|Year : 2017 | Volume
| Issue : 3 | Page : 98-107
Expert consensus on application of computer-assisted indocyanine green molecular fluorescence imaging technology in the diagnosis and surgical navigation of liver tumor
Chinese Society of Digital Medicine, Chinese Research Hospital Association of Digital Surgery Committee, The Medical Image and Equipment Specialized Committee of China Graphics Society, The Molecular Imaging Professional Committee of Biophysical Society of China
|Date of Web Publication||7-Dec-2017|
Source of Support: None, Conflict of Interest: None
Three-dimensional (3D) visualization technology is a tool used to display, describe, and explain the 3D anatomical and morphological features of tissues and organs, which has been widely used in liver surgery. Indocyanine green (ICG) molecular fluorescence imaging technique has been widely used as an auxiliary tool at cell function level in the diagnosis and surgical navigation of liver tumors. Computer-assisted ICG molecular fluorescence imaging technique can guide the diagnosis and surgical navigation of liver tumors from the perspective of 3D morphological anatomy and cell function of liver tissues, which has been proved by the clinical application to possess unique and accurate diagnosis and treatment value. This consensus provides recommendations for the hot issues of the application of the technique in liver tumors, hoping to provide certain guidance and reference value for surgeons engaging in, or aspiring to engage in the diagnosis and treatment model.
Keywords: Fluorescence imaging, hepatectomy, indocyanine green, liver tumor, three-dimensional visualization technology
|How to cite this article:|
Chinese Society of Digital Medicine, Chinese Research Hospital Association of Digital Surgery Committee, The Medical Image and Equipment Specialized Committee of China Graphics Society, The Molecular Imaging Professional Committee of Biophysical Society of China. Expert consensus on application of computer-assisted indocyanine green molecular fluorescence imaging technology in the diagnosis and surgical navigation of liver tumor. Digit Med 2017;3:98-107
|How to cite this URL:|
Chinese Society of Digital Medicine, Chinese Research Hospital Association of Digital Surgery Committee, The Medical Image and Equipment Specialized Committee of China Graphics Society, The Molecular Imaging Professional Committee of Biophysical Society of China. Expert consensus on application of computer-assisted indocyanine green molecular fluorescence imaging technology in the diagnosis and surgical navigation of liver tumor. Digit Med [serial online] 2017 [cited 2018 Mar 17];3:98-107. Available from: http://www.digitmedicine.com/text.asp?2017/3/3/98/220126
Address for correspondence:
Prof. Chihua Fang,
Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, Guangdong Province, China.
| Introduction|| |
Three-dimensional (3D) visualization technology is a tool used to display, describe, and explain the 3D anatomical and morphological features of tissues and organs, which has been widely used in liver surgery. Indocyanine green (ICG) is a type of near-infrared fluorescent dye. Protein-binding ICG can be activated by extraneous light with a wavelength of 750–810 nm and emits near-infrared light with a wavelength of about 840 nm. Since ICG molecular fluorescence imaging technique was first used by Ishizawa et al. to guide hepatectomy, the technique has been more and more widely used as an auxiliary tool at cell function level in the diagnosis and surgical navigation of liver tumors.,,,,
Computer-assisted ICG molecular fluorescence imaging technique can guide the diagnosis and surgical navigation of liver tumors from the perspective of 3D morphological anatomy and cell function of liver tissues, which has been proved by clinical application to possess unique and accurate diagnosis and treatment value. This consensus provides recommendations for the hot issues of the application of the technique in liver tumors, hoping to provide certain guidance and reference value for surgeons engaging in, or aspiring to engage in the diagnosis and treatment model.
| Application Process Of Three-Dimensional Visualization Technology|| |
Data collection and storage
The three-phase (plain scan phase, arterial phase, and portal venous phase) image data of epigastric enhanced computed tomography (CT) was collected. After scanning, the image data was transferred to CT postprocessing workstation, burned into a disk and stored.
The CT image data were imported into the 3D visualization imaging system, and the abdominal viscera, abdominal vascular system, and hepatic tumors were segmented, registered, and reconstructed. Individualized hepatic segmentation, hepatic volume calculation, and virtual hepatectomy  were conducted as required.
Recommendation: clinicians should cooperate with radiologists to setup standardized scanning parameters to obtain high-quality CT image data. Based on this, 3D visualization studies should be carried out according to the equipment, conditions, and clinical needs.
| Mechanism and Application Process of Indocyanine Green Molecular Fluorescence Imaging|| |
Targeted retention mechanism of Indocyanine green in hepatic tumors
The uptake of ICG is mainly completed by the organic anion transporting polypeptide 1B3 (OATP1B3) and Na +-taurocholate cotransporting polypeptide in hepatic cells, and the excretion of ICG is mainly conducted by the multidrug resistance-associated protein 2 carrier system expressed on the bile capillary. After excretion, ICG does not participate in the enterohepatic circulation., Therefore, in normal hepatic tissues, ICG can be rapidly taken in by hepatic cells and displays fluorescence under the irradiation of exciting light. With the excretion of ICG through the biliary system, the fluorescence gradually regressed. When hepatic tumors or cirrhosis nodules exist, the biliary excretory function of hepatic cells in diseased hepatic tissues is impaired, ICG has targeted retention in the diseased tissues, and regression delayed.
Use patterns of Indocyanine green
The acidophobe in ICG multi-ring structure determines that sterile water for injection is the preferred solvent for ICG, but the stability of ICG aqueous solution is limited and must be used within 6–10 h after dilution. Saline solution cannot be used for the preparation of ICG as it promotes the aggregation of ICG molecules., The timing, patterns, and dosage of ICG injection vary according to different purposes of use, and there is a great difference in the use patterns of different the centers.,,, The use standards recommended by this consensus are shown in [Table 1].
Detection of near-infrared light
ICG molecular fluorescence imaging system mainly includes near-infrared excitation light source, high-sensitivity near-infrared fluorescence video camera, and computer image processing system. The intraoperative operation methods are as follows: (1) after the liver is fully dissociated, the shadowless lamp in the operating zone is closed, and the near-infrared excitation light source is opened. The near-infrared fluorescence video camera is used to scan the liver and other abdominal viscera at a proper distance (according to the model type); (2) real-time location of the hepatic tumor is carried out, and the hepatic precutting line is calibrated according to the distribution of the fluorescence signal; (3) in performing anatomical hepatectomy, positive display, or negative display method is used to guide liver segmentation; (4) after hepatectomy, ICG molecular fluorescence detection on the residual liver and specimens in vitro is carried out; and (5) routine pathological examination on the specimens is performed.
ICG was applied in a clinical trial as early as in 1957 and passed the certification of the US Food and Drug Administration in 1959. The imaging medium has been used in clinical settings for over 50 years, the incidence of adverse reactions reported is <0.01%, and the drug instruction should be strictly followed in use.
Recommendations: (1) ICG should be sufficiently dissolved with sterile water for injection to avoid the occurrence of adverse reactions. (2) The timing, patterns, and dosage of ICG injection vary according to different purposes.
| Clinical Application of Three-Dimensional Visualization Technology|| |
Through 3D visualization model, the size, site, and morphology of liver tumors can be observed from multiple angles, the anatomic variations of the celiac vasculature can be clarified, and the spatial position relation between tumor and vital blood vessels in the liver can be determined. Individualized liver segmenting and liver volume calculation can be used to guide precise hepatectomy. Meanwhile, the 3D visualization model can be compared with the actual operation in real time, thus synchronously adjusting the anatomical position of the 3D visualization model and identifying and locating the key pipeline  [Figure 1].
|Figure 1: Evaluation of three-dimensional visualization. (a) Intrahepatic tumor and celiac vasculature displayed by three-dimensional visualization technology. (b) Liver segmenting in three-dimensional visualization|
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Recommendation: 3D visualization technology can be used to conduct accurate diagnosis and safety assessment of liver tumors before operation, and can identify and locate tumors and important blood vessels during operation, so as to guide the performing of precise operation.
| Clinical Application of Indocyanine Green Molecular Fluorescence Imaging Technology|| |
Initial identification on the differentiated degree of primary hepatic carcinoma
As low-differentiated hepatic carcinoma tissue has poor ability to take in ICG, the fluorescence signal provided by the focus is weak. However, since the normal tumor-surrounding liver tissues are compressed by the tumor, the excretion of ICG is delayed, thereby such tumors generally present as annular fluorescence surrounding the cancer tissues. Highly-differentiated hepatic carcinoma tissues still have certain ability to uptake ICG, but the biliary tract excretory function is abnormal, and thus fluorescence can be detected for a longtime and full-fluorescence signal is emitted. Part of the cells in medium differentiated hepatic carcinoma tissues have lost the uptaking function and usually emit partial-fluorescence signals  [Figure 2].
|Figure 2: Hepatectomy specimens and the fluorescent properties (these images are quoted from reference 35). (a and b) Full-fluorescence (highly-differentiated); (c and d) Partial-fluorescence (medium-differentiated); (e-f) Annular fluorescence (low-differentiated)|
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Recommendation: The differentiated degree of primary hepatic carcinoma can be preliminarily determined according to the intraoperative fluorescence signal characteristics of the liver tumor and based on rapid intraoperative pathological examination.
Recognition and localization of liver tumors
Primary hepatic carcinoma
At present, the postoperative recurrence rate of primary hepatic carcinoma is still high, which may be related to the presence of microdisseminated cancer focus or polycentric sources before the operation. When liver cirrhosis is obvious, the preoperative diagnosis and intraoperative detection of microhepatocellular carcinoma are somewhat difficult. After the further growth and metastasis of these carcinoma foci missing diagnosis, the chance of reresection has often been lost.
Research results suggest that there are some primary hepatic carcinoma foci that cannot be detected with the preoperative imaging materials or by intraoperative B ultrasound, intraoperative naked eye, and hand touch, and can only be identified by ICG molecular fluorescence imaging technology. The technology can detect primary hepatic carcinoma foci with the minimum diameter of merely 2 mm  [Figure 3]. Therefore, ICG molecular fluorescence imaging technology is of certain value in enhancing the radical resection rate of primary hepatic carcinoma.
|Figure 3: Identification and localization of primary hepatic carcinoma by Indocyanine green molecular fluorescence imaging technology (these images are quoted from reference). All the above images are from the same patient. (a) Epigastric-enhanced CT suggests right hepatic space occupying lesion; (b) No right hepatic tumor is found by intraoperative naked-eye detection and hand touch detection; (c) The tumor location, boundary, and fluorescence types can be clearly shown by intraoperative ICG molecular fluorescence imaging technology; (d) Right hepatic space occupying lesion is not found by preoperative CT and MRI or intraoperative naked-eye detection and hand touch detection; (e) A fluorescent node with the size of about 3 mm is found in the outer zone of the left liver using the ICG molecular fluorescence imaging technology (arrow), which is diagnosed as hepatocellular carcinoma by postoperative pathological examination|
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Recommendation: ICG molecular fluorescence imaging technology can be used to comprehensively detect the liver during operation, and identify high-intensity fluorescence signal. It is combined with intraoperative ultrasound, and rapid pathological examination, can help resecting suspicious carcinoma foci.
Hepatic metastases of colorectal cancer and pancreatic cancer
Liver is the hematogenous metastasis organ of malignant tumor, and the hepatic metastases of colorectal cancer and pancreatic neuroendocrine malignant tumor are commonly seen. At present, it is suggested to carry out radical excision on intrahepatic metastatic carcinoma on the premise that the primary cancer foci have been or can be radically resected,,, and the residual liver has adequate compensation function. However, conventional inspection methods such as CT, MRI, and intraoperative B ultrasound are likely to miss cancer foci with small diameter, which makes the complete resection of hepatic metastasis become difficult.
The hepatic metastatic carcinoma tissues do not possess hepatocyte functions, and it is generally presented as annular fluorescence around the tumor tissue under ICG molecular fluorescence detection. Studies showed that the recognition rate of preoperative imaging examination and intraoperative B ultrasound on metastatic cancerous nodes is far below that of ICG molecular fluorescence imaging technology. The minimum diameter of the nodes detected by fluorescence is 1.5 mm.,
Recommendation: for patients with hepatic metastases of colorectal cancer and pancreatic neuroendocrine malignant tumor, on the premise that the primary cancer foci have been radically resected and the residual liver is evaluated to have adequate compensation function, the metastatic cancer foci can be resected with ICG fluorescence imaging technology.
Extrahepatic metastatic tumor of primary hepatic carcinoma
In 2013, Satou et al. performed ICG molecular fluorescence detection on the extrahepatic metastatic tumor of primary hepatic carcinoma for the first time, suggesting that the detection means is of certain value for the identification and localization of such foci [Figure 4]. The study pointed out that the extrahepatic metastatic tumor cells of primary hepatic carcinoma have the ability to uptake ICG, and do not possess the excretory function of the biliary system or the metabolic function of other adjacent cells, which may be the reason for ICG retention in the metastatic tumor tissues. In addition, as the penetrating power of ICG in human tissues is determined by different absorbents (such as hemoglobin), the detectability of fluorescence signal of extrahepatic metastatic tumor of primary hepatic carcinoma may be different in different metastatic organs, which needs to be further investigated.
|Figure 4: Identification and localization of extrahepatic metastatic tumor of primary hepatic carcinoma by Indocyanine green molecular fluorescence imaging technology. (a) Three-dimensional visualization model of left hepatic massive hepatocellular carcinoma; (b) Indocyanine green molecular fluorescence imaging technology is used during operation to test the abdominal cavity and high signal region is found (as indicated by the arrow, the rest highlight regions are interference signals), suggesting the presence of lymph node metastasis of right gastric artery; (c) Detection is carried out after the resection of suspicious lymph nodes, low signal is detected (as indicated by the arrow), and cancer tissue can be seen in the lymph nodes by postoperative pathological diagnosis|
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Recommendation: ICG molecular fluorescence imaging technology can be used for the identification and localization of extrahepatic metastatic tumor of primary hepatic carcinoma.
Preliminary identification of the source of tumor connected with the liver
Peritoneal space-occupying lesions with unknown source are commonly seen in clinical settings. For example, tumors that adhere to or compress the liver and lie in the foci located in the left liver, the gap between the liver and stomach or the rear of the liver are easily misdiagnosed as liver cancer by imaging detection. Intraoperative rapid pathological examination is of great importance in determining the operation method for such patients. However, misdiagnosis and missed diagnosis still exist in the examination.,
For nonhepatic sourced tumors, due to the lack of ability of uptake and metabolism of ICG of the tumors and the surrounding tissues, the retention of fluorescence contrast medium does not occur. When ICG is injected through peripheral vein before operation and extensive metabolism is eliminated, there is small possibility that the focus is derived from the liver, if there is no fluorescent display in intraoperative detection on tumors and the surrounding tissues. In addition, 3D visualization technology is of unique value in determining the feeding artery of the tumors and the spatial relationship between tumors and the liver. The combined application of ICG molecular fluorescence imaging technology, 3D visualization technology, and intraoperative rapid pathological examination is of some value in improving the accuracy of intraoperative diagnosis and determining the operation method [Figure 5].
|Figure 5: Preliminary Identification of the source of tumor connected with the liver by Indocyanine green molecular fluorescence imaging technology. (a) The preoperative three-dimensional visualization evaluation suggests that the tumor blood flow is not from the liver; (b) Indocyanine green molecular fluorescence imaging technology is used to test the massive lump (as indicated by the arrow) under the left liver during operation and no fluorescence signal is found, suggesting that the tumor is not derived from the liver|
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Gastrointestinal stromal tumor is diagnosed by intraoperative frozen section and postoperative pathological examination.
Recommendation: ICG molecular fluorescence imaging technology can be used as a supplementary means for tumor identification, and it can improve the accuracy of intraoperative diagnosis in combination with preoperative 3D visualization evaluation and intraoperative rapid pathological examination results.
At present, there are two methods , to demarcate the hepatic segments using intraoperative ICG molecular fluorescence imaging technology: (1) positive display method: the portal vein of the hepatic segment to be resected is identified by intraoperative B ultrasound and 3D visualization model, ICG solution is extracted using fine puncture needle and injected into the target portal vein branch, and ICG molecular fluorescence detection is carried out to display the hepatic segment to be resected. The fluorescence signal of positive display is strong, but the technical difficulty is greater than that of negative display method. (2) Negative display method: the portal vein flow of the hepatic segment to be resected is separated and ligated, ICG solution is injected through the peripheral vein, and ICG molecular fluorescence detection is carried out to display the hepatic segment to be reserved. Negative display method is usually appropriate for hepatic segments with easily exposed portal vein branch, such as hepatic segments in the left lateral region (segments II and III) or the anterior region (segments V, VIII, and IV b). The disadvantage is that the concentration of ICG accumulation is not high, and the fluorescence signal is relatively weak. Studies showed that using ICG molecular fluorescence imaging technology, success rate of segmenting can achieve 95.8%. It can accurately display the boundaries of the hepatic segments on the surface of the liver as well as the fluorescence boundaries on the hepatic cross and has strong effect of visualized segmentation the hepatic surface and achieve 3D staining of hepatic parenchyma.
Recommendation: intraoperative positive display method or negative display method can be used to produce fluorescence signal in the target hepatic region or hepatic segment, so as to assist the performing of anatomical hepatectomy.
Definition of tumor boundary and hepatectomy extension
As the definition of tumor boundary is the key to the performing of R0 hepatectomy, it is required to precisely identify and define tumor boundary and hepatectomy extension. ICG molecular fluorescence imaging technology has been proved to be capable of realizing accurate and real-time contrast imaging between tumor tissues and normal hepatic tissues. When nonanatomical hepatectomy is to be performed, if ICG is injected through peripheral vein before operation, the tumor boundary can be defined by ICG molecular fluorescence detection, and hepatectomy extension can be defined at least 1 cm from the tumor. When anatomical hepatectomy is to be conducted, intraoperative positive display method or negative display method can be used to define the extension of the hepatic regions or hepatic segments to be resected, and precise hepatectomy can be performed. In addition, ICG molecular fluorescence imaging technology can be applied to detect the residual liver after hepatectomy and to help determine whether there is residual microtumor focus, so as to reduce the residual rate of tumor, as shown in [Figure 6].
|Figure 6: Definition of tumor boundary and hepatectomy extension and detection of residual tumor focus by Indocyanine green molecular fluorescence imaging technology. (a) Indocyanine green was injected before operation, and tumor boundary was defined by Indocyanine green molecular fluorescence detection during operation; (b) The negative display method was used during operation to define the parting line (as indicated by the arrow) between left and right liver; (c) Based on the definition of the boundary (as indicated by the arrow) of the right liver, narrowing right hemihepatectomy was performed according to the tumor location and the remnant liver volume ratio; (d) After the narrowing right hemihepatectomy was performed, residual high signal on the hepatic cross was detected by Indocyanine green molecular fluorescence imaging technology (as indicated by the arrow); and (e) After the resection of the residual focus, Indocyanine green molecular fluorescence detection was conducted, and it was found that the fluorescence nodes disappeared|
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Recommendation: ICG molecular fluorescence imaging technology can be used to define tumor boundary and hepatectomy extension during operation and detect residual tumor focus after hepatectomy.
Detection of bile leakage after hepatectomy
Bile leakage after hepatectomy is one of the important causes , of abdominal infection, hepatic failure and even death, and the incidence rate is within the range of 4% to 9.8%., The key to reducing the incidence rate is to detect and restore bile leakage in time during operation.
In recent years, angiography based on ICG molecular fluorescence imaging technology has been applied to evaluate the patency of blood flow. As bile contains proteins that can bind to ICG, bile leakage can be identified by injecting ICG through the ductus cysticus, temporarily blocking the common bile duct and conducting detection with ICG molecular fluorescence imaging technology. Some studies pointed out that the detection of bile leakage after hepatectomy using ICG molecular fluorescence imaging technology can significantly reduce the incidence of postoperative bile leakage compared with conventional methods., In addition, the technology is of some significance for preventing hepatic cyst and bile leakage after hepatic cystadenoma excision, as shown in [Figure 7].
|Figure 7: Detection of bile leakage after hepatic cystadenoma excision by Indocyanine green molecular fluorescence imaging. (a) Epigastric CT suggested hepatic cystadenoma; (b) Detection on bile leakage was carried out using Indocyanine green molecular fluorescence imaging technology after cystadenoma excision and basement membrane enuclearion, and high residual signal (as indicated by the arrow) was found; (c) Indocyanine green molecular fluorescence imaging technology was used to test the fracture surface after suture and other treatments, and the fluorescence signal disappeared|
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Recommendation: ICG molecular fluorescence imaging technology can be used to effectively detect bile leakage after hepatectomy.
Living donor liver transplantation
At present, ICG molecular fluorescence imaging technology is mainly used in two ways in living donor liver transplantation: (1) cholangiography: after ICG is injected through the cystic gall duct, clear biliary ductal anatomic images can be obtained using ICG molecular fluorescence imaging technology, which can help to accurately determine the donor liver preresection line and the bile duct cut point, as well as guide the biliary tract rebuilding between the donor and the receptor. This is also of certain value for reducing the incidence of bile leakage, bile duct stenosis, and other complications., (2) Evaluating vascular patency and liver function recovery condition after rebuilding: as ICG can rapidly bind to plasma proteins after intravenous injection and be distributed in systemic blood vessels, ICG molecular fluorescence imaging technology can be used for angiography; after liver transplantation, injection of ICG through peripheral vein during operation and detection using ICG molecular fluorescence imaging system (if ICG near-infrared light image is detected in the extrahepatic bile duct) can demonstrate that the transplanted liver cells secrete bile.
Recommendation: ICG molecular fluorescence imaging technology can be used in living donor liver transplantation to carry out cholangiography and guide biliary tract dividing and rebuilding; the function of the transplanted liver cells can be evaluated during operation in a variety of different types of liver transplantation.
| Limitations|| |
At present, ICG molecular fluorescence imaging technology has two major technical limitations. One is that its sensitivity toward deep nodules is low. Due to the limited ability of near-infrared light to penetrate human tissues, the fluorescence signals emitted by ICG can only penetrate liver parenchyma within 10 mm. Although Miyata et al. used photoacoustic-combined imaging to increase the detecting depth to some extent, the desired result had not been obtained. At present, only through dynamic detection of ICG molecular fluorescence on the hepatic cross during hepatectomy, intraoperative ultrasound and intraoperative rapid pathological examination, will the limited depth of ICG be partially remedied. The other limitation is the high false-positive rate of hepatic nodules, especially in patients with a medical history of hepatic cirrhosis, the fluorescence contrast ratio of hepatic tumor tissue to other hepatic tissues will decrease, and the sensitivity of detection will be further reduced. However, the detection rate and characteristics of false-positive foci need to be further clarified by plenty of case studies.
| Application Prospect|| |
The application of computer-assisted indocyanine green (ICG) molecular fluorescence imaging technique in the diagnosis and surgical navigation of liver tumors provides a new digital medical technology for the surgical treatment of liver tumors. At present, the research and application of ICG-targeted optical molecular imaging probe in the diagnosis and treatment of diseases have received more and more attention, It is believed that with the continuous intensive development of clinical practice and technical innovation, the technology will continue to be improved and perfected, thus presenting a favorable application prospect for precise diagnosis and treatment of liver tumors.
The committee of Expert Consensus on Application of Computer-assisted Indocyanine Green Molecular Fluorescence Imaging Technology in the Diagnosis and Surgical Navigation of Liver Tumor.
Validated by: Wan Yee Lau
Directors of the Committee: Shaoxiang Zhang, Hongchi Jiang, Lijian Liang
Participants: Jianqiang Cai, Yajin Chen, Chaoliu Dai, Chihua Fang, Lianxin Liu, Wan Yee Lau, Xiangcheng Li, Lijian Liang, Xiao Liang, Shichun Lu, Qiping Lu, Hongchi Jiang, Weidong Jia, Baogang Peng, Shuyou Peng, Lunxiu Qin, Liguo Tian, Jie Tian, Lu Wang, Gang Wu, Hong Wu, Yinmo Yang, Xuewen Zhang, Bixiang Zhang, Guojun Zhang, Shaoxiang Zhang, Xuting Zhi, Jian Zhou, Jie Zhou, Weiping Zhou.
Byliners: Chihua Fang 1,2, Zhikang Mo 1,2, Qiping Lu 3
1 Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China,2 The Clinical Engineering and Technological Research Center of Digital Medicine of Guangdong Province, Guangzhou 510282, China,3 Department of General Surgery, Wuhan General Hospital of Guangzhou Military, Wuhan 430064, China.
This article is based on the study first reported in Chinese Journal of Practical Surgery in 2017 (Volume 37, Issue 5, pages 531-538).
Financial support and sponsorship
The National Key R&D Program (No. 2016YFC0106500), the Major Instrument Project of National Natural Science Fund (No. 81627805), the NSFC-GD Union Foundation (No. U1401254), the Science and Technology Plan Project of Guangzhou (No. 201604020144), the Science and Technology Plan Project of Guangdong Province (No. 2016A020220013), the National Natural Science Foundation of China (No. 81601576, the National High Technology Research and Development Program of China (863 Program) (No. 2006AA02Z346 and 2012AA021105), the Natural Science Foundation of Guangdong Province, China (No. 6200171), the Science and Technology Program of Guangdong Province, China (No. 2012A080203013).
Conflicts of interest
There are no conflicts of interest.
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