Advances in research on near-infrared optical imaging assisted surgery navigation
Yang Xiaofeng
In recent years, due to the continuous development of molecular imaging technology, high-resolution in vivo optical imaging, including near-infrared fluorescence imaging, has emerged following radionuclide imaging, positron emission tomography, single photon emission computed tomography and magnetic resonance imaging. Attention has been paid to the current imaging of sentinel lymph nodes, evaluation of patency after coronary artery bypass grafting, intraoperative identification of tumors, diagnosis of iatrogenic biliary tract injury, and imaging of lymphatic vessels and blood vessels, all using near-infrared fluorescence imaging technology, gradually formed The new medical technology, new medical equipment and new clinical disciplines of NIR-assisted surgical navigation are summarized as follows:
1 . Surgical treatment and image technology
During the surgical procedure, the surgeon mainly performs the resection of the tumor according to the color, texture and shape of the tissue, so the extent of the resection is related to the doctor's clinical experience and the pathological positive rate of the margin. Further research suggests that doctors can obtain real-time tumor anatomy images during surgery, which will improve the success rate of surgery, reduce surgical trauma, reduce medical expenses, avoid accidents, and promote patient recovery. Imaging devices such as radionuclide imaging, positron emission tomography, single photon emission computed tomography, and magnetic resonance imaging are unlikely to be moved to the surgical room, and these imaging devices have some damage to doctors and patients during operation, so Further exploration is needed, real-time imaging of the surgical procedure, convenient operation, non-invasive, and non-damaging techniques.
2. Biological characteristics of the near-infrared light [1]
The ability of light to penetrate tissue is related to the intensity of light absorbed by tissue, the characteristics of light waves, the structure of biological tissues, and its physicochemical properties. Near-Infrared (NIR ) of 650-900 nm is called "Tissue Optical Window". Compared with visible light, (N) biological tissue has the least effect of absorption and scattering of near-infrared light in this band. Compared with visible light, near-infrared light can penetrate deeper tissues; (2) due to the small autofluorescence of near-infrared light in this band, and the relatively high signal-to-background ratio (SBR), it is possible It becomes an important theory for real-time imaging in the future of clinical medicine.
3. The basic principle of near infrared optical imaging [2]
When a cell or a macromolecule in a living body is labeled with a fluorescent dye or a reporter gene, light waves of a specific wavelength in vitro are irradiated, light passing through the tissue is excited, and the fluorescent material is excited to emit fluorescence, and the external optical imaging device takes in the emitted fluorescence. The formation of optical molecular images, which will truly reflect the expression of a certain gene in the body or the biological characteristics of macromolecules, and dynamically record and display molecular events and their dynamic processes. However, near-infrared light is invisible to the human eye, and a special optical imaging system is required. The near-infrared fluorophore is used as a contrast agent. When a wavelength of near-infrared light illuminates the surgical field, the surgical field emits another wavelength of near-infrared. Light, ingesting this emitted near-infrared light can accurately determine the position of the near-infrared fluorophore. When near-infrared fluorophores are labeled into living cells, tissues, and organs, the structure and lesions of the tissue can be visualized by near-infrared light in the surgical field. At present, indocyanine green is used as a near-infrared fluorescent developer, and near-infrared light imaging has been applied in the clinical treatment of breast cancer, gastric cancer and colon cancer.
4 near infrared optical imaging system [2]
In 2002, the Beth Israel Deaconess Medical Center in Boston, USA first introduced the first generation of surgical imaging system, which can take color and near-infrared fluorescence in real time. The biggest feature is that it can absorb both near-infrared fluorescence and the anatomy of the surgical field. The system is called the Fluorescence-Assisted Cutting and Probing Surgical Imaging System (FLARETM). For many years, the system has been mainly used for surgical research on large animals and is expected to be applied to human surgery. At present, research institutes such as Frangioni Laboratory in Boston, Hamamatsu Optoelectronics, Fluoptics in France, Canada and the Netherlands are engaged in research and development.
4.1 Basic structure of near-infrared optical imaging system [2]
The near-infrared optical imaging system mainly includes a near-infrared excitation light source, a near-infrared fluorescent contrast agent, a highly sensitive near-infrared fluorescent camera, a computer and an image processing software thereof.
4.2 Classification of near-infrared optical imaging system
Type I: FLARETM camera system
The FLARETM camera system was first developed in 2002 by the Beth Israel Deaconess Medical Center in Boston, USA and Georgia State University. FLARE is the abbreviation for fluorescence-assisted resection and exploration, which is fluorescence-assisted resection and detection.
  The basic solution of the FLARETM design is that during surgery, the display shows both the surgical anatomy and the near-infrared fluorescence that is invisible to the naked eye and can be superimposed on the color image. The basic components of the FLARETM system: (1) 400W cold light source, 40,000 lux of white light, wavelength 400 ~ 650nm, one of the two near-infrared excitation sources, the technical parameters are light intensity 4 mW / cm 2 , wavelength 700 nm (656 ~ 678 nm) The three near-infrared excitation light source, the technical parameters are light intensity 14 mW/cm 2 , wavelength 800 nm (745-779 nm), near-infrared light source adopts circular LED array, linear drive integration; (2) camera system includes color camera CCD , 400 ~ 650 nm peak quantum efficiency; 700 nm near-infrared camera CCD, 689 ~ 725 nm peak quantum efficiency, and 800 nm near-infrared camera CCD, 800 ~ 848 nm peak quantum efficiency, a total of three CCD simultaneous acquisition, pixel 640 × 480, system resolution 125 × 125 μm (x, y) to 625 × 625 μm (x, y), display refresh 15 Hz, NIR exposure time is 100 μsec to 8 sec, hands-free optics Auto zoom and focus.
Type II: Fluobeam ® Handheld Imaging System [3]
Fluobeam ® is developed by Fluoptics of Grenoble, France. Fluobeam ® is a handheld imaging system that takes in 2D in vitro fluorescence. Fluobeam ® has a corolla LED that emits near-infrared light for direct detection under white light. Fluobeam ® is available in two models, Fluobeam ® 700 and Fluobeam ® 800.
Type III: ArtemisTM Handheld Imaging System ().
The ArtemisTM Handheld Imaging System is a color and fluorescence dual CCD handheld camera system that provides full color real-time fluorescence imaging with 800nm ​​indocyanine green and 700nm fluorescent probe imaging for laparoscopic and open surgery. The imaging system has a resolution of 659 × 494 pixels, approximately 330,000 pixels, an image output of 5.6 x 5.6 μm, a frame rate of 5 to 60 fps, a read noise of 30 electrons, a well energy of 25,000 electrons, and a configuration of 390 mm and 190 mm. Laparoscopy.
Type IV: The Photodynamic Eye
The Photodynamic Eye is developed by Hamamatsu Optoelectronics Co., Ltd., which mainly evaluates the amount of tissue perfusion at the non-injury bedside. The image sensor is CCD and the emission source is LED.
Type V: Novadaq Probing Imaging System [4]
The Novadaq's SPY Imaging System, developed by Novadaq Technologies Inc. of Canada, is the first and currently the only device approved by the FDA for assessing patency after coronary artery bypass grafting [5], It is an important tool for plastic surgery and reconstruction surgery to evaluate the free flap blood supply [6,7]. It can also be used in the fields of organ transplantation, pediatric surgery and urology. One of the important functions of the Novadaq Probing Imaging System is its ability to be used flexibly in the operating room to quantify critical steps in the procedure.
Figure 4: The entire system is placed on a mobile vehicle, consisting of (1) excitation light/camera, camera is 30 frame rate/second CCD; (2) display, remote control center; (3) central processing system; ((4) laser generator The output power of the laser generator is 2.0 W, and the camera and laser output are accompanied. The laser irradiation area of ​​the heart is 56 cm 2 (7.5 cm × 7.5 cm). The lens is 30 cm from the heart during surgery.
5 near infrared optical imaging contrast agent
   In the near-infrared light range, most tissues rarely produce near-infrared fluorescence, and it is necessary to use near-infrared optical imaging contrast agents. The most commonly used organic NIR fluorophores are polymethine compounds, and the other is semiconductor nanocrystals or quantum dots. .
5.1 Non-targeted exogenous contrast agents
5.1.1 Indigo Green
Indocyanine green (ICG), also known as indigo green or Fuss green, is a water-soluble three-carbon anthraquinone dye with a molecular weight of 775 Daltons and a molecular formula of C4 3 H 47 N 2 NaO 6 S 2 with a maximum absorption spectrum of 805 nm. The maximum excitation wavelength is 835 nm. After being injected into the body, ICG is neither absorbed from the digestive tract nor enters the liver circulation. Instead, the liver parenchymal cells are taken up from the plasma and excreted as a whole molecule into the bile duct, and excreted with the feces. In recent years, in addition to the study of ocular blood vessels, especially choroidal vessels, ICG imaging has also been used for the detection of burn depth, gastrointestinal vascular defects, reduction of perfusion in patients with acute cerebral artery infarction, diagnosis of malignant tumors, microcirculation. Quantitative, brain tumor margin determination and tumor sentinel lymph node detection [8] .
Motomura et al [9] demonstrated that labeled lymph nodes were recognized by injection of 25 mg/5 mL indocyanine green in soft tissue surrounding breast cancer. Later, Kitai et al [10] confirmed that intradermal injection of 25 mg can guide the sentinel lymph node biopsy in patients with breast cancer. In addition, the combination of trace indocyanine green and molecular targeting markers can also effectively display lymph nodes and reduce the use of indocyanine green.
5.2 Non-targeting activatable organic fluorescent contrast agents
Studies have shown that the disordered growth of tumors is related to the up-regulation of proteolytic activity, so the expression of proteolytic enzymes in malignant tumor tissues is increased, which is related to tumor invasion and metastasis. These fluorescent probes often contain more than two equivalents or different The pigment group, the two pigment groups are closely linked to each other by an enzyme-specific polypeptide linker. When the polypeptide linkers are cleaved, their fluorophores are released and the fluorescence emission is restored. Enzyme targets are primarily limited to proteases, including cathepsins, caspase-specific proteases, matrix metalloproteinases, thrombin, HIV and HSV proteases, and urokinase-like plasminogen activators.
5.3 Targeting organic fluorescent contrast agents
Targeting an organic fluorescent contrast agent is the coupling of a fluorophore to a ligand that binds to a specific molecular target (active probe). The contrast agent binds to and stays at the target site, while the non-bound fluorophore is removed in the circulation. This method is most useful for imaging tumors because cancer overexpresses certain surface receptors.
Ligands can be small molecules, polypeptides, proteins, and antibodies. For example, epidermal growth factor receptor (EGFr) / Her2, vascular epithelial growth factor receptor (VEGFr) and αvβ3 integrin. Fluorescent groups that can be combined include Cy 5.5, Alexa Fluor 750, IRdye 800CW, etc. [11-13] .
6. The surgical treatment of the near-infrared optical imaging guidance application
6.1 Sentinel Lymph Node Mapping
Invasive bladder cancer has lymph node metastasis in 20 to 25% of patients, and lymph node dissection is performed during total cystectomy. Knapp et al. used IRDye TM 800CW, HSA800, and near-infrared fluorescent quantum dot three near-infrared fluorescent lymph node tracers. The peak of excitation light of HSA800 is 784 nm, the peak of emission light is 802 nm; the peak of excitation light of near-infrared fluorescent quantum dots It is 775 nm and the peak of the emitted light is 820 nm. Using the first-generation near-infrared fluorescence imaging system, experiments were carried out in dogs and pigs. It was found that the bladder wall immediately showed bright fluorescence after injection of the near-infrared fluorescent lymph node tracer, and the lymphatic fluorescence was displayed in 10 seconds, 30 seconds to 3 minutes. Sentinel lymph nodes were developed and the injection site and sentinel lymph nodes remained fluorescently developed at least 2 hours after injection. 25% of the lymph nodes were all brightly fluorescent; 45% of the lymph nodes were partially developed; and 30% of the lymph nodes were developed. At the same time, it was found that the intravesical pressure affects the movement of the lymph node tracer. The movement of the lymph node tracer is greater than 50 cm H 2 0 and less than 10 cm H 2 O. The intravesical pressure is an important factor affecting the optical effect of the bladder [14] ] . In addition, breast cancer surgery, cervical cancer and other tumor surgery can be used.
6.2 Intraoperative Ureteral Guidance
In ureteral injury or some surgical procedures, ureteral search is very difficult, Tanaka et al. use 0.5 mW/cm 2 400-700 nm white light, and 5 mW/cm 2 725-775 nm near-infrared light, the spot diameter is 15 cm. Near infrared imaging system. Injection of 7.5 μg was found in porcine model / kg CW800-CA can be seen in visible light without ureter, ureteral see the object is smaller than a 2.5 mm diameter, retrograde injection of 10 μM ICG to pinpoint leak point ureteral injury [15 ] .
6.3 Intraoperative Near-infrared Fluorescent Cholangiography
Tanaka et al [16] used NIR light and intravenous CW800-CA to display extrahepatic bile ducts in real time without affecting surgery.
6.4 assisted hepatectomy
Aoki et al [17] used the Photo Dynamic Eye-2 imaging system to clearly distinguish between segmentation and sub-segmentation of the liver 1 minute after the portal vein injection of ICG, and can be maintained for 10 minutes. The examination was performed on 35 patients with hepatic malignancies who underwent partial hepatectomy. Among them, 33 patients had obvious liver lobe differentiation. This method is effective, reliable and safe.
6.5 Assessment of coronary artery bypass grafting
Conventional coronary angiography is the gold standard for the diagnosis of coronary stenosis, but it is rarely used in coronary artery bypass surgery. Currently commonly used methods include intraoperative fluorescence imaging (IFI) and time-lapse blood flow (transit-time). Flowmetry, TTFM). Balacumaraswami et al. considered the evaluation of the effect of the Novadaq detection imaging system for coronary artery bypass surgery. IFI is more sensitive than TTFM, and the false positive rate is low [18] .
6.6 Application of cerebrovascular surgery
Woitzik et al [19] used near-infrared fluorescence surgery microscope to perform near-infrared fluorescence angiography in 32 patients with intravenous ICG 25mg/10ml. 13 cases of cerebral aneurysms, 4 cases of cerebral arteriovenous malformations, and 8 cases of intracranial and extracranial bypass were diagnosed. It is considered that routine ICG near-infrared fluorescence angiography is necessary during cerebrovascular surgery.
6.7 dentifying tumors intraoperatively
Intraoperative identification of tumors includes tumor recognition under open surgery and endoscopic surgery, determination of the margin of tumor resection, and identification of metastatic lymph nodes, but is still in preclinical studies. It is necessary to further improve the tumor-specific near-infrared fluorescent probe, study tumor targeting antibodies and non-toxic side effects of near-infrared fluorescent dyes, and develop highly sensitive near-infrared camera systems [20, 21] .
In short, near-infrared optical imaging theory and technology is a scientific achievement in the past decade. With the continuous deepening of research, it will be widely used in various fields of clinical medicine, becoming a new medical technology, medical equipment and new clinical disciplines.
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