Seeing the invisible during surgery

For centuries, the major ‘imaging system’ used by surgeons has been the eyes and brain. Visible light (400–650 nm), however, penetrates only a few hundred micrometres into living tissue. Near-infrared (NIR) light (700–900 nm) is capable of penetrating from millimetres to centimetres into tissue promising improved visualization of buried objects, such as tumours, blood vessels and nerves, invisible to the human eye. NIR light also provides quantitation of physiological parameters, such as tissue oxygenation, which are otherwise difficult to measure1. NIR light is invisible to the human eye. Approximately two decades of work in engineering, physics and chemistry was required to lay the foundation for its practical use in human surgery. What has emerged are two ways to exploit NIR light to provide information during surgery. These are endogenous and exogenous contrast methods. The former uses the natural optical properties of normal and diseased tissues to provide contrast2, whereas the latter requires the administration of a chemical (contrast agent) to provide contrast3. As endogenous methods do not require administration of contrast agents, only device regulatory approval is necessary. This technique can provide valuable information, such as oxygenation measurements, over the entire surface of a tissue. For the first time, surgeons can visualize the oxygenation status of tissues on which they are operating. Endogenous methods can also potentially detect the presence of certain tumours, although they suffer from relatively low sensitivity and specificity, and some techniques require postprocessing that can add time to surgery. Exogenous methods typically employ administration of a chemical called a fluorophore, which simply absorbs one NIR wavelength and converts it to a different NIR wavelength. The property of fluorescence creates high contrast (high sensitivity) and, because fluorophores can be targeted to specific tumours and tissues, high specificity. The major drawback to exogenous methods is that each contrast agent needs separate regulatory approval, costly in terms of time and money, and administration long enough before the surgical procedure for adequate biodistribution, targeting and clearance to occur. Exogenous contrast agents can be administered intravenously, intraparenchymally, intraluminally or applied directly to a surface depending on the clinical application. A host of imaging systems from academic and industrial sources has been developed for the use of NIR light for surgical guidance4. These systems are designed for either endogenous or exogenous imaging applications, and can be subdivided further into those for open or minimally invasive surgery. It is likely that endogenous and exogenous imaging systems will find clinical roles almost simultaneously, but for vastly different clinical applications. Endogenous imaging systems will probably focus on the measurement of tissue oxygenation to provide the surgeon with an ‘image’ of the functional status of tissue5. This information might prove critical during neurosurgery, cardiac, burn, transplantation and bowel surgery, where unrecognized poor perfusion can lead to postoperative morbidity. Real-time information during surgery provides the surgeon with the opportunity to intervene and correct defects. Exogenous imaging systems will most likely focus on either oncological applications, such as sentinel lymph node (SLN) mapping6,7 or tumour resection8, or graft and vascular patency in cardiac9, plastic and reconstructive surgery10. Two drugs already approved for other indications—indocyanine green (ICG) and methylene blue—are, coincidentally, NIR fluorophores. Investigation of these agents is already occurring and future regulatory approval is at least feasible. Methylene blue absorbs and emits close to 700 nm, and ICG absorbs and emits close to 800 nm, so even two-wavelength applications can be envisioned. The largest volume of reported clinical data for exogenous imaging systems is in the area of SLN mapping using ICG as the contrast agent. This can visualize lymphatic channels transcutaneously, and has the potential to improve localization of the SLN so that only a small incision is necessary. Over the next decade, newer improved NIR fluorophores should become available clinically for SLN mapping, tumour resection and nerve avoidance. Methylene blue and ICG have limited targeting capabilities, and should be viewed only as ‘enablers’ of exogenous imaging systems until optimized NIR fluorophores clear regulatory hurdles. NIR light does not provide ‘X-ray’ vision. Although much better than visible light, NIR light is still scattered by living tissue, resulting in significant blurring and fading of objects buried deeper than a few millimetres. Although intense effort is being applied to newer techniques that will permit visualization of objects several centimetres below the surface, NIR-guided surgery is currently a surface technique, with excellent results for millimetre depths and relatively poor results for centimetre depths. For the surgeon, NIR-guided surgery promises improved outcomes and shorter operations. For the patient, it promises more personalized care. For the healthcare system, it promises lower costs through lower rates of postoperative complications. All of this is achieved with relatively low-cost technology, a small footprint in the operating room and no ionizing radiation. The next decade should provide a definitive answer whether this technology can deliver on one or more of these promises. This work was supported in part by the Dutch Cancer Society grant UL2010-4732 to A.L.V., and National Institutes of Health grants R01-CA-115296, R01-EB-005805, R01-EB-010022 and R01-EB-011523 to J.V.F. All FLARE™ technology is owned by Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School. As inventor, J.V.F. may receive royalties if products are commercialized. J.V.F. is the founder and unpaid director of the FLARE Foundation, a non-profit organization focused on promoting the dissemination of medical imaging technology for research and clinical use. A.L.V. declares no conflict of interest.