Significance Cancer is a major public health challenge that threatens human health and social development. Cancer incidence has exhibited a high growth trend worldwide, where 19.3 million new cases and approximately ten million related deaths were reported in 2020. Surgery is currently the first choice for treating solid tumors. Complete resection of the tumor is very important for prognosis and long-term survival of patients, whereby the survival rate after complete resection is 2-5 times higher than that after partial resection. However, the global average recurrence rate after tumor resection is still as high as 40%, resulting in 80% mortality in cancer-recurring cases. The main reasons for high postoperative recurrence rate include various key factors, including residual tumor margins caused by incomplete operation, residual micro-metastases or small lesions that are difficult to find during the operation, and micro-metastasis of lymph nodes. In clinical diagnosis before surgery, medical doctors use ultrasound imaging (US), computed X-ray tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), and other imaging methods for accurate tumor localization and morphological confirmation. However, during the operation, doctors can only determine the tumor boundary, residual lesions, and micro-metastatic lesions via limited means of naked-eye observation, palpation, and ultrasound examination. This can easily cause residual surgical margin or missed detection of small lesions during the operation, leading to a high rate of recurrence and metastasis after operation, as well as impacting the prognosis and long-term survival of patients. Thus, there is an urgent need to develop a real-time operation guiding technology without radiation and with high sensitivity, high resolution, and high contrast, which can accurately determine the tumor boundary, display the important duct structure, and detect micro-metastatic lesions during the operation. The fluorescence surgical navigation technology arises at the historic moment. Progress Fluorescence surgical navigation technology relies on a fluorescence imaging system and fluorescence probe to display focus information more accurately during operation. Presently, the fluorescence surgical navigation probes approved for clinical use include sodium fluorescein, 5-aminolevulinic acid (5-ALA), methylene blue (MB), and indocyanine green (ICG). However, the excitation and emission wavelengths of sodium fluorescein, 5-ALA, and MB locate in the 400-700 nm region. Consequently, the penetration depth is very limited, only tissue surface imaging can be performed, and the signal-to-noise ratio is also very low. Therefore, applying these probes in surgical navigation has been gradually eliminated in the clinic. To achieve deeper tissue penetration depth and conduct more accurate fluorescence imaging and surgical navigation, it is necessary to use near-infrared fluorescence probes with longer excitation and emission wavelengths. Indocyanine green ( ICG) is presently the most widely used and thoroughly studied near-infrared fluorescence molecular probe in fluorescence surgical navigation. ICG, which Kodak Laboratory first synthesized in Japan in 1955, can be excited by light at the wavelength of 750-810 nm and emit near-infrared light with the maximum wavelength of 830 nm [Fig. 3( a)]. The near-infrared fluorescence surgical navigation technique based on ICG has been widely used in the field of tumor surgery, and many clinical studies have confirmed its clinical value in the aspects of surgical thoroughness, surgical convenience, recurrence-free survival, and total survival. However, NIR-I fluorescence imaging still has a series of inherent bottlenecks, such as low penetration depth, high background signal, poor signal-to-noise ratio, etc. Recently, with the deepening of NIR-II fluorescence imaging research and the rapid development of nanotechnology, a series of small organic molecules, organic nano-probes and inorganic nano-probes have been developed and used as NIR-II fluorescence molecular probes in the fields of fluorescence imaging and surgical navigation. In 2018, Professor Oliver T. Bruns and colleagues found that the tail band emission of ICG extended to NIR-II, although its emission spectrum reached its peak at NIR-I. In 2020, Tian Jie and colleagues completed a human trial of surgical resection of liver cancer guided by ICG NIR-II fluorescence imaging, and confirmed in clinical practice that this technique can find small and metastatic lesions of liver cancer that other imaging modes cannot detect, and significantly improves the thoroughness and accuracy of surgical resection [Fig. 4( b) - (c)]. Inorganic quantum dots (Ag2S) show good results in in vivo fluorescence imaging of NIR-II region. In situ and real-time imaging, high tissue penetration depth (>1.5 cm) , high time resolution (similar to 30 ms), and high spatial resolution (similar to 25 mu m) are obtained in in vivo level of small animals. Simultaneously, Ag2S quantum dots can significantly improve the accuracy and thoroughness of surgical resection in NIR-II fluorescence surgical navigation of gliomas [Fig. 8( a)] and breast cancer metastases [Fig. 8( b), (d)]. Additionally, there are several organic and inorganic nanoparticles with excellent performances in NIR-II fluorescence imaging, showing great potential in fluorescence surgical navigation application, such as donor-receptor organic small-molecule fluorescence probes, organic polymer nano-probes, aggregation-induced emission fluorescence probes, and rare earth nano-probes. Conclusions and Prospects The rapid development of NIR-II fluorescence imaging technology provides new opportunities and means to solve the bottleneck problems in surgical navigation. With the cross-integration of material science, chemistry, and optics, a series of NIR-II fluorescence surgical navigation molecular probes have been developed. However, these works are still in the stage of basic research and animal experiments. Clinical translation of these probes, which requires combined efforts from enterprises, hospitals, clinicians, and basic researchers, is yet to be promoted. Encouragingly, some preclinical studies have shown good clinical prospects, and laid a foundation for further promoting the translation and application of NIR-II fluorescence surgery navigation. This will provide a strong guarantee for precision surgery in the future.
