Real-Time Simultaneous Near-Infrared Fluorescence Imaging of Bile Duct and Arterial Anatomy

doi:10.1016/j.jss.2011.06.027

Journal of Surgical Research

Volume 176, Issue 1, July 2012, Pages 7-13

https://doi.org/10.1016/j.jss.2011.06.027 Get rights and content

Background

We hypothesized that two independent wavelengths of near-infrared (NIR) fluorescent light could be used to identify bile ducts and hepatic arteries simultaneously, and intraoperatively.

Materials and Methods

Three different combinations of 700 and 800 nm fluorescent contrast agents specific for bile ducts and arteries were injected into N = 10 35-kg female Yorkshire pigs intravenously. Combination 1 (C-1) was methylene blue (MB) for arterial imaging and indocyanine green (ICG) for bile duct imaging. Combination 2 (C-2) was ICG for arterial imaging and MB for bile duct imaging. Combination 3 (C-3) was a newly developed, zwitterionic NIR fluorophore ZW800-1 for arterial imaging and MB for bile duct imaging. Open and minimally invasive surgeries were imaged using the fluorescence-assisted resection and exploration (FLARE) surgical imaging system and minimally invasive FLARE (m-FLARE) imaging systems, respectively.

Results

Although the desired bile duct and arterial anatomy could be imaged with contrast-to-background ratios (CBRs) ≥ 6 using all three combinations, each one differed significantly in terms of repetition and prolonged imaging. ICG injection resulted in high CBR of the liver and common bile duct (CBD) and prolonged imaging time (120 min) of the CBD (C-1). However, because ICG also resulted in high background of liver and CBD relative to arteries, ICG produced a lower arterial CBR (C-2) at some time points. C-3 provided the best overall performance, although C-2, which is clinically available, did enable effective laparoscopy.

Conclusions

We demonstrate that dual-channel NIR fluorescence imaging provides simultaneous, real-time, and high resolution identification of bile ducts and hepatic arteries during biliary tract surgery.

Introduction

Laparoscopic cholecystectomy (LC) is one of the most commonly performed hepatobiliary surgeries. However, in 2.6% to 10% of cases 1, 2, 3, 4, 5, 6, 7, conversion to open cholecystectomy (OC) is necessary, typically due to unexpected anatomy (14.8%–74.5%), severe inflammation or adhesion (27.7%–62%), hemorrhage (3.2%–33.3%), or bile duct injury (4.3%–12%) 3, 4, 5, 6. We have previously described the use of intraoperative near-infrared (NIR) fluorescence imaging to visualize the extrahepatic bile ducts, as well as sites of their obstruction or injury, in real time 8, 9.

Due to possible anatomical variations of the hepatic artery, unexpected laceration and hemorrhage is also a major complication of LC 10, 11, 12, 13. Although typically not life-threatening, hemorrhage often leads to conversion to OC, and a prolonged hospital stay and convalescence [14]. Additionally, if concomitant hepatic arterial injury and bile duct injury has occurred, liver necrosis, abscess, or stenosis of the bile duct may result after reconstruction 13, 15, 16.

Presently, computed tomography (CT) and magnetic resonance (MR) angiography provide excellent visualization of the hepatic artery anatomy during preoperative planning 17, 18. Nevertheless, these studies are costly and do not provide intraoperative assessment and reassessment. The enabling technology for our studies is the fluorescence-assisted resection and exploration (FLARE) optical imaging platform and the minimally invasive FLARE system (m-FLARE), which provide simultaneous acquisition of color video and two independent channels of NIR fluorescence, one centered at 700 nm, and the other at 800 nm.

We hypothesized that by combining FLARE and m-FLARE with anatomy-specific NIR fluorescent contrast agents, most of which are already clinically available, both the bile duct and hepatic artery anatomy could be visualized in real-time intraoperatively, simultaneously, and with high resolution, during both OC and LC.

Section snippets

NIR Fluorescent Contrast Agents for Bile Duct and Hepatic Artery Imaging

Methylene blue (MB) was purchased from Taylor Pharmaceuticals (Decatur, IL) as a 10-mg/mL (31.3-mM) stock solution. Indocyanine green (ICG) was purchased from Akorn Inc., (Decatur, IL) and resuspended with the supplied diluent to yield a 2.5-mg/mL (3.2-mM) stock solution. ZW800-1 was synthesized from small molecule reactants [19] and resuspended in saline as a 2.5-mg/ml (2.2-mM) stock solution.

Optical Property Measurements

Optical properties of NIR fluorescent contrast agents were measured in swine bile or 100% fetal bovine

Optical Properties of Near-Infrared Fluorescent Contrast Agents

The chemical structure, absorbance, and fluorescence curves for all fluorescent contrast agents are shown in Fig. 1. Table 2 details the optical properties of each agent in FBS and swine bile. To summarize, MB exhibits fluorescence properties compatible with NIR fluorescence channel #1 (700 nm) of the FLARE and m-FLARE imaging systems, and ICG and ZW800-1 exhibits fluorescence properties compatible with NIR fluorescence channel #2 (800 nm) of the FLARE and m-FLARE imaging systems.

Dual-Channel NIR Fluorescence Imaging of Bile Ducts and Hepatic Arteries During Open Surgery

MB and ICG

Discussion

In this study, we explored the use of two independent wavelengths of invisible NIR fluorescent light to provide simultaneous contrast of extrahepatic bile ducts and hepatic arteries during hepatobiliary surgery. To maximize the likelihood of future clinical translation, two of the NIR fluorescent contrast agent combinations chosen (C-1 and C-2) were composed of injectable agents already FDA-approved for other indications. The third contrast agent combination was composed of a new, improved

Acknowledgments

This study was supported by the following grants from the National Institutes of Health: NCI BRP grant R01-CA-115296 (J.V.F.) and NIBIB grant R01-EB-010022 (J.V.F. and H.S.C.). All FLARE^TM technology is owned by Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School. As inventor, Dr. Frangioni may someday receive royalties if products are commercialized. Dr. Frangioni is the founder and unpaid director of The FLARE Foundation, a non-profit organization focused on

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IV

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Bioengineering/NanomedicineReal-Time Simultaneous Near-Infrared Fluorescence Imaging of Bile Duct and Arterial Anatomy

Background

Materials and Methods

Results

Conclusions

Introduction

Section snippets

NIR Fluorescent Contrast Agents for Bile Duct and Hepatic Artery Imaging

Optical Property Measurements

Optical Properties of Near-Infrared Fluorescent Contrast Agents

Dual-Channel NIR Fluorescence Imaging of Bile Ducts and Hepatic Arteries During Open Surgery

Discussion

Acknowledgments

Am J Surg

Surgery

J Gastrointest Surg

Surgery

Surgery

J Gastrointest Surg

Surgery

J Luminesc

Surgery

J Thorac Cardiovasc Surg

Risk factors for conversion of laparoscopic cholecystectomy to open cholecystectomy

Surg Endosc

Conversion of elective laparoscopic to open cholecystectomy between 1993 and 2004

Br J Surg

Risk factors affecting conversion in patients undergoing laparoscopic cholecystectomy

ANZ J Surg

Bioengineering/Nanomedicine
Real-Time Simultaneous Near-Infrared Fluorescence Imaging of Bile Duct and Arterial Anatomy