JIMT

Indocyanine green (ICG), a water-soluble fluorescent dye, has been widely applied in medical contexts since its development in 1955 and subsequent Food and Drug Administration (FDA) approval in 1959¹-⁴. Known for its fluorescent properties within the near-infrared (NIR) spectrum (750–950 nm)³, ICG is primarily bound to plasma proteins and is metabolized and excreted by the liver, with its half-life varying based on liver functionality⁴-⁶. The introduction of ICG in medical procedures, especially in fluorescence-guided surgery, represents a significant advancement in medical imaging and intraoperative navigation⁷-⁹.

Revolutionizing various surgical fields, ICG fluorescence-guided surgery enhances the visualization of anatomical structures, thus facilitating precise surgical navigation³,⁹. The utility of ICG in abdominal surgery is extensive, aiding in tasks such as evaluating perfusion, delineating extrahepatic bile duct anatomy, navigating lymph nodes, and assisting with liver surgery⁷-¹⁰. This technique is particularly valuable in colorectal surgery for intraoperative guidance, where it is applied in a range of procedures from assessing perfusion to identifying hepatic and peritoneal metastases²-⁵. Although research is still ongoing, early results are promising, especially for reducing anastomotic leaks in colorectal surgery¹,².

In gastrointestinal (GI) cancer surgery, accurate tumor localization is crucial, particularly for early stage cancers for which minimally invasive techniques are the norm. Traditional localization methods, such as endoscopic tattooing and metallic clipping, present challenges, including control issues in dye spreading and clip visibility¹¹-¹³. ICG fluorescence imaging, known for its minimal toxicity and cost-effectiveness, has significant advantages. Notably, it enhances the visualization of tumor location, particularly those of a small size that are challenging to detect with standard radiological tools¹³,¹⁴.

This study aimed to evaluate the feasibility and effectiveness of ICG-coated clips for GI tumor localization in minimally invasive procedures using animal models.

In this study, we used female Yucatan miniature pigs that were about 16 months old (obtained from Optipharm Co., Ltd.), with weights ranging from 25 to 30 kg (29.0 kg for the first pig, 29.8 kg for the second). Prior to surgery, the pigs were fasted for 48 hours and allowed only water. After this fasting period, they were moved to the laboratory where they received general anesthesia along with respiratory support through a ventilator. All animal experiments were carried out in approved facilities following standard animal experiment guidelines. The study protocol was approved by the Institutional Animal Care and Use Committee (BIOSTEP IACUC 24-HB-0179; March 5, 2024).

The ICG-coated clips used in this study were VITTZ clips from KOSCO Intercare Co., Ltd. The clips were not approved by the Korea Food and Drug Administration and were used exclusively for experimental research purposes. Surgical visualization of the ICG-coated clip was facilitated using Stryker 1588 and 1688 Advanced Imaging Modalities (AIM) Platforms with SPY fluorescence technology developed by Stryker Corporation.

For the stomach procedures, a gastroscope was used to mark an imagined tumor location in the stomach, around which four fluorescent clips were placed in a circle. After placing the clips, we removed any remaining air from the stomach using a gastroscope and withdrew the endoscope. We inserted laparoscopic ports (an 11 mm port for the camera and a 5 mm port for the instruments) and filled the abdominal cavity with carbon dioxide. We attempted to detect the clip locations using the ICG imaging system and checked these locations endoscopically for accurate detection.

During the colon procedures, we inserted a colonoscope through the anus to a site approximately 25–30 cm above the anal opening, which was assumed to be the tumor site, and applied three ICG-coated clips in different directions just below the tumor area. Subsequently, we removed the endoscope and confirmed the clip locations using ICG laparoscopy, following same steps as before. This process was repeated in the second pig.

The process of assessing clip location using the ICG laparoscopic system was conducted in two steps. Initially, in the first pig, the clip location was identified using the Endoscopic Near-Infrared Visualization (ENV) mode, which displays green NIR fluorescence on a grayscale image. In this mode, four bright illuminated spots were observed through the stomach wall at mid-body. Subsequently, in the overlay mode, which projects green NIR fluorescence onto a standard-color high-definition video image, bright illumination was detected in two of the four clips. However, the fluorescence intensity in overlay mode was notably weaker than that in ENV mode, as shown in Fig. 1. In the second pig, the fluorescent light from all four clips was easily discernible in both ENV and overlay modes.

Figure 1. Localization of a gastric lesion using indocyanine green (ICG)-coated clips in a porcine model. (A) Endoscopic placement of fluorescent clips around a simulated tumor site. (B) Endoscopic Near-Infrared Visualization (ENV) mode showing clip fluorescence through the gastric wall. (C) Overlay mode presenting clip fluorescence on color imaging.

While locating the clip in the large intestine, three exceptionally bright fluorescent lights were easily discernible in the sigmoid colon using both the ENV and overlay modes. As in the case of the stomach, the fluorescence brightness in the ENV mode was confirmed more clearly than in the overlay mode in the case of the colon (Fig. 2). These observations were also confirmed in the second pig.

Figure 2. Localization of a colonic lesion using indocyanine green (ICG)-coated clips in a porcine model. (A) Endoscopic application of three clips beneath a target tumor area. (B) Endoscopic Near-Infrared Visualization (ENV) mode highlighting intense fluorescence of clips in the sigmoid colon. (C) Overlay mode showing the clips’ fluorescence integrated with color imaging.

In this study, we confirmed that the use of ICG-coated clips for tumor localization during GI surgery is feasible and promising. These new approaches are noticeably different from existing methods traditionally used in the field. In this study, the feasibility of ICG-coated clips was investigated using the ICG laparoscopic system currently used in clinical practice, with a focus on its application in tumor localization during laparoscopic surgery. Our results were very clear, with ICG-coated clips providing improved visibility, which is critical for minimally invasive surgery in which traditional palpation methods are not possible. The implications of these findings are significant and are expected to revolutionize the way tumors are located during surgery, potentially improving surgical and minimally invasive surgical outcomes that consider patient function.

An important aspect of our study is that we depart from traditional methods such as endoscopic tattooing or endoscopic metal clipping, which are commonly used for localization¹⁴,¹⁵. Our method leverages the unique fluorescence properties of ICG to provide a noninvasive and highly accurate alternative for locating tumors, which is a safer and more accurate approach. This change is consistent with the growing trend in minimally invasive surgical procedures. Our study stands out methodologically because it integrates commercially available imaging platforms such as the Stryker 1588 and 1688 AIM platforms with SPY fluorescence technology. ICG-coated clips offer distinct advantages over various materials or fluorescent markers used in previous studies¹³,¹⁴. In addition, our method demonstrated compatibility with a wider range of surgical procedures including gastric or colon surgery. An analysis of our results compared to the existing literature indicates a significant improvement in the precise visualization of tumor localization. A level of precision in tumor site identification that was difficult to achieve in many previous studies can now be achieved owing to the improved visibility and ease of identification provided by ICG-coated clips.

However, our study has several limitations, such as the relatively small number of subjects, which may have affected the generalizability of the results. Another major limitation is that our results have not been validated using diverse imaging systems. Our results may differ for different systems, and these techniques may not be universally available. Additionally, the regulatory approval status of these ICG-coated clips is limited, as they have not yet been approved by regulatory agencies, such as the FDA. Moreover, as with any new technology, there is a potential for bias in its interpretation and application. Despite these limitations, the strengths of this study were noteworthy. Our innovative approach represents a groundbreaking leap forward in surgical technology, especially in minimally invasive surgeries. The excellent visibility of the clip greatly aids in accurate tumor localization. Moreover, our approach is consistent with the trend towards minimally invasive surgical techniques and is therefore highly relevant and timely in the context of modern surgical practice. The novelty of our study is the groundbreaking application of ICG-coated clips in GI surgery, which increases precision, and the introduction of a tumor localization method that is well suited to modern surgical practice.

Based on these findings, future studies on the application of ICG-coated clips in GI surgery should focus on several key areas. First, it would be beneficial to conduct comparative studies of ICG-coated clips and other fluorophores. This will help establish the specific advantages or potential limitations of ICG compared with alternative compounds, particularly its effects on tumor localization, biocompatibility, and long-term effects on the body. Further investigation into the use of various imaging systems with ICG-coated clips is important. These studies reveal how different imaging modalities affect the effectiveness of ICG-coated clips and may provide valuable insights for surgeons to select the most appropriate combination of dyes and imaging techniques for specific surgical applications. Moreover, translating these findings from animal models to human clinical trials is an important area of follow-up research. Future studies should focus on the challenges and nuances of applying these methods to human surgery, considering anatomical and physiological differences and the potential for diverse responses to ICG. It is also important to expand the scope of clinical trials to include broader and more diverse populations to ensure the generalizability of the results. A comprehensive cost-benefit analysis comparing ICG-coated clips with traditional tumor localization methods, along with clinical studies, could provide essential data for healthcare systems to evaluate the feasibility and economic viability of adopting this technology. Finally, continuing to explore the application of ICG in other types of surgery and various clinical conditions will likely greatly advance our understanding of the full potential of ICG in surgical oncology.

In conclusion, we anticipate that the use of ICG-coated clips in GI surgery could be an important advancement in surgical oncology. Although further research and clinical trials, particularly in human subjects, are essential for wider understanding and application, our findings demonstrate the potential for use in a new era of minimally invasive surgery.

None.

No potential conflict of interest relevant to this article was reported.

This work was supported by a grant from the National Research Foundation of Korea (NRF-2022R1A2C2009757) funded by the Ministry of Education, and the Korea Medical Device Development Fund (KMDF), grant number RS-2020-KD000107.