in situ ATR mea-
surement, since they are equipped with compact detector
(usually DTGS) which has limited sensitivity. Such in situ
measurements require a fiber probe with ATR tip
attached to the end of the fiber. Usually, in such fiber
arrangement loses of optical signal are 90% or even
larger, what makes the measurements meaningless.
In an early study, we have demonstrated that very
small areas of infiltrated kidney tumor can be detected by
IR spectroscopic imaging and supervised classification
[16]. In the next study, we found a particular spectral
region that contains spectroscopic signals from extracellu-
lar and intracellular molecules such as fatty acids, glycerol
and glycogen. The signals can be used as spectral markers
for classification of healthy and tumor cells of kidney tissue
[17]. These initial studies were focused mainly on deter-
mining whether and where reliable spectral differences
between normal and tumor kidney tissue are located.
Also, we have demonstrated that kidney tumor tissue
can be identified by measuring spectra of dried tissue
smears by using a portable IR spectrometer equipped
with a new type of a fiber ATR probe [18]. In the present
study, we demonstrate that kidney tumor tissue can be
identified during live surgery using this fiber setup for
the measurements of wet tissue nearly in its native condi-
tions. In contrast to other studies, the spectra are not
classified and results are not translated into a computer
based diagnose like “tumor”or “healthy.”Aimed on the
clinical application and in accordance to the regulations
in medicine, the concrete absorbance values of the
marker spectral bands are defined and represented with-
out any algorithm-based classification.
2|EXPERIMENTAL
Spectra of tissue were measured using ATR silver halide
fiber probe attached to the standard FTIR spectrometer
Alpha (Bruker Optik GmbH, Ettlingen, Germany).
Changeable fiber probe tips with single reflection germa-
nium ATR crystal were used. The schematics of the ATR
fiber probe (Art Photonics GmbH, Berlin, Germany)
accessory is presented in Figure 1.
The development of the complete system was
implemented by our researchers' group in cooperation
with “Art Photonics.”Optical fibers used in the setup are
made from silver halide. The focusing and directing of
the light in this accessory is done only by two elliptical
and four flat mirrors. The germanium ATR crystal is
fixed to the fiber by means of detachable plastic holder
(tip). Such approach gives an opportunity for a new and
sterile tip to be used for every successive measurement
and ensures that no contaminants are introduced to the
tissue thus reducing the risk of the complications during
FIGURE 1 Schematic diagram of fiber attenuated total
reflection (ATR) probe with changeable ATR crystal
2of7 SABLINSKAS ET AL.

the surgery. The ATR fiber accessory is made in a com-
pact way and allows the quick interchanging from the
conventional ATR setup of the portable FTIR spectrome-
ter and the ATR fiber setup without the need to use two
different spectrometers.
A liquid nitrogen cooled MCT detector (Infrared
Associates, Inc. Model IRA-20-00131) was coupled with
the whole system in order to compensate the loss of opti-
cal signal in the fiber which leads to the reduction of
signal-to-noise ratio. This spectroscopy system is rather
light and compact thus it can be easily fitted on a mobile
table for maneuverability.
The main advantage of the application of fiber probes
is that the sample could be analyzed in situ conditions
and it does not have to be transferred to the device. Also,
there are some drawbacks of the fiber ATR setup. The
spectral region is restricted due to scattering of light in
the fiber but it does not have impact while analyzing the
fingerprint spectral region. While performing measure-
ments in fiber ATR configuration the loss of optical sig-
nal is current; however, it could be compensated by using
more sensitive MCT detector. Fibers made of silver halide
are fragile and degradation of the fiber could be observed.
The IR absorption spectra of freshly resected human kid-
ney tissues, taken from 34 patients, were measured immedi-
ately after surgical resection inside the operation theater of
the Vilnius university hospital Santaros Clinics urology
department. The protocol for spectroscopic studies was
approved by Vilnius regional bioethics committee (approval
No. 158200-15-803-312). Before each measurement, a back-
ground spectrum was recorded from the clean ATR fiber
probe. Small amounts of suspected tumorous and normal
(bordertissuearoundthetumorexpectedtobenormal)tis-
suewereexamined.TheATRprobewasgentlypressedto
the freshly cut area of resected kidney tissue sample and
spectra of the tissue were collected. IR absorption spectra of
tumorous and normal human kidney tissue were measured
in 400 to 4000 cm
−1
spectral region with 4 cm
−1
spectral res-
olution. Sixty-four interferograms were averaged and Fourier
transformed into a spectrum applying three-term Blackman-
Harris apodization function and zero filling factor of 2.
Evaluation of spectral data was performed using the
MATLAB Package (Version 7, Math Works Inc. Natick,
Massachusetts). In order to minimize the data volume and
to exclude the strong absorption bands of water only the
region between 950 and 1350 cm
−1
was considered. Data
preprocessing involved a linear baseline correction by using
the msbackadj function of the Statistics Toolbox of
MATLAB. The baseline correction was performed to reduce
influences of light scattering. Spectra with a maximum
absorbance larger than 1.8 or smaller than 0.02 were identi-
fied as outliers and removed from the data set. Finally, the
selected spectra were area-normalized to eradicate spectral
differences due to different sampling conditions during the
measurements of different samples. Different overall absorp-
tion values of different samples are influenced by several
factors. One of the main factors is the contact between the
sample and the ATR crystal; in different measurements, it is
impossible to ensure the same pressing force on the sample.
The consistency and hardness of the samples are also differ-
ent, especially between normal and tumorous tissues due to
different amount of water and biochemical composition. A
training set of 24 spectra of each class was built for super-
vised classification. Aim of the supervised classification was
used to explore optimal spectral regions for discrimination
of normal and tumor tissue. The approach uses a genetic
algorithm to maximize the classification rate with the itera-
tive optimization of selected features and is similar to a
method described elsewhere [19]. Each spectrum was
reexpressed as a set of three intensity values, which were
used for the subsequent classification by quadratic discrimi-
nant analysis, done using the classify function available in
the Statistics Toolbox of MATLAB. The performance of the
classification was assessed with the leave-one-out-validation
method. An independent test set of 10 patients was used to
test the discrimination parameters.
3|RESULTS AND DISCUSSION
Examples of resected kidney tissue are represented in
Figure 2. While general differences between normal
FIGURE 2 Photographs of normal, A, and tumorous, B, tissue
samples, microscopy image of H&E stained tissue, C. After
microscopic histopathological examination, the borderline between
normal and tumorous kidney tissues is clearly visible
SABLINSKAS ET AL.3of7

(Figure 2A) and tumor tissue (Figure 2B) were in the
most cases visible, a sharp borderline is not observable.
The borderline becomes clearly visible after microscopic
histopathological examination (Figure 2C).
For each case, one part of the resected tissue was
examined by standard histopathological analysis; another
part of sample was used for the measurements of IR
absorption spectra. Diagnosed types of kidney tumors
and number of cases are summarized in Table 1.
Figure 3A shows the recorded raw ATR spectra of all
tumor (red) and normal (green) tissue samples. Due to
the strong water absorption bands, spectra were reduced
to the spectral region from 950 to 1350 cm
−1
. At the first
glance, the most important spectral bands that may allow
to discriminate tumor from normal tissue are located
around 1025 and 1155 cm
−1
.
Between 1000 and 1250 cm
−1
absorption bands mainly
due to carbohydrates, glycoproteins and phosphate groups
occur. Clearly, the IR spectrum captures a wealth of chemi-
cal information and slight variations in the band positions
and intensities reveal heterogeneity across the samples.
The key question addressed here is whether the biochemi-
cal information latent in these spectra is able to discrimi-
nate normal from tumor tissue. The absorption profile
between 1000 and 1050 cm
−1
, in particular the absorption
band around 1025 cm
−1
is stronger for tumor tissue than
for normal tissue. Furthermore, tumor tissue exhibits also
stronger absorption around 1150 cm
−1
and weaker signals
between 1200 and 1275 cm
−1
. The question that then arises
is which constituents could be responsible for these bands.
To illustrate the spectral changes more clearly, Figure 3B
shows the average spectra and standard deviation of both
types of the tissue. Table 2 summarizes the vibrational
modes in this spectral range.
The spectral band at 1025 cm
−1
is assigned to
ν(C O), ν(C C) stretching and δ(C O) bending
vibrations of C OH groups of glycogen while the band at
1155 cm
−1
is attributed to the ν(C O) stretching vibra-
tions [24]. Spectra of tumor tissue clearly show a higher
intensity at 1025 and 1155 cm
−1
. It is known that kidney
tumor cells tend to store glycogen in their cytosol
[25]. Generally, the stronger absorption signals arise
because tumor cells have a higher demand of energy than
normal cells because of their fast proliferation.
In case of clear cell renal cell carcinoma tumors, the
amount of fructose 1,6-bisphosphatase is decreased [25, 26].
Tumor cells express less of fructose 1,6-bisphosphatase thus
reinforces Warburg-like metabolic shift. Decreased amount
of this enzyme is associated with changed cellular meta-
bolic processes and increased amount of glycolytic flux in
tumorous cells as fructose 1,6-bisphosphatase antagonizes
TABLE 1 Diagnosed types of kidney tumors
Diagnosis
Number of
cases
Clear cell renal cell carcinoma 22
Clear cell renal cell carcinoma,
retention cysts
4
Papillary renal cell carcinoma 1
Papillary urothelial carcinoma 1
Chromophobe renal cell carcinoma 3
Chromophobe renal cell carcinoma,
retention cysts
1
Oncocytoma, retention cysts 1
SDHB renal cell carcinoma 1
Abbreviation: SDHB, succinate dehydrogenase deficient.
FIGURE 3 A, Spectra of normal (green) and tumor tissue
(red). Spectra were preprocessed as described and area
normalized. B, Plot of the mean (μ) spectra (bold) and standard
deviation (δ) bands. Differences between the spectral profiles of
tumor and normal tissue become clearly visible. C, Box whisker
plot of selected spectral regions. The three spectral regions were
identified as best positions by a supervised classification algorithm
as described elsewhere [27]
4of7 SABLINSKAS ET AL.

the glycolytic flux and inhibits the nuclear function of
HIF-αmetabolic regulator [25, 26]. The band located at
1240 cm
−1
is assigned to νPO−
2

asymmetric stretching
vibrations and to the amide III mode of proteins
[24]. Hereby, the decreased absorbance value of this band
possibly could be related with lower concentration of
fructose 1,6-bisphosphatase.
The optimization classification procedure of the algo-
rithm selects the best number of spectral bands and their
spectral positions. In respect to a practical use, in particu-
lar that the surgeon has to define the diagnosis based on
the intensity of spectral marker bands, the maximum
number of selected bands used for the genetic algorithm
was set to five. An optimized classification result could
be obtained by three selected bands. When the algorithm
involves more than three bands the accuracy of the train-
ings set becomes not better and the risk of an over deter-
mination increases. Therefore, a leave-one-out validation
was used to avoid an over-determination by too many
classifiers. It has to be noted that all three bands are nec-
essary for a successful classification and all bands have
the same “importance”for the classification result or
diagnosis, respectively. The optimal separation between
normal and tumor tissue was determined by linear dis-
criminant analysis. Thresholds of absorbance values
(A) are listed in Table 3. It has to be noted that the
defined thresholds are referred to area normalized spec-
tra as described above.
The absorbance values were determined and plotted
in Figure 4. After tissue discrimination according to the
defined thresholds, all normal tissue samples were identi-
fied correctly. Then, 27 of 34 kidney tumor samples were
correctly classified as tumor tissues. In two cases (#8 and
#33) tumor tissue and partly normal tissue exhibit absor-
bance values of the other, wrong tissue class. These two
cases are diagnosed as papillary renal cell carcinoma and
succinate dehydrogenase-deficient renal cell carcinoma
with retention cysts. Only single cases of papillary renal
cell carcinoma and succinate dehydrogenase-deficient
renal cell carcinoma with retention cysts were observed
during the study, while the most frequent type of kidney
tumors is clear cell renal cell carcinoma. Due to specific
biochemical processes in different tumor types, different
spectral markers are required for discrimination of vari-
ous tumor types.
In three cases (patients #7, #27 and #29), tumorous
tissue samples were classified as questionable. In these
cases, patients were diagnosed with chromophobe renal
cell carcinoma (patient #29), chromophobe renal cell car-
cinoma with retention cysts (patient #27) and clear cell
renal cell carcinoma with retention cysts (patient #7).
Specific morphological features of chromophobe renal
cell carcinoma may produce specific IR spectra that dis-
criminate this tumor type from other kidney tumors.
During the study 50% (patient #17 and #22) of chromo-
phobe renal cell carcinoma samples were identified as
tumorous tissue and 50% (patients #29 and #27) as ques-
tionable tissue. It could be linked to the fact that chromo-
phobe renal cell carcinoma morphologically has “classic”
and eosinophilic types. The latter has significant overlap
with oncocytoma and often poses a diagnostic problem.
The basic chromophobe cell type is characterized by large
polygonal cells with a transparent, slightly reticulated
cytoplasm with prominent cell membranes leading to a
plant cell-like appearance. Electron microscopically, the
cytoplasm is crowded by loose glycogen deposits and
numerous, sometimes invaginated and studded vesicles.
The second cell type in chromophobe renal cell carci-
noma is also characterized by an increased cytoplasmic
eosinophilia or granularity, due to an augmentation of
mitochondria. Both cell types can occur singly or in com-
bination within a given tumor. On the assumption that
in one part of chromophobe renal cell carcinoma tumors,
the amount of glycogen is altered, those tissues could be
classified as tumorous tissue as in case of clear cell renal
cell carcinoma which has specific biochemical feature of
increased amount of lipids and glycogen. In case when
loose glycogen is not apparent in the cells, it leads to the
misclassification of tissue. Chromophobe renal cell carci-
noma is infrequently occurring type of kidney tumors
TABLE 2 IR absorption spectral bands of kidney tissue in the
spectral region from 950 to 1350 cm
−1
and their
assignments [20–23]
Spectral position (cm
−1
) Assignment
1025 ν(C O), ν(C C), δ(C O)
1045 ν(C O), δ(C OH)
1080 ν
s
(PO
2
−
)
1155 ν(C O)
1164 ν(C C), ν(C O), δ(C OH)
1205 ν(C O C), ν(C O), amide III
1240 ν
as
(PO
2
−
)
1270 CH
2
rocking
1332 CH
2
wagging
Abbreviation: IR, infrared.
TABLE 3 Defined thresholds of absorbance values (A)to
discriminate tumor from normal tissue
Spectral position (cm
−1
) Tumor Normal
1025 A≥0.0064 A< 0.0064
1155 A≥0.005 A< 0.005
1240 A≤0.01 A< 0.01
SABLINSKAS ET AL.5of7

and different spectral markers are required for tissue dis-
crimination. For the more detailed conclusions, more
cases of chromophobe renal cell carcinoma should be
investigated.
In two cases (patients #2 and #26), tissue samples
were identified as suspected to be tumorous. In these
cases, patients were diagnosed with clear cell renal cell
carcinoma with retention cysts. In most cases, when the
retention cysts are present, tissues are not classified as
tumorous. The presence of retention cysts disables to rec-
ognize the tissue type according to changed concentra-
tions of biochemical components that could be assigned
as markers of cancer.
The results indicate that fiber ATR IR spectroscopy
could be used to aid clinical differentiation of normal
and tumor kidney tissue in a fast and sensitive way
during live surgery. It should be noted that the presen-
tation of spectral markers values in the form of labora-
tory data, without computer-based classification,
enables a real clinical application of the spectroscopic
approach. The final goal of such spectroscopic approach
is to detect the hard-to-see borderlines under
intraoperative conditions, because an incomplete
removal of the tumor is linked to recurrences which
dramatically reduce the prognosis of the patient. This is
the preclinical trial, so validation by a larger sample set
is the next step followed by an adaption of the fiber
optic probe for in situ applications.
The initial results of this study are promising and
demonstrate that the core idea is rather round.
4|CONCLUSION
In conclusion, this work has shown that fiber ATR IR
spectroscopy is suitable to obtain meaningful spectra of
normal and tumorous kidney tissues. The spectra of both
types of tissue contain enough information for the tissue
discrimination. Spectral bands at 1025 and 1155 cm
−1
assigned to glycogen and the band at 1240 cm
−1
assigned
to fructose 1,6-bisphosphatase were considered as spec-
tral markers for tumorous tissue identification. In case of
FIGURE 4 Representing spectroscopic diagnostic information similar to the standard form of laboratory-analyzed findings. The figure
shows a plot of the absorbance values at the selected spectral regions of normal (green) and tumor (red) tissue. Spectra of patients #1 to #24
were used as training set for determination of optimal spectral regions. Ten Spectra (#25 to #34) were classified as independent test set. In
this figure, the spectral data of patients #1 to #24 are reclassified
6of7 SABLINSKAS ET AL.

tumorous tissue of the intensity of the spectral bands,
corresponding to glycogen gets higher, while the absor-
bance of the band corresponding to fructose
1,6-bisphosphatase gets lower. Concrete intensity values
of marker spectral bands used for the discrimination of
normal and tumorous tissue were defined. Identification
of tumorous tissue in case of presence of retention cysts
in it can leads to misclassification due to changed con-
centrations of biochemical components that are present
in cancerous tissue. The newly designed fiber probe could
be developed in the future; method has potential to be
moved towards intrasurgical applications for the more
efficient surgical treatment.
ACKNOWLEDGMENT
This research was funded by a grant SEN-16/2015 from
the Research Council of Lithuania.
CONFLICT OF INTEREST
The authors declare no financial or commercial conflict
of interest.
AUTHOR CONTRIBUTIONS
F. J., A. L. and D. D. were involved in sample preparation
and histopathological analysis, V. S. was involved in con-
ceptualization and project management, G. S. was
involved in conceptualization, statistical analysis, writing
and editing, R. B. was involved in investigation and writ-
ing and J. C., M. V. and V. U. were involved in the experi-
ment setup.
DATA AVAILABILITY STATEMENT
Data can be requested from the authors.
ORCID
Gerald Steiner https://orcid.org/0000-0002-7625-343X
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Sablinskas V,
Bandzeviciute R, Velicka M, et al. Fiber attenuated
total reflection infrared spectroscopy of kidney
tissue during live surgery. J. Biophotonics. 2020;
e202000018. https://doi.org/10.1002/jbio.202000018
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