Intraoperative Ureter Visualization Using a Novel Near-Infrared Fluorescent Dye

Abstract

Ureters can be accidentally severed during pelvic surgeries, significantly prolonging the times in the operating room to allow for complete repair of damaged ureters and leading to significant morbidities associated with consequent ureter obstruction and possible kidney dysfunction. In an effort to prevent these complications, light-emitting stents and urine-excreted dyes have been introduced to illuminate the ureter during surgery. However, problems with mechanical insertion, ureter spasm, image contrast, and localized injection have limited interest in their clinical applications. We report here the synthesis and characterization of a new near-infrared (NIR) fluorescent dye (UreterGlow) that can be injected systemically but is excreted primarily through the renal system, allowing ureter imaging with an NIR fluorescence camera. Following intravenous injection of 0.1 mg/kg UreterGlow, we have monitored the flow of UreterGlow through the proximal, medial, and distal segments of the ureter. The timing of ureter visualization was calculated from the time of injection of the drug. The null hypothesis was that "Visualization of the ureter in pigs is possible 60 min after administration of UreterGlow using an NIR camera". UreterGlow displayed excitation and emission maxima of λ = 800 nm and λ = 830 nm in phosphate buffered saline, pH 7.4, and could be imaged in the urinary tract in mice. Shortly after injection of UreterGlow into Yorkshire pigs, peristalsis of the ureter could be observed. The distal ureter could be visualized under NIR illumination after 60 min with constant fluorescence in all five pigs for >2 h. The same ureters could not be seen using visible light ( X, p = 0.0001). Because both excitation and emission of UreterGlow occurs at >30 nm longer wavelength than most tumor-imaging fluorescent dyes, it should be possible to distinguish ureter fluorescence from tumor fluorescence with this dye.

Near-infrared fluorescent coatings of medical devices for image-guided surgery

“…Fluorescent probes that operate in the near-infrared (NIR) region between 650-900 nm gained increasing attention, because biological tissues have low autofluorescence and negligible absorption coefficients in the NIR region [37,[45][46][47][48]. NIR dyes and nanoparticles ensure deeper tissue penetration ability with less scattering in the NIR window [47,48], which is particularly attractive for biomedical imaging and image-guided surgery [33,45,[49][50][51][52][53]. Indocyanine green (ICG) is one of the NIR fluorophores approved by the United States Food and Drug Administration (FDA) for some clinical use [49].…”

Currently available and experimental dyes for intraoperative near-infrared fluorescence imaging of the ureters: a systematic review

“…One study reported on the synthesis of UreterGlow [ 38 ]. IV injection (0.1 mg/kg) allows ureter visualization after 15 min for at least 2 h in pigs.…”

Near-infrared fluorescent molecular probes for imaging and diagnosis of nephro-urological diseases

“…Although aforementioned uorophores have been tested in a swine model, such studies are insufficient for clinical translation because the ureteral wall of pigs is both thinner and covered by less fat relative to humans. 71 (iii) Bladder: nanoformulation is generally used to convert intrinsically hydrophobic compounds into water-soluble nanoparticles. Such nanoprecipitation oen produces nanoparticles with the size from several ten nanometers to several hundred nanometers, 22 which are larger than the threshold of kidney ltration ($5.5 nm) and are difficult to excrete from kidney to bladder.…”

“…8c and d ). 71 UreterGlow exhibited an excitation and emission peak at 800 nm and 830 nm in PBS, respectively. It was determined to be highly stable in a pH range from 3.5 to 10, indicating it could be feasible for ureter imaging in vivo .…”