Photodiagnosis and Photodynamic Therapy 45 (2024) 103976

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Photodiagnosis and Photodynamic Therapy
journal homepage: www.elsevier.com/locate/pdpdt

A novel Foley catheter made of high-intensity near-infrared fluorescentsilicone rubber for image-guided surgery of lower rectal cancer
Takayuki Sato a, *, Ichiro Kitani bab

Department of Cardiovascular Control, Kochi Medical School, Oko, Nankoku 783-8505, Japan
R&D Marketing Department, Mizuho Corporation, 3-30-13, Hongo, Bunkyo-ku, Tokyo 113-0033, JapanA R T I C L E I N F O

A B S T R A C T

Keywords:
Foley catheter
Image guided surgery
Laparoscopic surgery
Near infrared fluorescence
Rectal cancer
Silicone rubber
Urethral injury

Background: Urethral injury occurs in 1–6 % of male cases during minimally invasive surgery of lower rectal
cancer. A Foley catheter emitting near-infrared (NIR) fluorescence of sufficient intensity has been expected tolocate the urethra during image-guided surgery. Although it has been difficult to impart NIR fluorescent prop­
erties to biocompatible thermosetting polymers, we have recently succeeded in developing a NIR fluorescentcompound for silicone rubber and a NIR fluorescent Foley catheter (HICARL). Here, we evaluated its NIR
fluorescence properties and visibility performance using porcine anorectal isolation specimens.
Methods: The HICARL catheter was made of a mixture of solid silicone rubber and a NIR fluorescent compoundthat emits fluorescence with a wavelength of 820–880 nm, while a conventional transparent Foley catheter was
made of solid silicone rubber only. As a standard for comparison of the intensity of NIR fluorescence, a trans­parent Foley catheter the lumen of which was filled with a mixture of indocyanine green (ICG) and humanplasma was used. As a comparison to assess the visibility performance of the HICARL catheter, a transparent
Foley catheter into which a commercially available NIR fluorescent polyurethane ureteral catheter (NIRC) was
placed was used.
Results: A NIR fluorescence quantitative imaging analysis revealed that the Foley-NIRC catheter and the HICARL
catheter emitted 3.42 ± 0.42 and 6.43 ± 0.07 times more fluorescence than the Foley-ICG catheter, respectively.
The location of the HICARL catheter placed in the anorectum with a wall thickness of 3.8 ± 0.1 mm was clearlydelineated in its entirety by NIR fluorescence, while that of the Foley-NIRC catheter was faintly or only partiallyvisible.
Conclusions: The HICARL catheter emitting NIR fluorescence of sufficient intensity is a promising and easy-to-use
tool for urethral visualization during image-guided surgery of lower rectal cancer.

1. Introduction
Transanal total mesorectal excision (TaTME) is a minimally invasive
approach for the radical treatment of lower rectal cancer [1], but TaTME
is a complex procedure in male patients. Urethral injury has been re­ported to occur in 1 % to 6 % of cases when incising the rectus-urethralis
muscle close to the urethra [2–5]. Therefore, intraoperative urethralvisualization methods utilizing the high tissue permeability ofnear-infrared (NIR) light and fluorescence have been proposed. In the
NIR light method using an illuminated ureteral stent (IRIS U-Kits,
Stryker, Kalamazoo, MI, USA), a set of optical fiber and a transparent
catheter for guiding the fiber were passed through a transparent silicone
Foley catheter placed in the urethra, and the optical fiber was connected

to an external laser light source with a wavelength of 830 nm. Atallah
et al. demonstrated that the urethra was transilluminated by the illu­
minated ureteral stent in a cadaveric model [6]. However, the illumi­
nated ureteral stent in the urethra was visible only in a dark field and notunder normal white light. Surgical procedures in a dark field are often
dangerous, and the use of illuminated ureteral stents for trans­
illumination of the urethra has not been approved by the FDA.
Barnes et al. used NIR fluorescence imaging to successfully identify
the urethra in cadavers during TaTME procedures by injecting a mixtureof indocyanine green (ICG) and lubricant gel directly into the urethra[7] or by filling the lumen of a transparent silicone Foley catheter with acoagulating mixture of ICG and ethanol [8]. However, intraurethral
injection of ICG has not been approved by the FDA, and filling Foley* Corresponding author.
E-mail address: tacsato@kochi-u.ac.jp (T. Sato).
https://doi.org/10.1016/j.pdpdt.2024.103976
Received 18 November 2023; Received in revised form 30 December 2023; Accepted 12 January 2024
Available online 14 January 2024
1572-1000/© 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

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Photodiagnosis and Photodynamic Therapy 45 (2024) 103976

catheters interferes with urine volume monitoring. Therefore, thesemethods do not appear to be clinically practical.
Our method of incorporating NIR fluorescent dyes with thermo­
plastic resins [9] has led to the development of indwelling devices, suchas clips [10] and catheters [11], for NIR fluorescence-guided surgery.
Kisu et al. demonstrated a clinical usefulness of NIR fluorescent poly­
urethane ureteral catheters (NIRC, Cardinal Health Japan, Tokyo,
Japan) for the real-time intraoperative visualization of the ureters dur­ing gynecological laparoscopic surgery [12]. A case report by Onishi
et al. showed that a 6-Fr NIRC ureteral catheter placed in the urethra wasuseful for detection of the urethra in a 3-kg male neonate with anorectal
malformation during laparoscopy-assisted anorectoplasty [13]. When
this method is applied to adult males, who have thicker urethras thanneonates, a transparent silicone Foley catheter with a pre-inserted NIRC
ureteral catheter can offer an intraoperative tool to visualize the urethra
without the need for connection to an external light source. Morepromising, however, is a Foley catheter made of NIR fluorescent silicone
rubber and having the same structure and implantation method as aconventional Foley catheter.
Although it has been difficult to impart NIR fluorescent properties tobiocompatible thermosetting polymers [14], we have succeeded indeveloping a NIR fluorescent compound for silicone rubber and a NIR
fluorescent Foley catheter. Here, we evaluated its fluorescent properties
by bench performance tests and assessed its visualization performanceusing porcine anorectal isolation specimens.

2.4. Bench performance tests
The NIR fluorescence brightness of the conventional transparent
Foley catheter, the Foley-ICG catheter, the Foley-NIRC catheter, and the
HICARL catheter was measured with a NIR fluorescence quantitative
imaging system (FL View, Nirec, Kochi, Japan). Each sample was placedon an optical absorption sheet (Super Black IR, Shibuya Optical, Wako,
Japan) so that background noise caused by the reflection of the excita­tion light that transmitted through the catheters was reduced to less than
1.6 %. The wavelength of the excitation light was set to 780 nm. The
irradiance at the sample surface was adjusted to 30 mW/cm2. NIR
fluorescence at a wavelength of 820–880 nm was measured andanalyzed.
2.5. Visibility performance assessment with anorectal isolation specimens
Porcine anorectal isolation specimens were purchased from the Kobe
Medical Device Development Center. The visibility performance of NIR
fluorescence emitted by the Foley-NIRC catheter and the HICARL
catheter implanted in the anorectum was evaluated with a custom-madelaparoscopic system that simultaneously images visible light and NIR
fluorescence [9]. In the overlay image of visible light and NIR fluores­
cence, the NIR fluorescence was shown in green. The irradiance of theexcitation laser light at a wavelength of 780 nm was adjusted to 15 or 30
mW/cm2 at the center of the tissue surface while the irradiance wasmeasured with an optical power meter system (model 8230 and 82311B,
ADC, Saitama, Japan). The laparoscopic working distance was set to 50
mm. NIR fluorescence at a wavelength of 820–880 nm was detected witha fixed exposure time of 1/30 second, and the brightness of NIR fluo­
rescence was analyzed using ImageJ Version 1.54d. On an 8-bit gray­scale NIR fluorescence image with a resolution of 1280 horizontal pixels
by 1020 vertical pixels, a circular region with a diameter of 40 pixels
centered on the highest point of brightness was set as the region of in­terest. For each NIR fluorescence image, the average value of thebrightness within the region of interest was calculated as the visibility
performance score. After laparoscopic observation of each catheter, thethickness of the anorectal wall on the catheter was measured with anultrasound system (Vscan, GE Healthcare, Chicago, IL, USA).

2. Materials and methods
This study was performed under the approval of the Animal ResearchCommittee of the Kobe Medical Device Development Center (permit No.
IVT22–113). Written consent was not needed, as this study did notinclude human subjects.
2.1. Conventional transparent Foley catheters and HICARL catheters
A newly developed NIR fluorescent Foley catheter (HICARL, Mizuho,
Tokyo, Japan) was made of a mixture of solid silicone rubber and a
proprietary NIR fluorescent compound that emits fluorescence at awavelength of 820–880 nm in response to excitation light at a wave­
length of 740–800 nm, while a conventional transparent Foley catheter
was made of solid silicone rubber only. The 14-Fr size tubes were
manufactured using an extrusion and thermosetting system. All mate­rials used passed physical property and biocompatibility testing inaccordance with medical regulatory standards.

2.6. Statistical analysis
Statistical analysis between independent groups was performed byMann-Whitney U test or Steel-Dwass multiple comparison test using
Kyplot Version 4.0.1 (KyensLab, Tokyo, Japan). Paired difference tests
for repeated measures in a single sample were performed by the Wil­coxon signed-rank test. Differences were considered significant at p <0.05. Values are expressed as mean ± SD.

2.2. Foley-NIRC catheters

3. Results

A conventional 14-Fr transparent Foley silicone catheter into which a
NIRC ureteral polyurethane catheter was placed was used as a com­
parison to evaluate the visibility performance of the HICARL catheter.
Since NIRC ureteral catheters are only commercially available in the 6Fr size [11,12], a 14-Fr Foley catheter with an inner diameter of 2.4–2.6
mm was selected to fit a NIRC ureteral catheter. The transparent Foley
catheter with a pre-inserted NIRC ureteral catheter is hereafter referred
to as the “Foley-NIRC catheter”.

An overall view of the NIRC ureteral catheter, Foley-NIRC catheter,and HICARL catheter is shown in Fig. 1; for the Foley-NIRC catheter, theNIRC ureteral catheter is visible through the transparent Foley catheter.
Fig. 2 shows representative examples of 8-bit grayscale images of thetransparent Foley catheter, Foley-ICG catheter, Foley-NIRC catheter,and HICARL catheter during excitation light exposure. No fluorescence
was observed from the transparent Foley catheter. Scaling the mean NIR
fluorescence brightness of the Foley-ICG catheter to 1, the NIR fluores­
cence brightness of the Foley-NIRC catheter was 3.42 ± 0.42 and that of
the HICARL catheter was 6.43 ± 0.42. (Fig. 3). Of these three types of
NIR fluorescent catheters, the HICARL catheter was the most signifi­
cantly brighter (p < 0.05, n = 5 for each group).
The visibility performance of the Foley-NIRC catheter and HICARL
catheter implanted in the porcine anorectum with a wall thickness of 3.8± 0.1 mm was evaluated with a custom-made laparoscopic imaging
system. Fig. 4 shows representative examples of visible light (RGB),

2.3. Foley-ICG catheters
A mixture of ICG (Diagnogreen, Daiichi Sankyo, Tokyo, Japan) andhuman plasma (Cosmo Bio USA, Carlsbad, CA, USA) at a final concen­
tration of 10 μg/mL, which emits its brightest fluorescence [15], wasprepared as a standard for comparing the intensity of NIR fluorescence.
The transparent Foley catheter with ICG plasma solution sealed in thelumen is hereafter referred to as the “Foley-ICG catheter”.
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Photodiagnosis and Photodynamic Therapy 45 (2024) 103976

Fig. 1. Photographs showing an overall view of the NIRC ureteral catheter, Foley-NIRC catheter, and HICARL catheter. In an inset showing a magnified image of the
Foley-NIRC catheter, the NIRC ureteral catheter is visible through the transparent Foley catheter.

Fig. 2. Representative examples of 8-bit grayscale images of the transparent Foley catheter, Foley-ICG catheter, Foley-NIRC catheter, and HICARL catheter during
irradiation of excitation light. Each sample was placed on a light absorption sheet, so that background noise due to unwanted diffuse reflection of excitation light andrepetitive emission of NIR fluorescence was less than 1.6 % in the wavelength range of 250 nm to 2500 nm. No fluorescence was observed from the transparent
Foley catheter.

NIRC catheter required more intense excitation light exposure. The re­sults of the evaluation of the two types of catheters are summarized inFig. 5. For both types of catheters, the level of excitation light exposure
significantly affected the intensity of NIR fluorescence (p < 0.05, n = 5
for paired samples). At all irradiation levels, the HICARL catheter hadsignificantly higher visibility performance scores than the Foley-NIRC
catheter (p < 0.05, n = 5 for each group).
4. Discussion
In the present study, we evaluated NIR fluorescence properties of a
newly developed HICARL catheter by bench performance tests andassessed its visibility performance with isolated preparations of the
porcine anorectum. The results suggest that the HICARL catheter is apromising tool for intraoperative urethral visualization by NIR fluores­
cence imaging.
Recently, two approaches to visualize the urethra by NIR fluores­
cence imaging have been reported; i.e., an intraurethral ICG injection
method [7] and a method using a transparent silicone Foley catheter inwhich NIR fluorescent materials are sealed or packed [8]. However,both approaches have several drawbacks. First, a direct injection of ICG
into the urethra has not been approved. Second, repeated injections of
ICG into the urethra during several hours of anorectal surgery are notpractical clinically. Third, narrowing and occluding the lumen of Foley
catheters by sealing or packing with NIR fluorescent materials would
impede urine flow. Taken together with these points, Foley cathetersthat emit NIR fluorescence without compromising an original function

Fig. 3. Graph showing NIR fluorescence brightness of the Foley-ICG catheter(white filled circles), Foley-NIRC catheter (red filled circles), and HICARL
catheter (blue filled triangles) during irradiation of excitation light. The
average value of NIR fluorescence brightness of the Foley-ICG catheter wasscaled to 1. *p < 0.05, n = 5 for each group. a.u., arbitrary units.

overlay (RGB-NIR), and 8-bit grayscale fluorescence (NIR) images under
weak (15 mW/cm2) and strong (30 mW/cm2) excitation light. Bothcatheters could be located on NIR fluorescence images, but the Foley3

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Photodiagnosis and Photodynamic Therapy 45 (2024) 103976

Fig. 4. Representative examples of visible light (RGB), overlay (RGB-NIR), and 8-bit grayscale fluorescence (NIR) images of the Foley-NIRC catheter and HICARL
catheter during weak (15 mW/cm2) and strong (30 mW/cm2) irradiation of excitation light. In the overlay image, the NIR fluorescence is shown in green.

of the Foley catheter seem to be highly needed in clinical practice. Our
NIR fluorescent Foley catheter, which has the same structure and im­plantation method as a conventional Foley catheter, would be aneasy-to-use tool for visualizing the urethra during image-guided surgery
of lower rectal cancer.
The bench performance tests revealed that the Foley-NIRC catheter
and HICARL catheter emitted 3.42 and 6.43 times more fluorescencethan the Foley-ICG catheter, respectively. In a recent quantitative study,
Barberio et al. demonstrated that a Foley catheter coated with NIR
fluorescent acrylic resin, which emitted NIR fluorescence four times
brighter than the Foley-ICG catheter, can accurately guide the locationof the urethra in cadavers [16]. Based on their findings, the HICARL
catheter is also expected to guide the location of the urethra by its NIR
fluorescence, while the Foley-NIRC catheter would be less promising.
As expected from the results of the bench performance tests, thelocation of the HICARL catheter placed in the anorectum with a wall
thickness of approximately 4 mm was clearly delineated in its entirety
by NIR fluorescence, whereas that of the Foley-NIRC catheter was faintly
or only partially visible. The required performance for a Foley catheter
to locate the urethra would be to emit NIR fluorescence that is at least
four times brighter than that of the Foley-ICG catheter. To our knowl­edge, this is the first report of a medical-grade Foley catheter that is
made of silicone rubber with sufficient NIR fluorescence intensity for
intraoperative urethral visualization.
While the present study demonstrated feasibility of our NIR

Fig. 5. Graph showing visibility performance (VP) score of the Foley-NIRC
catheter (red filled circles) and HICARL catheter (blue filled triangles) during
weak (15 mW/cm2) and strong (30 mW/cm2) irradiation of excitation light. *p< 0.05, n = 5 for each group; #p < 0.05, n = 5 for paired samples. a.u., arbi­
trary units.
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Photodiagnosis and Photodynamic Therapy 45 (2024) 103976

fluorescent Foley catheter, there remains to be done in the future.
Clinical tests are required to confirm its efficacy. Although we used ourcustom-made laparoscopic system for the visibility performanceassessment, differences in visibility of the HICARL catheter between
models of commercially available laparoscopic systems should be
investigated prior to clinical studies.
In conclusions, a newly developed HICARL catheter, which has thesame structure and implantation method as a conventional Foley cath­eter, emits NIR fluorescence that is more than four times brighter thanthat of the Foley-ICG catheter. Therefore, the HICARL catheter is apromising and easy-to-use tool to prevent urethral injury during NIR
fluorescence-guided surgery of lower rectal cancer.

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Funding
This work was supported by a Grant-in-Aid for Scientific Researchfrom the Japan Society for the Promotion of Science (Grant Number
JP19H04487).
CRediT authorship contribution statement
Takayuki Sato: Writing – review & editing, Writing – original draft,
Visualization, Validation, Supervision, Methodology, Investigation,
Funding acquisition, Formal analysis, Conceptualization. Ichiro Kitani:
Writing – review & editing, Validation, Resources, Project administra­tion, Investigation.
Declaration of competing interest
Takayuki Sato and Ichiro Kitani have no conflict of interest to
disclose.
Acknowledgments
None.
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