Evaluation of a novel dye for near‐infrared fluorescence delineation of the ureters during laparoscopy (original) (raw)
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Journal of Laparoendoscopic & Advanced Surgical Techniques, 2020
Background: Iatrogenic ureteral injury is one of the feared complications during intrapelvic surgery. There are limited data on the use of novel near-infrared fluorescence (NIRF) imaging dyes for the purpose of noninvasive ureteral visualization in robot-assisted laparoscopic surgery (RALS). In this study, we evaluated the feasibility of NIRF imaging of the ureter using the IRDye Ò 800BK dye as the fluorescence dye and a robotic platform with FireflyÔ technology as an imaging system. Materials and Methods: An intravenous dose of 0.15 mg/kg was administered in 3 pigs and NIRF imaging was performed for a total duration of 60 minutes. The intraoperative video recordings were analyzed to determine fluorescence intensities and the target-to-background ratio (TBR). Results: In all included animals, a clear delineation of the ureter was achieved from 5 minutes after dye administration until the end of the study. During this time period, the ureter was clearly distinguishable from its surroundings and no statistical differences in TBR were observed. Conclusion: The IRDye 800BK dye, a novel NIRF dye currently undergoing clinical translation, is a promising contrast agent used for noninvasive ureteral imaging, which has the potential to be valuable during RALS.
Molecules
The inadvertent severing of a ureter during surgery occurs in as many as 4.5% of colorectal surgeries. To help prevent this issue, several near-infrared (NIR) dyes have been developed to assist surgeons with identifying ureter location. However, the majority of these dyes exhibit at least some issue that precludes their widespread usage such as high levels of uptake in other tissues, overlapping emission wavelengths with other NIR dyes used for other fluorescence-guided surgeries, and/or rapid excretion times through the ureters. To overcome these limitations, we have synthesized and characterized the spectral properties and biodistribution of a new series of PEGylated UreterGlow derivatives. The most promising dye, UreterGlow-11 was shown to almost exclusively excrete through the kidneys/ureters with detectable fluorescence observed for at least 12 h. Additionally, while the excitation wavelength is similar to that of other NIR dyes used for cancer resections, the emission is shift...
Fluorescence Ureteral Visualization in Human Laparoscopic Colorectal Surgery Using Methylene Blue
Journal of Laparoendoscopic & Advanced Surgical Techniques, 2016
Background: Ureteral injury during laparoscopic surgery is rare, but when it occurs, it can be a serious problem. Near-infrared fluorescence (NIRF) with methylene blue (MB) administration is a promising technique for easier and potentially earlier intraoperative visualization of the ureter. Aim of this prospective study was to assess the feasibility of NIRF imaging of the ureter during laparoscopic colorectal surgery, using MB. Methods: Patients undergoing laparoscopic colorectal surgery were included and received intravenous injection of MB preoperatively. The ureter was visualized using a laparoscope, which offered both conventional and fluorescence imaging. Intraoperative recognition of the ureter was registered. The precision of ureter distinction with MB imaging was compared to the conventional laparoscopic view. Results: Ten patients were included. All procedures were initially performed using a laparoscopic approach. Dose per injection ranged between 0.125 mg/kg and 1.0 mg/kg bodyweight. There were no adverse effects attributable to MB administration. The ureter was successfully detected in five patients, with highest contrast between ureter and surrounding tissue at an administered dose of 0.75-1.0 mg/kg. The fluorescent signal was only picked up after the ureter was already visible in the conventional white light mode. Conclusion: Ureteral fluorescence imaging using MB proved to be safe and feasible. However, the present technique does not provide practical advantage over conventional laparoscopic imaging for identification of the ureter during laparoscopic colorectal surgery. Future research is necessary to explore more extensive dose finding, alternative fluorescent dyes, or improvement of the imaging system to make this application clinically beneficial.
Ureter Identification In an Inflammatory Pig Model Using a Novel Near‐Infrared Fluorescent Dye
Lasers in Surgery and Medicine, 2019
Background and Objectives:Ureters are at risk of injury in settings of inflammation and distorted anatomy. The use of a fluorescent dye can improve intraoperative ureteral identification without the need for any additional invasive procedures. Our team has previously described the development of a preclinical ureter-specific dye, UL-766, tested in a rat model. Here, we present the use of the fluorescent dye during laparoscopy to assist in ureteral identification in a swine model with an inflamed abdomen; the results of this study serve as proof of feasibility for use in the setting of tissue edema and erythema.Study Design/Materials and Methods:With institutional approval, two 20–25 kg pigs underwent abdominal surgery with the use of a Food and Drug Administration-approved fluorescence laparoscopic system. Using standard laparoscopy, inflammation was induced with sharp and blunt dissection and irritation was induced with gauze. The animals were allowed to recover and returned to the operating room after 7 days. Images of the inflamed right retroperitoneum, with fluorescence imaging, turned on, were taken before and after intravenous injection of the novel fluorescent dye at 120 μg/kg. The time until fluorescence visualization of the ureters was measured, and the fluorescent signal was measured for up to 4 hours from the time of the initial dye injection. Partial and complete transection of ureteral injuries was made by scissors and monitored under both standard video and fluorescence laparoscopy.Results:Inflammation reduced the certainty of ureter identification by white light alone. Despite surrounding tissue erythema and edema, ureteral visualization under fluorescence laparoscopy was achieved within 5–10 minutes after dye injection. The fluorescent signal remained visible for at least 4 hours after injection, and the fluorescent dye showed a partial ureteral injury that would not have been observed under standard laparoscopy.Conclusions:UL-766 is a preclinical fluorescent dye useful for the intraoperative identification of the ureters and ureteral injuries in an inflamed abdomen. With the acquisition of additional preclinical data, this novel dye can be a valuable tool during laparoscopic abdominal and pelvic surgeries. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
Intraoperative ureter identification with a novel fluorescent catheter
Scientific Reports
Iatrogenic ureteral injuries (IUI) occur in 0.5–1.3% of cases during abdominal surgery. If not recognized intraoperatively, IUI increase morbidity/mortality. A universally accepted method to prevent IUI is lacking. Near-infrared fluorescent imaging (NIRF), penetrating deeper than normal light within the tissue, might be useful, therefore ureter visualization combining NIRF with special dyes (i.e. IRDye 800BK) is promising. Aim of this work is to evaluate the detection of ureters using stents coated with a novel biocompatible fluorescent material (NICE: near-infrared coating of equipment), during laparoscopy. female pigs underwent placement of NICE-coated stents (NS). NIRF was performed, and fluorescence intensity (FI) was computed. Successively, 0.15 mg/kg of IRDye 800BK was administered intravenously, and FI was computed at different timepoints. Ureter visualization using NS only was further assessed in a human cadaver. Both methods allowed in vivo ureter visualization, with equal ...
Real-time, near-infrared, fluorescence-guided identification of the ureters using methylene blue
Surgery, 2010
Background-The aim of this study was to determine whether the invisible near-infrared (NIR) fluorescence properties of methylene blue (MB), a dye already FDA-approved for other indications, could be exploited for real-time, intraoperative identification of the ureters. Methods-The optical properties of MB were quantified in vitro. Open surgery and laparoscopic NIR fluorescence imaging systems were employed. Yorkshire pigs were injected intravenously with: 0.1 mg/kg MB (n = 8), 10 mg furosemide followed by 0.1 mg/kg MB (n = 6), or 0.5 mg/kg MB (n = 6). The contrast-to-background ratio (CBR) of the kidney and ureters, and MB concentration in urine, were quantified. Results-Peak MB absorbance, emission, and intensity in urine occurred at 668 nm, 688 nm, and 20 μM, respectively. After intravenous injection, doses as low as 0.1 mg/kg MB provided prolonged imaging of the ureters, and a dose of 0.5 mg/kg provided statistically significant improvement of CBR. Pre-injection of furosemide increased urine volume but did not improve CBR. Laparoscopic identification of the ureter using MB NIR fluorescence was demonstrated. Conclusions-Ureteral imaging using MB NIR fluorescence provides sensitive, real-time, intraoperative identification of the ureters during open and laparoscopic surgeries.
Improved urethral fluorescence during low rectal surgery: a new dye and a new method
Techniques in Coloproctology, 2018
Background The aim of this study was to demonstrate highlighting of the urethra during surgery through the use of two different methods: a new near-infrared fluorophore IRDye800BK, and indocyanine green (ICG) mixed with silicone. Methods Male cadavers from the department of anatomy at the University of Oxford were used to visualise the urethra during near-infrared fluorescence excitation. To assess IRDye800BK, a perineal incision was utilised after infiltrating the urethra directly with an IRDye800BK solution mixed with Instillagel. ICG-silicone was assessed when the urethra was purposely exposed as part of a simulated transanal total mesorectal dissection. ICG was previously mixed with ethanol and silicone and left to set in a Foley catheter. Fluorescence was visualised using an in-house manufactured fluorescence-enabled laparoscopic system. Results IRDye800BK demonstrated excellent penetration and visualisation of the urethra under fluorescence at an estimated tissue depth of 2 cm. An ICG-silicone catheter demonstrated excellent fluorescence without leaving any residual solution behind in the urethra after its removal. Conclusions The newly described ICG-silicone method opens up the possibility of new technologies in this area of fluorescence guided surgery. IRDye800BK is a promising alternative to ICG in visualising the urethra using fluorescence imaging. Its greater depth of penetration may allow earlier detection of the urethra during surgery and prevent wrong plane surgery sooner.
Real-Time Intraoperative Ureteral Guidance Using Invisible Near-Infrared Fluorescence
Journal of Urology, 2007
Purpose-Invisible near-infrared (NIR) light is safe and penetrates relatively deeply through tissue and blood without altering the surgical field. Our hypothesis is that NIR fluorescence imaging will enable visualization of ureteral anatomy and flow, intraoperatively and in real-time. Materials and Methods-The carboxylic acid form of NIR fluorophore IRDye™800CW (CW800-CA) was injected intravenously and its renal clearance kinetics and imaging performance quantified in 350 g rats and 35 kg pigs. High-performance liquid chromatography (HPLC) and electrospray-time of flight (ES-TOF) mass spectrometry were used to characterize CW800-CA metabolism in the urine. The clinically available NIR fluorophore ICG was also used via retrograde injection into the ureter. Using both NIR fluorophores, ureters were imaged under conditions of steady state, intraluminal foreign bodies, and injury. Results-In rat models, the highest signal-to-background ratio (SBR) for visualization occurred after intravenous (IV) injection of 7.5 μg/kg CW800-CA, with values of ≥ 4.0 and ≥ 2.3 at 10 min and 30 min, respectively. In pig models, 7.5 μg/kg CW800-CA clearly visualized normal ureter and intraluminal foreign bodies as small as 2.5 mm in diameter. Retrograde injection of 10 μM ICG also permitted detection of normal ureter and pinpointed urine leakage caused by injury. ES-TOF mass spectrometry, and absorbance and fluorescence spectral analysis, confirmed that the fluorescent material in urine was chemically identical to CW800-CA. Conclusions-A convenient IV injection of CW800-CA, or direct injection of ICG, permits high sensitivity visualization of ureters under steady state and abnormal conditions using invisible light.
Nature Communications, 2019
Iatrogenic injury of the ureters is a feared complication of abdominal surgery. Zwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, which leads to renal-exclusive clearance and ultralow non-specific background binding. Such molecules could solve the ureter mapping problem by providing realtime anatomic and functional imaging, even through intact peritoneum. Here we present the first-inhuman experience of this chemical class, as well as the efficacy study in patients undergoing laparoscopic abdominopelvic surgery. The zwitterionic near-infrared fluorophore ZW800-1 is safe, has pharmacokinetic properties consistent with an ideal blood pool agent, and rapid elimination into urine after a single low-dose intravenous injection. Visualization of structure and function of the ureters starts within minutes after ZW800-1 injection and lasts several hours. Zwitterionic near-infrared fluorophores add value during laparoscopic abdominopelvic surgeries and could potentially decrease iatrogenic urethral injury. Moreover, ZW800-1 is engineered for one-step covalent conjugatability, creating possibilities for developing novel targeted ligands.
Surgical Endoscopy
Background Intraoperative ureteral injury, a serious complication of abdominopelvic surgeries, can be avoided through ureter visualization. Near-infrared fluorescence imaging offers real-time anatomical visualization of ureters during surgery. Pudexacianinium (ASP5354) chloride is an indocyanine green derivative under investigation for intraoperative ureter visualization during colorectal or gynecologic surgery in adult and pediatric patients. Methods In this phase 2 study (NCT04238481), adults undergoing laparoscopic colorectal surgery were randomized to receive one intravenous dose of pudexacianinium 0.3 mg, 1.0 mg, or 3.0 mg. The primary endpoint was successful intraoperative ureter visualization, defined as observation of ureter fluorescence 30 min after pudexacianinium administration and at end of surgery. Safety and pharmacokinetics were also assessed. Results Participants received pudexacianinium 0.3 mg (n = 3), 1.0 mg (n = 6), or 3.0 mg (n = 3). Most participants were female...