Robotics SIG Tech Update: IS-001

IS-001 is an IV administered, renally metabolized, ureteral fluorescent dye.  IS-001 is currently in phase 3 preclinical trials, and can potentially reduce the risk of ureteral injury during gynecology and general surgery procedures. Ureteral injury, is a well-known and serious complication of gynecological and colorectal surgery that frequently goes unrecognized intraoperatively.   Iatrogenic ureteral injury occurs during laparoscopic gynecologic surgery with an incidence of 0.03-2.5% with injury rates for high-risk reconstructive pelvic surgeries up to 11%. Only about one-third of ureteral injuries are detected intraoperatively, leading to delayed diagnosis and treatment, frequently with deleterious consequences for the patient.  iatrogenic ureteral injury imposes a significant burden in terms of morbidity and increased health care costs and represents a medicolegal challenge for physicians.  Sequelae can include fistula and loss of the affected kidney.

Risk factors for ureteral injury include the ureter’s close proximity to the gynecologic organs within the pelvis, distortion of normal anatomic relationships by pathology like endometriosis, and surgeon experience. Avoidance of ureteral injury depends upon clear understanding of anatomic relationships and meticulous surgical technique, including careful dissection of pelvic structures.

Visualization of the ureter during surgery can help prevent ureteral injury and reduce subsequent complications. Current methods for intraoperative ureter visualization including ureteral stent placement with palpation, illuminated catheters, X-ray fluoroscopy with iodine contrast or dye injections come with significant additional risk to the patient, operating room workflow issues or lack the required sensitivity.

Intraoperative near-infrared (NIR) fluorescence imaging in conjunction with the application of exogenous contrast agents is a promising technique that offers real-time visual information about specific tissues and anatomical structures, without the use of ionizing radiation or the need to stain or alter the visible surgical field. Invisible to the human eye, NIR light between 700 and 900 nm wavelengths has important advantages for intraoperative imaging including low absorption, low scatter and low auto-fluorescence yet allows relatively deep tissue penetration.

The use of fluorescent contrast dyes in conjunction with near-infrared imaging is well-known in medicine.  IS-001 is an investigational small molecule imaging agent that is fluorescent at exposure to approximately 800 nm wavelength NIR light. IS-001 belongs to a class of dyes called cyanines, which were first synthesized in the early 1900’s with the intent of increasing the number of wavelengths used in early photographic film to create more realistic pictures. Indocyanine green (ICG), the most common cyanine dye administered to humans, was originally used to evaluate cardiac and liver function in the United States in the late 1950’s. While several dyes such as Cy3¹⁶, Cy5¹⁷, Cy5.5¹⁸, Cy7¹⁹, the Alexafluor and Fluoprobe families of dyes have been used for decades in the research community, few have undergone human testing.

The only two clinically approved NIR fluorophores currently available are ICG and methylene blue (MB). Intravenous ICG is rapidly cleared by the hepatobiliary system and has no detectable urinary excretion, therefore cannot be readily used for ureter visualization without retrograde infusion. Intravenous MB is excreted renally and displays moderate fluorescence with peak excitation at 668 nm, however, MB has a relatively low extinction coefficient and quantum yield..

NIR fluorescence imaging in conjunction with the fluorescent dye IS-001, which has a peak excitation near 800 nm, higher extinction coefficient, and quantum yield than MB, can provide better penetrative depth and stronger contrast for more sensitive and accurate ureter visualization. IS-001 is renally excreted and in pre-clinical pharmacology studies provided distinct ureter NIR fluorescence over a 30 to 120-minute time-course post IV injection at the proposed clinical doses.  In addition, the excitation and emission spectra of IS-001 is compatible with clinically available robotic and laparoscopic imaging systems.

Image: Ureter IS-001

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