The Evolution of Fluorescence-Guided Surgery

Abstract

There has been continual development of fluorescent agents, imaging systems, and their applications over the past several decades. With the recent FDA approvals of 5-aminolevulinic acid, hexaminolevulinate, and pafolacianine, much of the potential that fluorescence offers for image-guided oncologic surgery is now being actualized. In this article, we review the evolution of fluorescence-guided surgery, highlight the milestones which have contributed to successful clinical translation, and examine the future of targeted fluorescence imaging.

Keywords: Fluorescence-guided surgery; Molecular imaging; Oncology.

Fig. 1

Milestones in the evolution of fluorescence-guided surgery. Fluorescein was initially discovered in the middle of the nineteenth century, but ICG became the first FDA-approved fluorescent dye. Subsequent clearance of the Novodaq SPY imaging system paved the way for device development, and a growing clinical experience has provided the foundation for FDA approval of fluorescent agents for intraoperative use.

Fig. 2

ICG angiography in microvascular reconstructive surgery. A Identification of a perforator is crucial during an anterolateral thigh free flap harvest but can be challenging with reflected light visualization only. B The perforator can be readily identified (arrow) through its course in muscle by NIR imaging. ICG angiography is also useful in assessment of flow through a microvascular anastomosis. C By reflected light imaging, venous flow (arrow) is difficult to ascertain. D By ICG angiography and SPY NIR imaging, the artery is observed to have adequate flow (arrowhead), but the venous flow (arrow) is insufficient (D). E Restoration of venous flow subsequently confirmed by ICG imaging (arrow).

Fig. 3

Assessment of tissue perfusion with SPY NIR imaging using intravenous ICG infusion. A The right lingual artery was ligated during an oncologic head and neck surgery. Vascularity to the right hemitongue (arrows) appears normal on reflected light images. B However, a complete absence of vascular flow is apparent on ICG angiography (B).

Fig. 4

Sentinel lymph node identification using ICG. A A total of 5 mg of ICG was injected submucosally around a left tongue squamous cell carcinoma (arrowheads). B The neck was subsequently imaged using a handheld SPY NIR imaging system, and a submental lymph node (arrowhead) was identified by fluorescence.

Fig. 5

Fluorescence-guided surgery workflow. First, the fluorescence tracer is venously infused preoperatively. During surgery, in vivo open-field camera systems are used to visualize tumor tissue, and to assess adjacent tissue and the wound bed. After the tumor resection, the tumor specimen (i.e., the tumor with a cuff of healthy surrounding tissue) is imaged within a closed-field ex vivo fashion. Thereafter, during histological assessment, the fluorescence is traced within the tumor specimen to ascertain if fluorescence areas correspond with tumor areas.

Fig. 6

Activatable fluorescence probes. A Enzyme-activable probes allow for fluorescence signal to emit only in the presence of specific enzymatic activity. B An alternative strategy allows for fluorescence activation after incorporation of the agent by surface molecule binding and lysosome phagocytosis by the targeted cancer cell.

Fig. 7

pH induced fluorescence agent activation. The agent is in quenched state within a micelle in a pH neutral environment. As the micelle reaches the acidic tumor environment, it dissolves and the agent starts to emit its photons when excitation takes place.