Fbioe 07 00487

REVIEW
published: 30 January 2020

doi: 10.3389/fbioe.2019.00487
Recent Progress in NIR-II Contrast

Agent for Biological Imaging
Jie Cao 1,2,3*, Binling Zhu 3,4,5 , Kefang Zheng 2,3 , Songguo He 2,3 , Liang Meng 4,5 , Jibin Song 6*
and Huanghao Yang 6*
1
Fuzhou University Postdoctoral Research Station of Chemical Engineering and Technology, Fuzhou University, Fuzhou,
China, 2 Scientific Research and Experiment Center, Fujian Police College, Fuzhou, China, 3 Fujian Police College Judicial
Expertise Center, Fuzhou, China, 4 Department of Forensic Science, Fujian Police College, Fuzhou, China, 5 Engineering
Research Center, Fujian Police College, Fuzhou, China, 6 The Key Lab of Analysis and Detection Technology for Food Safety
of the MOE and Fujian Province, State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry,
Fuzhou University, Fuzhou, China
Fluorescence imaging technology has gradually become a new and promising tool for
in vivo visualization detection. Because it can provide real-time sub-cellular resolution
imaging results, it can be widely used in the field of biological detection and medical
Edited by:
detection and treatment. However, due to the limited imaging depth (1–2 mm) and
Yanbo Pei,
Harbin Institute of Technology, China self-fluorescence background of tissue emitted in the visible region (400–700 nm),
Reviewed by: it fails to reveal biological complexity in deep tissues. The traditional near infrared
Shuai Yu, wavelength (NIR-I, 650–950 nm) is considered as the first biological window, because
University of Texas at Arlington,
United States it reduces the NIR absorption and scattering from blood and water in organisms. NIR
Guangcun Chen, fluorescence bioimaging’s penetration is larger than that of visible light. In fact, NIR-I
Chinese Academy of Sciences, China
fluorescence bioimaging is still interfered by tissue autofluorescence (background noise),
*Correspondence:
and the existence of photon scattering, which limits the depth of tissue penetration.
Jie Cao
[email protected] Recent experimental and simulation results show that the signal-to-noise ratio (SNR)
Jibin Song of bioimaging can be significantly improved at the second region near infrared (NIR-II,
[email protected]
Huanghao Yang 1,000–1,700 nm), also known as the second biological window. NIR-II bioimaging is able
[email protected] to explore deep-tissues information in the range of centimeter, and to obtain micron-level
resolution at the millimeter depth, which surpass the performance of NIR-I fluorescence
Specialty section:
This article was submitted to
imaging. The key of fluorescence bioimaging is to achieve highly selective imaging
Nanobiotechnology, thanks to the functional/targeting contrast agent (probe). However, the progress of NIR-
a section of the journal
II probes is very limited. To date, there are a few reports about NIR-II fluorescence
Frontiers in Bioengineering and
Biotechnology probes, such as carbon nanotubes, Ag2 S quantum dots, and organic small molecular
Received: 17 September 2019 dyes. In this paper, we surveyed the development of NIR-II imaging contrast agents and
Accepted: 30 December 2019 their application in cancer imaging, medical detection, vascular bioimaging, and cancer
Published: 30 January 2020
diagnosis. In addition, the hotspots and challenges of NIR-II bioimaging are discussed. It
Citation:
Cao J, Zhu B, Zheng K, He S,
is expected that our findings will lay a foundation for further theoretical research and
Meng L, Song J and Yang H (2020) practical application of NIR-II bioimaging, as well as the inspiration of new ideas in
Recent Progress in NIR-II Contrast
this field.
Agent for Biological Imaging.
Front. Bioeng. Biotechnol. 7:487. Keywords: fluorescence imaging technology, the second region near infrared (NIR-II), biological imaging, contrast
doi: 10.3389/fbioe.2019.00487 agents, biomedical applications
Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 1 January 2020 | Volume 7 | Article 487
Cao et al. Development of NIR-II Biological Imaging
INTRODUCTION difference is found for the light scattering coefficients in NIR-I

and NIR-II regions. The penetration depth of light to the
Optical imaging technology has become a very important skin can be seen from Figure 1D, from which we could find
research method in the field of biomedicine, especially for a sweet spot (largest penetration depth) of 1,125 nm in NIR-
its ability to monitor biomolecules, cells, tissues, and living II. Overall, the range of 1,000–1,125 nm in NIR-II shows a
organisms in real-time and multi-dimensional visualization. better performance than NIR-I for skin. We may get the similar
Optical imaging technology has many advantages, in that it is conclusions for human subcutaneous fat tissue (Figures 1E,F)
non-invasive and safe, has visualization capabilities and high and human subcutaneous adipose tissue (Figures 1G–I). Again,
spatial resolution, has high rapid output, and is a low-cost it is difficult to compare directly the performance of NIR-I
method. It has been widely used in biomolecular detection and NIR-II because the absorption coefficients in the latter
imaging, drug distribution metabolic tracking, disease detection shows a turning point in the middle of NIR-II (at ∼1,125 nm).
and diagnosis (Sevick-Muraca et al., 2002; Hilderbrand and The sweet spot of 1,000–1,125 nm of NIR-II shows the lowest
Weissleder, 2010; Chen et al., 2014). Especially in early absorption coefficients for both red blood cells (RBCs) and
cancer diagnosis and imaging-guided treatment, optical imaging hemoglobin with or without saturated oxygen, which is also
technology have a good application prospect. applicable for water (see Figure 1J). In fact, it can be seen from
In the process of optical in vivo bioimaging, the penetration Figure 1J of the relationship between water absorption coefficient
depth of photons primarily depends on the absorption and with wavelength that the wavelength below 800 nm is the least
scattering of tissue elements. Meanwhile, the fluorescence absorbed by water, which is the optimal excitation wavelength.
and scattering photons generated by tissue itself will cause The closest point in NIR-II to eliminate the absorption from
interference noise and background radiation to the photon water is at 1,100 nm. It also can be seen from Figure 1K that the
penetration process. Therefore, fluorescence imaging technology effective light scattering of 100% and 0% oxygen saturation RBCs
also has limitation in its practical applications in that some shows no significant differences in NIR-I and NIR-II. However,
active components in organisms (such as melanin, hemoglobin, the autofluorescence from tissue or endogenous compounds
cytochrome, etc.) have higher light absorption and light limits the signal-to-noise ratio (SNR) of NIR-I fluorescence
scattering within the visible band (400–700 nm), which will imaging. The SNR of NIR-II fluorescence imaging, on the other
reduce the penetration depth of visible light. Because organisms hand, is enhanced due to the elimination of autofluorescence
are rich in many luminescent macromolecules (usually located noises. For example, Lim et al. (2003) studied the optical imaging
in the visible region), these biomolecules can also produce non- process in different biological media (including tissue and blood)
specific fluorescence emissions under visible light excitation, thus and simulated the process and established relevant models. From
interfering with imaging results (Weissleder, 2001). the results of this study, it can be concluded that the SNR of
Because near-infrared light (NIR) is less absorbed and quantum dot fluorescent clusters emitting at 1,320 nm is more
scattered in biological tissues than visible light, the former can than 100 times higher than that of quantum dots emitting at
penetrate biological tissues, such as skin, more effectively. As 850 nm. This result aroused great interest of the researchers in
shown in Figure 1A (top), the effective attenuation coefficients exploring biocompatible NIR-II fluorescence probes. Therefore,
(EACs) of tissue components, such as whole blood (oxygenated compared with visible light (400–700 nm) and traditional NIR-I
or deoxygenated), skin, and fat are significantly lower in the window, NIR-II can avoid background interference such as
range of 650–950 nm than that in visible light range, which is spontaneous fluorescence and photon scattering (Smith et al.,
considered as the “first (optical) window” (NIR-I) (Frangioni, 2009; Welsher et al., 2011). In 2009, Welsher et al. (2009)
2003; Smith et al., 2009). In the practice of NIR-I biological first reported on a class of single-walled carbon nanotubes
imaging, the imaging quality in deep tissue is far from adequate (SWCNTs), whose fluorescence emission wavelength is 950–
resolution. Due to the large amount of background noise 1,600 nm. Further experiments show that such material can
generated by tissue’s auto-fluorescence, the tissue penetration be used for imaging in living mice. The fluorescence signal
depth of photons in NIR-I is only 1–2 cm (Croce and Bottiroli, of SWCNTs at 950–1,400 nm can be detected to obtain high-
2014). resolution imaging of blood vessels under deep skin tissue.
Typically, the NIR-II window that may be suitable for Since then, more and more NIR-II fluorescent probes have been
bioimaging application is from 1,000 to 1,700 nm. Tissue successfully developed and have been applied to biomedical
components show a strong EAC from 1,350 to 1,700 nm, as imaging field.
shown in Figure 1A (top). We herein narrowed down the At present, the application of NIR-II imaging window
wavelength range to 1,000–1,350 nm, as labeled as “second is still not fully utilized, due to the lack of research on
window” in Figure 1A (top). In this review, the “NIR-II” probe materials and the restriction of imaging equipment. The
in this manuscript only refers to the wavelength range of Figure 1A (bottom) shows the relationship between incident
1,000–1,350 nm. The relationship between wavelength and the light wavelength and quantum efficiency when cameras with
absorption coefficient or the light scattering coefficient in the different sensors are used, including silicon (Si), InGaAs, and
skin is shown in Figures 1B,C respectively. The absorption to the HgCdTe. Furthermore, Si camera is the most sensitive to the light
skin in NIR-I decreases slowly with the increase of wavelength, of NIR-I, while InGaAs camera is the most sensitive to the light of
and the trend continues into NIR-II. It reaches the lowest point NIR-II. In addition, HgCdTe camera is less sensitive to the light of
at ∼1,125 nm and starts spiking after 1,250 nm. No significant these two windows although it has a higher resolution array, and
FIGURE 1 | Prahl et al. (1993) reported the inverse double increase (IAD) method and the power law approximation are used to process experimental data and
determine the optical properties of tissues. In this figure, µ’s is calculated as µ’s = µs (1-g), where µs is the scattering coefficient and g is the anisotropic coefficient of
scattering. The solid line corresponds to the average experimental data, and the vertical line shows the SD value. (A Top) NIR-I (first window) and NIR-II (second
window) imaging windows (Smith et al., 2009). The effective attenuation coefficient represents the how easily a volume of material can be penetrated by a beam of
light. (A Bottom) The sensitivity curves of the sensor in the signal detector camera with silicon (Si), indium gallium arsenic (InGaAs), and mercury telluride cadmium
(HgCdTe). Unlike the charge coupled device (CCD) camera using silicon sensor, the core component of near infrared camera is semiconductor alloy sensor, including
InGaAs and HgCdTe, which has a narrower band gap. In particular, InGaAs cameras exhibit high quantum efficiency when used in the NIR-II window, i.e., high
sensitivity. Adapted from Smith et al. (2009) written by Smith, A.M., etc. with permission. (B,C) Show the relationship between the incident light wavelength and
absorption coefficient (µa ) or the reduced light scattering coefficient (µ’s ) in human skin in vitro, respectively. (B) Adapted from Bashkatov et al. (2005) with permission.
In (C), except for the solid line, the remaining data marker points correspond to the experimental data obtained in reference (Chan et al., 1996; Simpson et al., 1998;
Du et al., 2001; Troy and Thennadil, 2001; Bashkatov et al., 2005). Adapted from Chan et al. (1996), Simpson et al. (1998), Du et al. (2001), Troy and Thennadil (2001),
and Bashkatov et al. (2005) with permission. (D,I) Show the penetration depth (δ) of light to skin and human mucosal tissue in the range of incident light wavelength
from 400 to 2,000 nm, respectively. Adapted from Bashkatov et al. (2005) with permission. (E,F) Show the relationship between wavelength and µa or µ’s in
subcutaneous adipose tissue, respectively. In (E), all the data markers except the solid line correspond to the experimental data obtained in Peters et al. (1990).
(Continued)
FIGURE 1 | Adapted from Peters et al. (1990) with permission. In (F), all the data markers except the solid line correspond to the experimental data obtained in Peters
et al. (1990) and Simpson et al. (1998). Adapted from Peters et al. (1990) and Simpson et al. (1998). with permission. (G,H) Show the relationship between
wavelength and µa or µ’s in human mucosa, respectively. Adapted from Bashkatov et al. (2005) with permission. (J) Shows the relationship between wavelength and
µa for red blood cells (RBC) with or without saturated oxygen in the 33.2% hematocrit (HCT) brine solution, as well as the relationship between wavelength and µa for
hemoglobin with or without saturated oxygen in the 96.5 g/dl hemoglobin solution. Adapted from Friebel et al. (2009) with permission. (J) Shows the relationship
between wavelength and µ’s for RBC with or without saturated oxygen in the 33.2% HCT brine solution. Adapted from Friebel et al. (2009) with permission.
it is most sensitive to the light of longer wavelength. Silicon-based in vivo (Hong et al., 2014), they found that the fluorescence of
CCD (Si-CCD) is usually used to collect fluorescence signals carbon nanotubes could penetrate 2.6 mm deep into a mouse
from NIR-I window. However, the quantum yield of this kind of skull, which not only provided imaging of the distribution of
CCD in NIR-II window is low, which is not sufficient for signal blood vessels in the head of mice, but also clearly showed the
acquisition. Near infrared CCD based on InGaAs is commonly fine structure of the brain capillaries. In 2019, Toshiya Okazaki
used as a NIR-II window detector, but the high cost of use restricts and other Japanese scholars used oxygen-doped SWCNTS and
its widespread use in research (Smith et al., 2009). enveloped it with phospholipid polyethylene glycol (o-SWCNT-
In recent years, there have been a few successful applications PEG). They found that it has special potential and can emit
of Nanofluorescent probes developed by NIR-II technology in 1,300 nm NIR-II fluorescence under 980 nm light excitation.
bioimaging, which include the use of carbon nanotubes (Hong Therefore, it is considered to be a promising angiographic
et al., 2014; Diao et al., 2015), Ag2 S quantum dots (Hong et al., imaging probe (Takeuchi et al., 2019). In addition, o-SWCNTs
2012b; Zhang et al., 2012) and small organic molecules (Antaris were injected intravenously into living mice as a contrast agent
et al., 2016). Next, the applications of various near infrared for vascular imaging. The biological factors of the angiographic
nanomaterials and bioimaging will be introduced in detail. probe in vivo, including retention time, biological distribution,
and toxicity, were studied. The results showed that o-SWCNT-
CATEGORIES OF REPORTED NIR-II PEG, an angiographic probe, had low toxicity in vivo, and that
it can be successfully used in angiographic imaging within the
NANOMATERIALS
NIR-II wavelength range.
Single-Walled Carbon Nanotubes
Semiconductor-based single-walled carbon nanotubes Semiconductor Quantum Dots
(SWCNTs) have unique optical properties due to the existence A second successful application of Nanofluorescent probes
of the bandgap. When photons interact with SWCNTs, they developed by NIR-II technology is the use of semiconductor
are absorbed and released as fluorescence. It is worth noting quantum dots. Among the many kinds of semiconductor
that the absorption wavelength of SWCNTs is generally in the fluorescent quantum dots available, Ag2 S quantum dots have
visible region (400–700 nm) and NIR-I (650–950 nm). However, been most widely used in near infrared imaging because of their
their emission wavelength is in NIR-II (1,000–1,700 nm), strong NIR-II fluorescence and low biological toxicity. Their
and the energy from absorbed photons is not released by biological toxicity is lower than other quantum dots containing
radiation relaxation in the form of heat (O’Connell et al., 2002). Se, Te, Cd, Pb, As, and other acute or chronic toxic elements,
SWCNTs has been widely used in the fields of photothermal and and the fluorescence can be tuned from 687 nm in NIR-I to
photodynamic therapy (Robinson et al., 2010; Murakami et al., 1,294 nm in NIR-II (Yang et al., 2013; Gui et al., 2014a,b;
2012), fluorescence labeling, and fluorescence imaging of deep Zhao and Song, 2014). At the same time, it also has high
tissue in vivo (Welsher et al., 2011; Hong et al., 2012a, 2014). In fluorescence stability and fluorescence quantum efficiency. Ag2 S
addition, the use of SWCNT surface functionalization (Zheng quantum dots have smaller particle sizes [3.7 nm (Zhao and Song,
et al., 2003) using coating surfactants, polymers, DNA, proteins, 2014), 1.6–6.8 nm (Yang et al., 2013), 2.6–3.7 nm (Gui et al.,
and even viruses can greatly enrich the scope of application for 2014b), 3.5 nm (Gui et al., 2014a)], which are very suitable for
SWCNTs in the biological field. However, the characteristically bioimaging applications.
low fluorescence quantum efficiency (<1%) of SWCNTs is a For example, in 2012 Wang’s and Dai’s research teams
major issue still needing to be addressed. collaborated to report on NIR-II Ag2 S quantum dots with
SWCNTs are used in vivo imaging because of their inherently a fluorescence of 1,200 nm. The solubility of Ag2 S QDs was
wide NIR-II fluorescence emissions (Yi et al., 2012; Ghosh et al., changed by using a surface modification of water-soluble PEG
2014). In 2014, Belcher’s research team coated SWCNTs with molecules. And then Ag2 S QDs can be dissolved in water. Ag2 S
an M13 virus, using the M13 virus surface polypeptide, which was first used in NIR-II cell imaging and non-specific tumor
targets tumor cells, to specifically bind SWCNTs to tumor tissue. detection (Hong et al., 2012b). Additionally, in 2012, they applied
Using SWCNTs, Blecher was able to achieve targeted fluorescence PEG modified Ag2 S quantum dots with high quantum efficiency
imaging of tumor tissues in mice, which proved that the system to NIR-II imaging in vivo (Zhang et al., 2012), using nude mice
could be applied to clinical diagnosis (Ghosh et al., 2014). In inoculated with 4T1 tumors. Not only did the Ag2 S quantum
the same year, Hong et al. combined an IRDye-800 fluorescent dots were proven to be a good NIR-II fluorescence contrast
group with SWCNTs and intravenously injected the IRDye-800 agent, but interestingly, after injection into the tail of nude mice,
fluorescent group into mice. Using a NIR-II fluorescence imaging Ag2 S quantum dots gradually accumulated in the tumors of
nude mice as the circulation time increases. They believe that elements such as Ho3+ , Tm3+ , and Nd3+ (Naczynski et al.,
the reason for above observation is the non-specific enhanced 2013; van Saders et al., 2013). Using the basic structure of
permeability and retention effect (EPR effect) of cancer tissue. rare earth nanocrystals, multi-shell complex core-shell rare
Subsequently, Wang’s team did an in-depth study on the long earth nanoparticles have been developed. For example, in 2013,
period cytotoxicity of Ag2 S quantum dots in vivo (Zhang et al., Moghe team reported on a core-shell structure nanoparticle of
2013). The reticuloendothelial system (RES), such as liver and NaYF4 which had been regenerated on the surface of existing
spleen, is the main accumulation site of Ag2 S QDs in vivo, but it NaYF4 Yb:Ln nanocrystals (Naczynski et al., 2013). By changing
can be gradually metabolized or excreted over time. Additionally, the doped lanthanides (Er, Ho, Tm, Pr), NIR-II fluorescence
the results of the blood biochemical analysis and histological with different wavelengths can be obtained under 800 nm
examination of the rats given the Ag2 S quantum dots for 2 excitation, and the longest wavelength can reach up to 1,500 nm.
months showed that Ag2 S quantum dots had no obvious toxicity. Compared with up-conversion rare earth nanoparticles, down-
conversion nanoparticles have received less attention, but they
Nanoparticle Alloys are still widely applied in vivo bioimaging research (Naczynski
In materials science, mixing various metal elements to form et al., 2013, 2014; Jiang et al., 2016). Li et al. reported on a
intermetallic compounds or alloys can greatly expand the dual-function particle system using up-conversion and down-
properties of metals. Binary or ternary metal nanoparticles conversion (Li et al., 2013), where the particle can emit visible
(or nanoalloys) can synthesize intermetallic compounds with (800 nm) and near-infrared light (980 nm) according to the
controllable properties and structures on a nanoscale, which has excitation light of different wavelengths and can be used in
attracted extensive attention from researchers (Ferrando et al., biological imaging.
2008). The main reason why alloy nanoparticles are fascinating In recent years, it has been found that Nd ion not only
is that the chemical and physical properties of alloy materials has NIR-II fluorescence emission with wavelength of 1,050 or
change with changes in composition, atom distribution, and 1,300 nm, but also has the sensitization effect on Ytterbium
particle size. ion. It is excited at a biocompatibility wavelength below
Researchers who have devoted themselves to in-depth studies 800 nm, which has the lowest absorption of water. Nd3+
of these metal nanoalloys have found that metal alloy materials has been recognized gradually as a photosensitizer (Hemmer
not only have excellent catalytic properties, but also have et al., 2016), and Nd3+ doped near infrared fluorescent
excellent fluorescence properties. Further research shows that nanoparticles have attracted great interest from researchers
these fluorescent alloy nanoparticles inherit many advantages of who study lanthanide-doped biological probes. One kind
the original metal nanoparticles, such as fluorescence properties, of Nd3+ doped near infrared fluorescent materials is an
water solubility, and biocompatibility. They also can adjust the NaYF4 type down-conversion lanthanide nanocrystal (Chen
optical properties of the main metal nanoparticles or develop et al., 2012), and the other is an Nd3+ doped fluoride
new functions through the introduction of another metal. For nanoparticle (Pokhrela et al., 2014). For example, in 2015,
example, in 2013, Millstone’s team (Andolina et al., 2013) Garca’s group synthesized Nd3+ doped SrF2 nanoparticles and
introduced copper into fluorescent Au nanodots to form Au/Cu used them reduce background fluorescence (Villa et al., 2015),
alloy nanodots. By adjusting the content of copper in the alloy since minimizing any background fluorescence is essential
nanodots, the fluorescence of Au/Cu alloy nanodots gradually for high contrast bioimaging. The excitation wavelength of
shifted from NIR-I to NIR-II. Their group further introduced the nanoparticles is 808 nm, and the emission wavelength
the Co element into fluorescent Au nanodots to prepare Au/Co is 1,100 nm, which belongs to NIR-II fluorescence. The
alloy nanodots, which had both magnetic and near infrared nanoparticles are mixed into the feed and fed to mice. After
fluorescence tunable functions (Marbella et al., 2014). Compared the nanoparticles enter the mice through the digestive system,
to the traditional near infrared quantum dots, the multi- in vivo fluorescence imaging is performed. It was found that
functional alloy nanodots with near infrared fluorescence not an NIR-II fluorescence of 1,300 nm generated by the 4 F3/2 -
only free of toxic elements, such as heavy metals, but also have 4I 3+ effectively eliminated the
13/2 orbital transition of Nd
many functions in the same material. These mutli-functional background fluorescence. It can realize the NIR-II imaging of
alloy nanodots have wide prospects for application in bioimaging, deeper structure, inorganic spontaneous fluorescence and high
especially in the field of multi-mode imaging. distinguishability in vivo. In addition, in 2016 Prasad’s team
prepared a hybrid organic-inorganic system to form an epitaxy
Down-Conversion Rare Earth of NaYF4 : Yb3+ /X3+ @NaYbF4 @NaYF4 :Nd3+ (X = null, Er, Ho,
Nanoparticles Tm or Pr) core/shell/shell (CSS) nanocrystals, and coated ICG
Recent research results have shown that rare earth nanomaterials on the external layer of CSS nanocrystals. This hybrid system
have the ability of down-conversion luminescence, which is, can capture NIR light in a wide excitation spectrum range (700–
when near-infrared light (980 nm) is used as excitation light 860 nm) by ICG and produce effective polychromatic narrow-
to irradiate nanoparticles, its emission light is in the NIR- band NIR-II emission light from 1,000 to 1,600 nm according to
II spectrum range (Tan et al., 2009). The structure of these the different doping elements in the nucleus. Further experiments
nano-materials is very similar to that of up-conversion nano- show that the NIR-II emission fluorescence can be used to image
particles. Nanocrystals such as lanthanide nanocrystals (NaYF4 ) clearly at a tissue depth of 9 mm and detect optical signal at a
are used as primary materials, which doped with lanthanide tissue depth of 23 mm (Shao et al., 2016).
Nanoparticles Based on Organic above are organic products with low water solubility, which
Fluorescent Dyes need to be encapsulated in a hydrophilic matrix to enhance
Until now, organic fluorescent dyes are still the most biocompatibility in vivo imaging. Recently, Li et al. (2018)
widely used luminescent markers in fluorescence imaging. developed a novel small molecule fluorescent dye FD-1080
Organic fluorescent dyes have attracted much attention through a structural redesign of a typical anthocyanin dye.
due to their high fluorescence quantum efficiency, easy Its excitation and emission wavelength are both in the range
functionalization, and adjustable luminescence spectra (Thekkek of NIR-II. Besides there are reports about indocyanine green
and Richards-Kortum, 2008; Willmann et al., 2008; Kobayashi (ICG). ICG is a NIR fluorescent dye with strong absorption,
et al., 2010; Sinkeldam et al., 2010). The commonly used low toxicity, no involvement in biological transformation in vivo
organic fluorescent dyes presently include naphthalimides, and rapid excretion. It is the only NIR optical imaging contrast
coumarins, fluoresceins, rhodamine, anthocyanins, BODIPY agent approved by the US Food and Drug Administration
(Lu et al., 2014), porphyrin phthalocyanine, and other (FDA) for clinical use. Because the absorption and fluorescence
macrocyclic molecules. The absorption and emission spectra of ICG are in the NIR-I window (650–950 nm), ICG
wavelengths of these commonly used organic fluorescent has been widely used in cardiovascular system, liver function
dyes cover the ultraviolet, visible, and near infrared regions evaluation, visualization of retina and choroid, ophthalmic
(Mishra et al., 2000; Lavis and Raines, 2008; Ma and Su, angiography, cerebral angiography, and other clinical fields.
2010). Recently Starosolski et al. (2017) found that ICG dye also has
Over the years, how to convert NIR-I fluorescent probes NIR-II fluorescence characteristics in the NIR-II window. This
directly into NIR-II fluorescent probes by molecular engineering discovery has opened up new uses of ICG and will greatly
methods and design principles has been a highly discussed expand the application scope of ICG. In the experiment, the
topic among investigators. According to the available literature absorbance and NIR-II fluorescence emission of ICG were
(Yang et al., 2017; Zhu et al., 2018, 2019; Wu et al., 2019), detected in different concentrations of ICG media, including
the specific design principles are as follows: (1) The typical PBS, plasma and ethanol. The customized spectral NIR module
structure of NIR-II small molecule fluorescent dyes is a is used for in vitro and in vivo tests, and the images of NIR-
molecular structure composed of donor-acceptor-donor (D-A- I and NIR-II windows are obtained at the same time. The
D) (e.g., CH1055-PEG), which is modified to form a class of results show that ICG has a significant fluorescence emission
dyes with similar properties and emission wavelengths. The in the NIR-II window at the wavelength of about 1,100 nm,
specific emission principle uses aromatic π-bridge connectors as and this emission (similar to the absorption curve) is essentially
molecular wiring. These electron-supplying groups can produce affected by the molecular environment of ICG. The results of
enhanced electron shifts and low energy gaps to the central in vivo imaging further illustrated that ICG can be used as
electron acceptor, resulting with the dye molecule having the NIR-II fluorescent dye and the contrast-to-noise ratios (CNR)
capability of NIR-II emission. (2) By systematically adjusting the value was twice that in NIR-I window. Clinical transformation
electronic donor part, the π-bridge connector and the functional of NIR-II imaging technology can be accelerated when ICG, an
groups at the end of the fluorescent dye molecule promote FDA approved imaging agent, is used. Later, the research team
quantum yield. Specific strategies to improve the brightness published another paper on NIR-II fluorescence imaging using
of small molecular dyes include enhancing intramolecular indocyanine green nanoparticles (Bhavane et al., 2018). In this
charge transfer and molecular stiffness, creating complexes study, they collected the fluorescence spectra of ICG liposomes
with serum proteins, such as human serum albumin (HSA), in PBS and plasma. In vivo imaging research was carried out
and introducing a protecting group (S) to produce a S-D- to observe the vascular structure of the hind limbs and the
A-D-S structure at the end of the dye, which protects the intracranial region in real time. Free ICG, NIR-I imaging and
dye’s pillars from intermolecular interactions and fluorescence cross-sectional imaging (MRI and CT) were used as controls.
quenching polymerization. (3) By increasing the conjugate length The results showed that the liposome ICG had strong NIR-II
to separate electron donor/acceptor and heteroatom substitution, fluorescence, similar to the free ICG in plasma. In vitro studies
the fluorescence emission of existing polymethine dyes (i.e., have shown that liposome ICG has better performance than
cyanine dye) can be re-shifted to produce a new fluorescent dye free ICG in the NIR-II imaging of deep (≥4 mm) vascular
that can emit NIR-II fluorescence with high quantum yield and analog structure. In vivo, NIR-II fluorescence imaging with
absorption coefficient (ε) (Figure 2). At present, polymethine liposome ICG can significantly improve the contrast (P < 0.05)
molecular dyes with emission wavelength more than 1,000 nm compared with long-term free ICG, and make the hind limbs
are available on the market, including IR-1040, IR-1048, IR- and intracranial vessels visualized within 4 h after injection.
1051, and IR-1061. Unlike the previous method of for red- Compared with NIR-I imaging, liposome ICG enhanced
shifting anthocyanin dyes by simply increasing the length of NIR-II imaging has better vascular clarity. Subsequently,
polymethine chain, by Cosco et al. (2017) propose of a new several research papers on tumor imaging using Second-
method of extending heterocyclic conjugation and adding new Window-ICG (SWIG) technique were published, and this field
electron donor groups. This new method has been proven as a has become the latest research hotspot of NIR-II imaging
feasible method for red-shifting anthocyanin dyes. In addition, (Zeh et al., 2017; Cho et al., 2019a,b; Suo et al., 2019; Wang et al.,
most of the NIR-II small molecule fluorescent dyes mentioned 2019b).
FIGURE 2 | Increasing the length of polymethine chain was proved to result in the red shift of cyanine dye’s emission. Cosco et al. developed new methods of
heterocyclic conjugation and added new electron donor groups (Cosco et al., 2017; Zhu et al., 2018). (A) Molecular structure of cyanine dye series of compounds for
optical fluorescence imaging. (B) The blue structure is the compound of dimethyl-flavylium heterocycles, which can be used to replace the indolenines to prepare
flavylium polymethine fluorophores. (C) The emission and absorption of Flav7, the modified organic small molecule fluorescent dye, was in the NIR-II window. Adapted
from Cosco et al. (2017) and Schnermann (2017) with permission.
APPLICATIONS OF NIR-II WINDOW for the design of nanomaterials for medical applications in
BIOIMAGING IN BIOMEDICINE the future.
The key to the implementation of above-mentioned study is
Tumor Imaging and Image-Guided Surgery the in vivo assembly of novel NIR-II fluorescent nanoparticles,
Solid tumor patients often fail in treatment due to local which is also the ingenuity of this research design. The specific
recurrence. Cytopenic surgery is targeted to improve staging assembly principle is shown in Figure 3. At the top of Figure 3 is
and reduce tumors using fluorescence imaging to guide the a schematic of the step-by-step construction of DNA and FSHβ
specific resection of tumors and significantly improve the modified down-conversion nanoparticles (DCNPs-L1 -FSHβ ).
prognosis. Recently, this application field has become a high- The core of the nanoprobe are lanthanide doped core-shell
interest topic in research, resulting in the publishing of many nanoparticles, consisting of a 5.0 nm luminescent gadolinium
high-level papers. tetrafluoride sodium doped 5% neodymium (NaGdF4 :5% Nd)
Papers published by Wang et al. (2018) in Nature encapsulated by a 2.5 nm thick homogeneous gadolinium sodium
Communications, for example, report on a novel down inert shell. This type of a structure can avoid fluorescence
conversion nanoparticle emitted in the NIR-II window for quenching by water and bind complementary DNA (L1 or L2 ) on
living assembly. In metastatic ovarian cancer, fluorescent its surface. FSHβ is a follicle stimulating hormone peptide that
nanoprobes modified with DNA and targeted polypeptides specifically binds to ovarian cancer epithelium to enhance the
are used to ensure the precision of cytoreduction surgery. targeting efficiency of the fluorescent nanoprobe. Because of the
The image distinguishability of NIR-II nanoparticles is great potential of DNA complementary strand hybridization, the
better than that of clinically recognized ICG, mainly due nanoprobe can be stable hybridized on the surface of tumors in
to its better light resistance and deeper tissue penetration vivo for bioimaging. Next, a process diagram of the fluorescent
(8 mm). After the nanoprobe is assembled in vivo, the stable nanoprobe assembly in vivo is presented in the lower part of
preservation time of the nanoprobe on tumors is up to 6 h, Figure 3. It greatly enhances the tumor targeting of the probe,
so the nanoprobe can be used in precise tumor resection but also enables the probe to be excluded from the body by
surgeries. The probe successfully obtained a superior ratio the liver and kidney more quickly after the operation. The
of tumors to normal tissues, which can help to delineate specific process is to implement two-step injection of DCNPs-
the resection profile in the surgery for metastatic abdominal L1 -FSHβ and DCNPs-L2 -FSHβ , in succession. In order to verify
ovarian cancer. The results also showed that metastases the performance of two-step in vivo simultaneous assembly of
<1 mm could be completely removed under the guidance of fluorescent nanoprobes, the fluorescent dye Cy5 was grafted
NIR-II bioimaging. This novel method provides a new idea into the probe assembly structure of the first needle, i.e.,
FIGURE 3 | Construction of NIR-II nanoprobe schematic diagram in surgery for metastatic ovarian cancer guided by NIR-II bioimaging (Wang et al., 2018). The
diagram above shows the preparation of DCNPs (DCNPs-L1-FSHβ ) modified by DNA and FSHβ . The schematic diagram below shows the further assembly of the
NIR-II nanoprobe in vivo by a two-step sequential injection of DCNPs-L1-FSHβ (the first injection) and DCNPs-L2-FSHβ (the second injection), which is beneficial to
improve tumor targeting and rapid liver and kidney clearance. Under the guidance of NIR-II imaging, metastatic ovarian tumors can be clearly observed and accurately
removed. Adapted from Wang et al. (2018) written by Fan Zhang etc. with permission.
DCNPs-L1 -(Cy5)-FSHβ, and Cy7 were combined to the probe second, further packaging is completed with the cancer cell
assembly structure of the second needle, i.e., DCNPs-L2 -(Cy7)- membrane. The fabricated biomimetic nano-biological probes
FSHβ . When the complementary DNA fragments L1 and L2 in have a bright and highly stable fluorescence in the NIR-II
the two components of the probe are hybridized close to each window. Through the second step of surface encapsulation
other, the two dyes will cause fluorescence resonance transfer of active homologous tumor membranes, the probe enhances
(FRET), which is more than twice as strong as two dyes without the ability to target tumors. Tumor targeting occurs through
FRET. The results show that the two components of the probe the passive enhancement of permeability and retention of
can be specifically assembled on the surface of tumors in vivo. homologous cancer cell membranes, which can increase the
Ultimately, surgery guided by NIR-II imaging can clearly observe accumulation of probes in the tumor sites. Zhang et al.
metastatic ovarian cancer and precisely resection it. successfully prepared a novel biomimetic NIR-II fluorescence
Other recent representative work includes the development nanoprobe which showed characteristics of ultra-bright, stable
of Ag2 Te quantum dots by Zhang et al. (2019), which can fluorescence, homologous targeting and high biocompatibility,
emit fluorescence at 1,300 nm wavelength after assembly. The which can significantly enhance the imaging of living tumors.
assembly process is divided into two steps; first, polymerization In 2018, Yang et al. (2018) reported on a NIR-II lanthanide
is conducted with polylactic-co-glycolic acid (PLGA), and complex (Nd-DOTA) probe that can be rapidly excreted. Within
3 h after injection, more than 50% of the probe can be excreted the probe can detect and evaluate inflammation in vivo in real
through the kidney. The molecular weight of the probe is time with high imaging quality. The specific process of in vivo
only 0.54 KDa, and in terms of light resistance and tissue inspection of inflammation in real time by the fluorescence
penetration, the NIR-II imaging quality of the new probe is sensor of the ratio meter is shown in Figure 4, including the
much better than that of the clinically approved ICG. Yang device diagram of fluorescence probe used for confirmatory
et al. also demonstrated the ability to obtain an excellent testing in vivo, the fluorescence value of the ratio meter
tumor-to-normal tissue ratio, which can help to accurately (I980 /I1180 ) channel at different times, the quantitative curve
mark the profile of micro-tumors in surgery for abdominal of ratiometer fluorescence (I980 /I1180 ), and the corresponding
metastatic ovarian cancer. Metastatic tumors <1 mm can be concentration of hydrogen dioxide at different times.
completely removed under the guidance of NIR-II bioimaging. Figure 4A is the device diagram of the ratiometer fluorescent
In addition, the probe Nd-DOTA has the same structure as Gd- probe used for confirmatory testing in vivo, and Figure 4B
DOTA, and Gd-DOTA is a clinically recognized MRI contrast is a photograph of a mouse treated with fragments of
agent. Therefore, it may be a straightforward path for the a micromanipulator needle. Figures 4C–E show the 980,
clinical transformation of the new NIR-II probe. In 2018, Shou 1,180, and ratio gauge (I980 /I1180 ) channels, respectively. The
et al. (2018) prepared a semiconductor polymer nanoparticle of micromanipulator needle fragments obtained fluorescence values
diketopyrrolopyrrole (PDFT1032) and developed it as a NIR-II at different times after LPS-induced inflammation. Figure 4F is a
(near infrared window 1,000–1,700 nm) fluorescent probe for in quantitative curve of the ratio meter fluorescence (I980 /I1180 ) of
vivo tumor imaging and image-guided tumor re-sectioning. The the micromanipulation needle fragments and the corresponding
NIR-II probe has many advantages, including stable fluorescence concentration of hydrogen peroxide at different times. It can
emission, high absorption efficiency at 809 nm, large Stokes be used to quantify the degree of actual inflammation in
shifting, biocompatibility, and lower toxicity in vivo. Moreover, clinical tests.
research has shown this NIR-II probe has a wide range of Other recent studies in this field include Zhao et al.
applications in the biomedical field. For example, tumor imaging (2019) which reported on an original method for the accurate
in terms of subcutaneous osteosarcoma patterns, evaluating imaging of inflammation in vivo using in situ cross bonding
vascular embolization treatment on tumors, in-situ cytoreduction of glutathione-combined ultrafine lanthanum nanoparticles with
surgery guided by NIR-II images, and sentinel lymph node NIR-II fluorescent emission. Although nanoprobes have been
biopsy with superior temporal-spatial resolution (SLNB). In proven to be promising bioimaging platforms by reason of
general, PDFT1032 not only has good biocompatibility and their EPR effects, to the inability to enrich nanoprobe at target
hydrophilicity, but also excellent chemical and optical properties. position has been a key bottleneck to improve detection ability
The NIR-II fluorescent probe has a wide application prospect in and effect. While cross bonding of nanoparticles in vivo can
the imaging of malignant tumors and cytoreduction surgery. increase the enrichment of EPR region (e.g., inflammatory areas),
nanoparticles are absorbed by RES, resulting in unidirectional
Medical Testing cross bonding in non-target organs. Based on these difficulties,
Fluorescence bioimaging can detect deep tissues in the NIR-II the principle of this strategy was developed to enhance the in
window, and it has the smallest self-fluorescence and tissue vivo imaging by using sub-10 nanometer glutathione (GSH)
scattering. Nevertheless, in vivo NIR-II fluorophores detection combined lanthanide nanoparticles, which react with reactive
is merely concentrated on direct disease lesions or living organ oxygen species (ROS) in the inflammation region to locate and
imaging, and producing real-time dynamic NIR-II fluorescence image reactive oxygen species rapidly in the NIR-II window. At
biosensor has been challenging. In recent years, new methods the same time, these nanoprobes can be excreted quickly because
and breakthroughs have been emerging in this field, such as of their ultrafine magnitude. Based on the in-situ crosslinking
the conception and progress of quantitative detection with and rapid excretion ability of the probe, this method can achieve
fluorescent probe of ratio meter. accurate biological imaging and is suitable for other ultrafine
In Fan Zhang’s paper (Liu et al., 2018) published in contrast agents.
Angewandte Chemie International Edition in 2018, he reports a In 2019, Wang et al. (2019a) developed a reverse quenched
novel Erbium-sensitized up-conversion of nanoparticles, which NIR-II molecular fluorophore and applied it to high contrast
have the characteristics of both 1,530 nm excitation and 1,180 nm imaging and pH sensing in vivo. Currently, the molecular
emission in the NIR-II window, which can be used in vivo fluorophore with contrast and sensitivity in NIR-II window
biosensors. This research studies a micro-manipulation needle (1,000–1,700 nm) have both been developed in vivo fluorescence
debris sensor for in vivo inspection of inflammation in real time, imaging. However, the solvation of long-wavelength absorbed
where the detection principle of the sensor is based on the ratio fluorophore in aqueous solution, results in quenching, which
meter fluorescence combined with efficient NIR-II fluorescent is challenging to avoid. Therefore, a series of reverse-quenched
emission and the organic probe sensitive to hydrogen peroxide pentamethine cyanine fluorophore have been developed, which
under the action of Fenton catalyst Fe2+ . Finally, the dynamic significantly overcome the serious solvation coloration, thus
detection of inflammation in vivo is successfully produced. providing a stable absorption/emission of fluorescence over
This NIR-II radiometric probe has the following advantages: 1,000 nm in aqueous solution. The fluorescence intensity
large anti-Stokes displacement, low background fluorescence, increases up to ∼44 times and has excellent photostability. The
low absorption, and scattering in biological tissues. Therefore, conditions for lymphatic imaging can be met thanks to these
FIGURE 4 | Operational diagram of ratiometer fluorescence sensor (Liu et al., 2018). (A) In vivo bioimaging experimental apparatus. (B) Pictures of mice treated with
microneedle patches. After lipopolysaccharide was used to induce inflammation in mice, the upconversion luminescent images of microneedle patch at 980 nm (C),
1,180 nm (D), and ratio (I980 /I1180 ) (E) channels were detected at different times. (F) Ratiometric fluorescence (I980 /I1180 ) of microneedle patches at different time and
corresponding H2 O2 concentration. Adapted from Liu et al. (2018) written by Fan Zhang etc. with permission.
advantages, including the need for tissue penetration up to 8 mm, signal of drug-generated liver injury. Therefore, the structure
high definition, and optical stability. Its imaging effect is better of the fluorescent probe is designed as the combination of
than the clinically approved indocyanine green. In addition, benzothiophenacyl cyanine skeleton and phenyl borate group.
the fluorophore display pH-responsive fluorescence allows for The NIR-II fluorescence of this probe can be activated by
non-invasive ratio meter fluorescence imaging and gastric pH ONOO− and can detect ONOO− sensitively. When the probe
quantification in vivo. The results show that this method is IRBTP-B and the target ONOO− exist at the same time,
consistently accurate when tissue depth is 4 mm compared to the structure of probe changes to produce the fluorescent
the standard pH electrode method. This work opens up the group IRBTP-O to turn on the NIR-II fluorescence. The linear
potential of reverse quenching pentamethylene cyanine in NIR-II relationship between the NIR-II fluorescence intensity and the
biological applications. concentration of ONOO− is acceptable. Tissue model studies
In 2019, Li et al. (2019c) developed a NIR-II fluorescence confirm that reliable activation signals can be obtained at
molecular probe activated by peroxynitrate for drug-induced penetration depths up to 5 mm. With this probe, the up-
hepatotoxicity detection. Drug-generated liver injury is a key regulation of ONOO− in the model of incubation period drug-
problem to the safety of drug research and use. The emergence generated hepatotoxicity and the repair effect of N-acetylcysteine
of peroxynitrite (ONOO− ) is considered to be an initial (NAC) in vivo could be seen. In conclusion, this method will
be used as a general method to develop activated NIR-II probes is marked at the Gaussian fitting fluorescence intensity profile at
triggered by specific analytes based on hydroxyl functionalization the 808 and 1,064 nm excitation wavelengths, respectively. It is
reaction sites. obvious that at 1,064 nm the fluorescence intensity is higher and
the peak is narrower. When stimulated at 1,064 nm (1,300 nm
Vascular Biological Imaging long pass filter), the clear emission of the FD-1080-FBS complex
The number of people with cardiovascular and cerebrovascular enables the imaging of an alert or anesthetized mouse to detect
diseases has increased, as has the ability to detect these diseases the signal fluctuations produced by liver movement (Figure 5E).
using examination technology, which, in turn, has led to an Figure 5F is a spectrogram of the breathing rate of alert (above)
increase in incidence of cardiovascular and cerebrovascular and anesthetized (below) anesthetized mice. The graph shows
diseases. The commonly used techniques in clinical angiography that there are obvious differences in the spectrogram of breathing
include B-mode ultrasonography, CT scans, and nuclear rate between the two groups of mice, which can be used to
magnetic resonance (NMR). However, these techniques are quantify the respiratory rate of mice under different conditions.
non-tumor-specific, have low-sensitivity and high-cost, and Other studies have also been recently conducted in this
can’t be used for real-time detection or clinical practice in field, including Li et al. (2019a) in 2019, who developed
surgical operations. In recent years, some research groups have a rare earth nanoprobe triggered by 808 nm laser, which
designed NIR-II fluorescence probes and injected them into emitted NIR-II fluorescence for small tumor detection and
mice intravenously, after which the NIR-II fluorescence is used angiography. In this study, polyacrylic acid (PAA) modified
to perform vascular imaging in vivo. The results showed that sodium tetrafluorolutetium: gadolinium/neodymium nanorods
the NIR-II fluorescence could penetrate the skull of mice to a (PAA-NRs) were prepared into single crystal hexagonal phase
deeper level, not only imaging the distribution of blood vessels and unified magnitude, and then further developed as a highly
in the heads of mice, but also clearly showing the fine structure sensitive NIR-II imaging probe for optical imaging navigated
of capillaries. detection of tiny tumors, angiogenesis-related diseases, and
In 2018, Li et al. (2018) published papers within this field angiogenesis diagnosis. The NIR-II emission wavelength with
of study in the Angewandte Chemie, regarding the successful sodium tetrafluorolutetium: gadolinium as the main body can
synthetization of a small molecule fluorescent probe FD-1080, be easily adjusted by changing neodymium doping, which
which has excitation and emission both in the NIR-II region makes it hopeful that the emission center will have high
and it has excellent bioimaging capability of the vascular system optical stability at 1,056 and 1,328 nm. The probe has a high
in vivo. The structure of heptamethine in fluorescent probe spatial resolution (∼105 µm) for small blood vessels in vivo
FD-1080 has been ingeniously designed as a key group for and can detect them clearly. The in vivo tracking experiments
the conversion of absorption and emission into the NIR-II with time changes confirmed that PAA-NRs probe was mostly
region. An acidic sulfuric acid group and cyclohexene group collected in the RES, and discharged from the body by the liver.
were applied to intensify the water dissolvability and chemical Histological examination revealed that the hydrophilic nanorods
durability of the probe. The quantum yield of FD-1080 was had very low toxicity and great biological compatibility in
0.31% and improved to 5.94% when combined with bovine fetal living animals.
serum (FBS). It is noteworthy that compared with the excitation In the same year, Li et al. (2019b) reported a polydopamine-
wavelength from 650 to 980 nm in NIR-I region in the previous coated multifunctional lanthanide diagnostic agent, which
work, the excitation wavelength at 1,064 nm in NIR-II region can be used for angiography of vascular malformations and
has proved to have stronger penetration in biological media tumors, as well as photothermal therapy guided by imaging
and excellent imaging quality. FD-1080 can not only achieve at wavelengths above 1,500 nm. NIR-II optical imaging with
non-invasive, high-resolution, in-depth tissue bioimaging of the emission wavelengths >1,500 nm can be used as the next
vascular and cerebrovascular systems, but it also quantifies generation fluorescence imaging technology to guide the display
respiratory frequencies of awake and anesthetized mice according technology of tumor vessels and vascular malformations, which
to dynamic images of respiratory craniocaudal motion within the can then be used for early tumor diagnosis and recognition
liver. The key steps in this study included the schematic diagram of tumor-related vascular characteristics. This study is based
of the vascular imaging device, the fluorescence imaging of the rat on the core-shell structure of NaLuF4 nanorods@polydopamine
cerebral vascular system with the NIR-II fluorescence probe FD- (NRs@PDA), which combines advanced NIR-II fluorescence
1080, and the breathing rate detection graph of the rat, as shown imaging ultra 1,500 nm wavelength and photothermal (PTT)
in Figure 5. functions. This is a high-performance integrated nano-platform
Figure 5A is a device diagram of NIR-II fluorescence for diagnosis and treatment developed for visualization of
penetrating the scalp and skull brain tissue for an angiography. tumor-related vascular malformations and imaging-guided
Figure 5B is the disappearance spectra of the scalp (black) and photothermal therapy.
skull (red). It has been found that the strongest penetration In 2018, Wan et al. (2018) developed a bright organic NIR-
is at 1,064 nm. Figure 5C contrasts the fluorescence images of II fluorescent nanocluster (p-FE) for three-dimensional imaging
FD-1080-FBS complex in a rat brain vasculature system under of biological tissues, which can provide bright NIR-II fluorescent
different excitation lengths (1,300 long pass filter), where it was emission light with a wavelength >1,100 nm for non-invasive
found that the clearest angiogram was at the wavelength of in vivo blood flow tracking in the rat cerebrovascular system.
1,064 nm in NIR-II region. In Figure 5D, a red line of interest Moreover, p-FE can produce a layer-by-layer image of the
FIGURE 5 | Fluorescence imaging of rat brain vascular system and breathing rate of mice using NIR-II fluorescence probe FD-1080 (Li et al., 2018). (A) Schematic
diagram of NIR-II optical imaging through brain tissue scalp and cranial bone. (B) Extinction spectra of scalp skin and skull. The black curve represents the scalp skin
and the red curve represents the skull. (C) Fluorescence images of FD-1080-FBS complex were compared under different excitation conditions as indicated. (D) The
fluorescence intensity profile fitted by gaussian was distributed on a red line of interest, with excitation wavelengths of 808 and 1,064 nm, respectively. (E) The distinct
emission of the FD-1080-FBS complex made the awake and anesthetized mice imaged, and under the excitation of 1,064 nm detected the signal fluctuations
generated by the liver movement. (F) Respiratory rates in awake (upper) and anesthetized (lower) mice. Adapted from Li et al. (2018) written by Fan Zhang etc. with
permission.
vascular system based on single-photon and three-dimensional results demonstrated excellent dual imaging of vascular system
confocal imaging in a fixed rats brain tissue. Its depth is up to and tumors.
1.3 mm, and it has a spatial resolution of up to 10 microns. The
study also completed in vivo dual-color fluorescence imaging Diagnosis and Treatment of Cancer
in the NIR-II window, using p-FE emitted between 1,100 and Each imaging technology has its own unique advantages and
1,300 nm as a vascular imaging reagent, as well as single-walled inherent limitations. For example, fluorescence imaging has
carbon nanotubes (CNTs), which emitted more than 1,500 nm excellent sensitivity, but low tissue penetration and spatial
as a contrast agent to highlight tumors in mice. Ultimately, the resolution in turbid media. MRIs, CT scans, and ultrasound
FIGURE 6 | IVM technique of time-resolved imaging for tumor biomarkers (Fan et al., 2018). (A) A diagram showing the procedure of an animal experiment. Three
groups of Er nanoparticles with different lifespans were combined with three antibodies (anti-ER, anti-PR, and anti-HER2) and were transplanted into mice via the
caudal vessel. Lifespan distinguished imaging was then accomplished with IVM to quantitatively analyze biomarker expression on the tumor. (B) The lifespan
distinguished images of McF-7 and bt-474 tumors were decomposed into three lifespan paths, which were red, green and blue monochromatic images. The pattern
of biomarker expression was determined by integrating the intensities of each component and standardizing the overall intensity of the whole tumor area. Using the
results of in vitro western blot (C) and in vitro immunohistochemistry assay (D), the biomarker expression modes of IVM in two tumor hypotypes were calculated.
Adapted from Fan et al. (2018) written by Fan Zhang etc. with permission.
imaging have better spatial resolution, but their sensitivity is was designed to create an adjustable lifetime range of nanoprobes,
limited. The sensitivity of PET-CT scan is relatively high, but it which had a luminescence time spanning three orders of
can’t provide the structural information of the imaging material. magnitude and had only one emission band. When the depth of
Therefore, multi-mode imaging, which integrates two or more the NIR-II nanoparticle probe in biological tissue reached 8 mm,
imaging technologies, can supplement the imaging information the selected nanoparticle duration was continuously resolved,
and diagnose diseases with reliable accuracy. In order to meet and the SNR was taken from the time node when light intensity
the needs of multi-mode imaging, researchers usually combine was <1.5. Powerful time-length editors have been shown to be
fluorescent nanomaterials with functionalized small molecules independent of tissue penetration depth, and in vivo multiplexing
or particles by doping, bonding and coating to make them technology (IVM) has been used to diagnose tumor hypotype
multi-functional nanoparticles, which can be used in multi-mode in living animals. The data in this paper are in good agreement
biological imaging. with those of a standard ex vivo immunohistochemistry assay,
Deep tissue imaging within the NIR-II window has great which proves that the luminescent time-length imaging can serve
prospects in physiological research and biomedical applications. as a microinvasive method for tumor definite diagnosis. The
However, the inhomogeneous signal attenuation in biological research process and key points of IVM for tumor biomarkers
material limits the application of multi-wavelength NIR-II probes using specific luminescence time-length imaging are shown in
in the imaging of various biomarkers and cancer diagnoses. For Figure 6.
example, Fan et al. reported in 2018 (Fan et al., 2018), that Figure 6A illustrates the schematic diagram of conducted
NIR-II nanoparticles doped with lanthanides have the ability to animal experiments. Three batches of Erbium nanoparticles were
design the luminescence time for quantitative imaging in vivo bound to three different kinds of antibodies (anti-ER, anti-PR,
after using multiplexing in the time domain. To achieve this, a anti-HER2) and were transplanted into mice via the caudal vessel
systematic research method based on controllable energy transfer and resulted showed that each had a different luminescence
duration. Then, time-resolved images using in vivo multiple on the Fluorescence and Surface Enhanced Raman Scattering
techniques were used to quantitatively analyze the expression of (SERS) technique which has unique optical characteristics as
biomarkers in the tumors. In vivo multiple technology devices a main signal reader. The paper also focused on the review
include CCD and charge coupling devices. Figure 6B shows of the multiplexing strategy in biomedical field and the recent
the time-processing image, which decomposes MCF-7 and BT- advances in biosensors from multi-analyte and multi-color cell
474 tumors into three time-long paths, indicated by the red, tracking to multi-channel bioimaging in vivo. Finally, the paper
green, and blue monochrome image collections. The expression provided forecasting of future challenges and opportunities
of biomarkers was determined by integrating the intensity of each of multi-bio-analysis.
component and normalizing the total intensity to synthesize all In 2018, He et al. (2018) proposed that the structural design
tumor regions. Figures 6C,D are the results of in vitro protein and synthesis of fluorophores emitted in NIR-II biological
imprinting: Figure 6C shows the result of immunohistochemical window are moving toward multi-mode imaging, as well as
experiment of indirect in vitro therapy, While Figure 6D shows toward multimodal diagnosis and treatment. He et al. reviewed
the result of determined biomarker expression modes of the two some progress of NIR-II fluorophores and molecular probes
tumor hypotypes by using IVM. and considered the synthesis of NIR-II fluorescent group fit
At present, this field has become a vital resource for for multimode imaging will become a new way to obtain
biomedical diagnosis and treatment, and many research groups high-resolution images through the structural design. NIR-II
are competing to continue pushing forward in expanding its fluorophores can convert NIR-II photons into heat required for
study. Several high-level research papers and reviews have been photothermal therapy and can also be stimulated by NIR-II light
reported recently, such as Guo et al. (2019), who used NIR- to generate singlet oxygen for photodynamic therapy. The single
II fluorescence and photoacoustic imaging to study the precise probe has both diagnostic and therapeutic functions which can be
identification of the vascular system and micro-tumors in 2019. used for precise treatment. He et al. details the latest development
It is well-known that the diagnosis of cerebrovascular structure in structural design and synthesis of various NIR-II fluorophores
with complete blood-brain barrier and microtumors is of great and provides a discussion on the similarities and differences in
significance for the timely treatment of patients with nervous known NIR-II imaging systems and the recent research on NIR-II
system diseases. The combined diagnosis and treatment of NIR- imaging in biomedical applications.
II fluorescence and photoacoustic imaging (PAI) is anticipated
to provide improving performance, for instance, excellent spatial Tracking the Transplanted Stem Cells
and temporal distinguishability, large penetration depth and Stem cell (SC) is one type of pluripotent cells with self-replication
great SNR, and accurate brain diagnosis. In this study, conjugated ability, which can differentiate into a variety of functional cells
polymer nanoparticles (CP NPs) with biocompatibility and under certain conditions. SC therapy is showing the hope of
photostability were prepared, and bimodal brain imaging was curing major human diseases. In the process of SC therapy, how
achieved using its NIR-II window. The nanoparticles with to observe the transplanted SCs non-invasively in real time has
a uniform size of 50 nm can be prepared by microfluidic become a challenge in experimental and clinical research. NIR
device. The emission peak was at 1,156 nm and had strong imaging based on exogenous markers has always been one of the
absorption of 35.2 Lg−1 cm−1 is at 1,000 nm. NIR-II fluorescence best methods to trace stem cells in vivo.
imaging provides a solution to the depth and resolution issues In recent years, NIR fluorescent probes, with their strong
previously experienced with the hemodynamic and cerebral biological penetration ability, low photon detection domain
vascular systems, providing an imaging depth of 600 microns value, high detection sensitivity, relatively simple operation, and
and a spatial resolution of 23 microns. After an ultrasound- advantages of real-time imaging during surgery, have made the
induced opening of the blood-brain barrier, NIR-II PAI could shift of emission from NIR-I window to NIR-II window to
successfully perform non-invasive imaging of deep micro-brain track transplanted stem cells. For instance, Chen et al. (2018b)
tumors (2.4 mm below dense skull and scalp <2 mm) with a has reviewed the research progress of tracking transplanted SCs
SNR of 7.2. This study showed that CP-NPs is a promising brain with NIR fluorescence NPs. The latest development of NIR-II
diagnostic contrast agent. window fluorescence imaging technology was introduced. The
In 2019, Fan et al. (2019) published an overview of emergence of new fluorescent functional NPs (QDs, RE-doped
optical multiplex techniques for biological detection to improve NPs, organic fluorescent NPs, etc.) makes stem cells easy to be
biomedical diagnosis, arguing that traditional methods according labeled and tracked, greatly promoting the further development
to the detection of single disease markers may not be precise of stem cell therapy. NIR-II fluorescence emission is absorbed
enough, since disease progression usually involves a variety of little by tissues, and the scattering and spontaneous fluorescence
chemicals and biomolecules. Multi-target simultaneous analysis in NIR-II region are the least in tissues. Therefore, the signal-
is of great importance in basic biomedical research and clinical to-background ratio can be greatly improved, yielding to a large
application, promoting simultaneous multi-target analysis that tissue penetration depths and a good spatial-temporal resolution.
requires the development of a high-throughput multi-target Moreover, NIR-II fluorescence imaging technology for accurate
biological analysis technology. In order to improve the level of optical tracking can improve our comprehending of the fate and
biomedical diagnosis, this paper reviewed the research progress regeneration ability of transplanted SCs and provide immense
of optical multiplexing analysis technology used in biomedical potential development of SC-based regenerative medicine. Up
diagnosis over the recent years. The review primarily focused to now, only a few research labs are exploring the feasibility of
FIGURE 7 | Ag2 S quantum dots of NIR-II emitting were used to track the transplanted MSCs (Chen et al., 2018b). (A) Representative TEM pictures and fluorescence
emission spectra of Ag2 S QDs with diverse sizes. Adapted from Zhang et al. (2014) written by Qiangbin Wang etc. with permission. (B) Ag2 S QDs labeled MSCs were
(Continued)
FIGURE 7 | injected into mice by vein, and NIR-II fluorescence imaging was accomplished on the mice with 100 ms exposure. When excited at 808 nm, the
InGaAs/SWIR camera was used to obtain the NIR-II image. NIR-II fluorescence signal value in liver and lung of mice at diverse time points was quantitatively analyzed.
Adapted from Chen et al. (2018a) written by Qiangbin Wang etc. with permission. (C) MSCs were tracked in mice with acute liver failure and labeled by Ag2 S quantum
dots. MSCs were injected into mice in combination with or without heparin and imaged. Adapted from Chen et al. (2013) written by Qiangbin Wang etc. with
permission. Homing of MSCs was studied by (D) in vivo imaging and (E) fluorescence quantification. The MSCs were transplanted intravenously into a mouse model
with skin trauma. The left trauma was cured with a collagen scaffold loaded with SDF1-α. The right trauma was cured with collagen scaffold. The data are shown as
mean ± SD values from n = 3, *p < 0.05, **p < 0.01. Adapted from Chen et al. (2015) written by Qiangbin Wang etc. with permission.
using NPs emitted in NIR-II to track SCs in vivo. Ag2 S QDs-based stay around the footprint for the longest time, with the highest
NIR-II imaging is currently the only method that has succeeded cell retention rate. In addition, quantitative kinetics studies
in SC tracking research in vivo. In order to greater improve the showed that labeled MSCs were cleared by feces and urine.
performance of NPs emitted in NIR-II in SC-based regeneration Histomorphological analysis showed that therapeutic effect of
research, more efforts should be made to conquer the defects the medium density group was the best, and the labeled MSCs
(such as water solubility, physiological stability, biocompatibility, showed no damage or inflammatory response to the main organs,
and metabolic capacity) of current NIR-II NP-based imaging suggesting that too much or too little MSCs administration
technology. In addition, new strategies are needed to take full might reduce its efficacy. This imaging method provides spatio-
advantage of NIR-II excitation and emission. The comparison temporal evidence for the response of MSCs therapy in vivo,
diagram of transplanted mesenchymal stem cells (MSCs) tracked which is helpful for the optimization of MSCs therapy.
by Ag2 S quantum dots emitted NIR-II fluorescence is shown Moreover, in 2018, Huang et al. published a paper on NIR-II
in Figure 7. fluorescence and bioluminescence multiple imaging for in
Figure 7A shows typical TEM pictures and fluorescence vivo observation of the location, survival and differentiation
emission spectrum of Ag2 S quantum dots with different particle of transplanted stem cells (Huang et al., 2019). An NIR-II
sizes. Figure 7B shows the real-time NIR-II fluorescence imaging fluorescence/bioluminescence composite imaging method is
of Ag2 S QDs labeled MSCs after intravenous injection into successfully developed covering 400–1,700nm visible light and
mice exposed for 100 ms. When excited at 808 nm, NIR-II NIR-II window for in vivo monitoring of location, survival, and
fluorescence images were collected with InGaAs/SWIR camera. osteogenic differentiation of human bone marrow mesenchymal
The fluorescence intensity of NIR-II in liver and lung of mice stem cells (hMSCs) in a mouse model of skull defect. The
at diverse time points was measured, and then quantitative long-term biological distribution of transplanted hMSCs was
analysis was performed. In Figure 7C, Ag2 S quantum dots were observed by using Ag2 S quantum dot with NIR-II window.
labeled on MSCs and then injected into mice with acute liver Bioluminescent imaging (BLI) based on endogenous red firefly
failure for tracking study. MSCs were combined with or without luciferase (rfluc) and gaussia luciferase (gluc) driven by collagen
heparin and then transplanted intravenously into mice and type 1 promoter were used to report the survival and osteogenic
imaged. Figures 7D,E, respectively show in vivo imaging and differentiation status of transplanted hMSCs. At the same time,
fluorescence quantitative homing behavior of MSCs to the wound by combining the three imaging channels, they can not only
in a mouse model with skin trauma. MSCs were transplanted directly observe the various dynamic biological behaviors of the
intravenously into model mice. The left and right wounds transplanted hMSCs, but also further observe the promoting
were treated with SDF1-α-loaded collagen scaffolds and collagen effects of immunosuppression and bone morphogenetic protein 2
scaffolds, respectively. on the survival and osteogenic differentiation of the transplanted
Other related researches on the tracking of transplanted CS hMSCs. This new multifunctional imaging technique can
with NIR-II quantum dots include an article published in 2019 widely extend the analysis of the fate and therapeutic capacity
by Chen’s team about the fate of intraarticular injection of MSCs of transplanted stem cells and help to promote stem cell-
in vivo for the useful treatment of supraspinatus tendon tears based regenerative therapy and its transformation in the
(Yang et al., 2019). This paper reports that MSCs have a strong clinical applications.
therapeutic potential in the treatment of supraspinatus tendon
tears. However, by reason of the finite evidence of dynamic CONCLUSION
visualization of cell behavior in vivo, MSC therapy has not been
fully utilized and may even be underestimated. Here, PbS QD In summary, compared with traditional NIR-I imaging
labeled MSCs can treat supraspinatus tendon tears in mice. PbS technology and other medical imaging methods, NIR-II
QD is a biocompatible NIR-II fluorescence imaging probe, which bioimaging technology not only has a deeper imaging depth,
can provide a cell migration map and information about the but also can better avoid background interference such as
biological distribution and clearance process of MSCs injected spontaneous fluorescence and photon scattering of tissue. So
into the joints with three densities. Intra-articular injection can far, a variety of NIR-II dyes, such as inorganic nanomaterials
avoid MSCs being wrapped by filtered organs and reduces organ (single-walled carbon nanotubes, semiconductor quantum dots,
toxicity induced by quantum dots. It is worth noting that MSCs rare earth nanomaterials), conjugated polymers and organic
have similar migration directions, but the migration efficiency of small-molecule materials, have been successfully synthesized
the medium density group is higher. In the repair stage, MSCs and prepared. Because of its special properties, NIR-II dyes can
TABLE 1 | NIR-II contrast agent and its biomedical application.
Fluorophore Fluorescence property Biomedical applications References
SWCNTs 808/950–1,400 nm (excitation/emission) High-resolution imaging of blood vessels Welsher et al., 2009
M13-SWCNTs 808/950–1,100 nm Targeted fluorescence imaging of tumor tissues in Ghosh et al., 2014
(excitation/emission) mice
IRDye-800- SWCNTs 808/1,300–1,400 nm Imaging of the distribution of veins in the head of mice Hong et al., 2014
(excitation/emission) and the fine structure of the brain capillaries
A synthetic organic molecule (CH1055) 750/1,055 nm Tumor imaging and precise image-guided Antaris et al., 2016
(excitation/emission) tumor-removal surgery
o-SWCNT-PEG 980/1,300 nm Used in angiographic imaging Takeuchi et al., 2019
(excitation/emission)
Ag2 S QD 800/1,200 nm Used in NIR-II cell imaging and non-specific tumor Hong et al., 2012b;
(excitation/emission) detection Zhang et al., 2012, 2013
Au/Cu alloy nanodots or Au/Co alloy 808/950–1,100 nm It is a non-toxic and multifunctional nanodots for used Andolina et al., 2013;
nanodots (excitation/emission) in biological imaging, especially in multi-mode imaging Marbella et al., 2014
NaYF4 :Yb/Ln@NaYF4 (Ln= Er, Ho, Tm, 800/∼1,500 nm (excitation/emission) Widely applied in vivo bioimaging research Naczynski et al., 2013
Pr)nanocrystals
SrF2 :Nd3+ NP 808/1,100 nm (excitation/emission) In vivo NIR-II optical imaging Villa et al., 2015
NaYF4 :Yb3+ /X3+ @NaYbF4 @NaYF4 : 700–860/1,000–1,600 nm NIR-II in vivo imaging of deep tissue Shao et al., 2016
Nd3+ (X = null, Er, Ho, Tm or Pr) (excitation/emission)
FD-1080 1,046/1,080 nm (excitation/emission) non-intrusive high distinguishability deep tissue Li et al., 2018
hindlimb vascular system and brain veins biological
imaging
Free ICG 810–830/1,100 nm Utility in NIR-II navigated cytoreductive surgery of Starosolski et al., 2017;
(excitation/emission) cerebral cancers and accelerate the clinical translation Zeh et al., 2017; Cho
of NIR-II imaging technology et al., 2019a,b; Wang
et al., 2019b
liposomal-ICG (Lip-ICG) 782/950–1500 nm Long-term imaging of hind limb and intracranial Bhavane et al., 2018
(excitation/emission) vessels in vivo
ICG conjugated bevacizumab (Bev-ICG) 808 nm/>900 nm Immensely facilitate the application of NIR-II clinical Suo et al., 2019
(excitation/emission) bioimaging
Core:DCNPs(NaGdF4:5%Nd@NaGdF4) 808/1,060 nm Tumor imaging and image-guided surgery Wang et al., 2018
In vivo assembly nanoprobe: (excitation/emission)
DCNPs-L1 /L2 -FSHβ (L1 and L2 are
conjugated DNA; FSHβ is a follicle
stimulating hormone peptide)
Ag2 Te quantum dots (QDs) 808/1,300 nm Tumor imaging and image-guided surgery Zhang et al., 2019
lanthanide complex (Nd-DOTA) 808/1,060 and 1,330 nm Accurately mark the profile of micro-tumors in surgery Yang et al., 2018
(excitation/emission) and thoroughly removed under the guidance of NIR-II
biological imaging
semiconductor polymer nanoparticle of 809/1,032 nm Widely used in clinical imaging and surgical treatment Shou et al., 2018
diketopyrrolopyrrole (PDFT1032) (excitation/emission) of malignant tumors
NaErF4 :2%Ho@NaYF4 UCNPs 1,530/1,180 nm Used to quantify the degree of actual inflammation in Liu et al., 2018
the sensor is based on the ratio (excitation/emission) clinical tests
meter fluorescence
DCNPs(NaGdF4 :5%Nd@NaGdF4 )@GSH 808/1,060 nm Accurate imaging of inflammation in vivo Zhao et al., 2019
pentamethine cyanine NIR-II molecular 1,015/1,065 nm high-quality imaging and pH sensing in vivo Wang et al., 2019a
fluorophore (excitation/emission)
Peroxynitrate NIR-II molecular 575 and 905/>1,000 nm Drug-induced hepatotoxicity detection Li et al., 2019c
fluorophore IRBTP-O (excitation/emission)
Polyacrylic acid (PAA) modified 808/1,056 and 1,328 nm For Fluorescence imaging-guided detection of small Li et al., 2019a
NaLuF4 :Gd/Nd nanorods (PAA-NRs) (excitation/emission) tumors, angiogenesis-related diseases, and
angiogenesis diagnosis
NaLuF4 : Gd/Yb/Er NRs@PDA 980/1,525 nm Visualization of tumor-related vascular malformations Li et al., 2019b
(excitation/emission) and imaging-guided photothermal therapy
A bright organic NIR-II fluorescent 980/1,100 nm As a vascular imaging reagent for non-invasive in vivo Wan et al., 2018
nanocluster (p-FE) (excitation/emission) blood flow tracking in the rat cerebrovascular system
(Continued)
TABLE 1 | Continued
Fluorophore Fluorescence property Biomedical applications References
NaGdF4 @NaGdF4 :Yb,Er@NaYF4 : 808 nm/Er3+ at 1,525 nm. As a microinvasive probes for disease diagnosis Fan et al., 2018
Yb@NaNdF4 :Yb Ho3+ at 1,155 nm,
Pr3+ at 1,289 nm,
Tm3+ at 1,475 nm
Nd3+ at 1,060 nm
Conjugated polymer nanoparticles (CP 980/1,156 nm Accurate brain diagnosis Guo et al., 2019
NPs) (excitation/emission)
Ag2 S QDs 808/From 900 to 1,700 nm Tracking the transplanted stem cells Chen et al., 2013, 2015,
(excitation/emission) 2018a; Zhang et al.,
2014; Huang et al., 2019
C18 -PMH-PEG-Ag2 Se 808/1,300 nm Tracking the transplanted stem cells Dong et al., 2013; Chen
(excitation/emission) et al., 2018b
PbS QDs 808/1,100 nm Tracking the transplanted stem cells in vivo to provide Yang et al., 2019
(excitation/emission) evidence for therapy and promote the optimization of
therapy
AgInTe2 QDs 700 nm/between 1,095 and 1,160 nm In vivo bioimaging and solar energy conversion Langevin et al., 2015;
(excitation/emission) systems Kameyama et al., 2016;
Chen et al., 2018b
be used not only as biomedical contrast agent, but also in the functions, such as combining dye with targeted molecules,
fields of photothermal and photodynamic therapy, drug delivery, improving the aggregation ability of dye in specific parts of the
surgical guidance and tracking the transplanted stem cells. In organism, and promoting the development of disease targeting
this article, the reported NIR-II fluorescent probes and their and early diagnosis in clinical practice.
biomedical applications are summarized in Table 1.
With the development of molecular design theory and AUTHOR CONTRIBUTIONS
nanomaterials, more and more NIR-II imaging systems will be
designed, developed and promoted into clinical trials. It is worth JC wrote the draft and corresponded to submittal, revision,
noting that at present, most of NIR-II fluorescent molecules and coordination. BZ, KZ, SH, LM, JS, and HY participated
have poor water solubility and physiological stability, and low in manuscript revision. JS and HY oversaw the design, quality
fluorescence quantum yield. For polymers and inorganic nano assurance, and finalization of the manuscript.
systems, problems, such as slow metabolism, high toxicity, and
lack of specific tissue targeting, still exist. New methods and FUNDING
materials will be helpful to promote the application of NIR-
II imaging technology in the field of biology. In general, the This work was supported by the National Natural Science
following points should be paid attention to in the development Foundation of China [grant number 21874024], Young and
and design of NIR-II dyes. Firstly, in order to improve the water middle-aged teacher foundation of Education Department
solubility and physiological stability of organic NIR-II fluorescent of Fujian Provence [grant number JAT160157], the start-up
dyes, reduce the band gap when choosing the appropriate space funds for new teachers in Fujian Agriculture And Forestry
configuration, and consider the influence of the group on the University [grant numbers 61201400908, 61201400916], the
water solubility of dyes when modifying the group. Secondly, in Science and Technology Program of Fujian Entry-Exit Inspection
order to improve the biocompatibility and metabolic capacity of and Quarantine Bureau of P.R.C. [grant numbers FK2013-
the probe, the molecular structure should be designed reasonably. 29, FK2014-01], the National Natural Science Foundation of
In particular, when the probe is a polymer molecule dye and Fujian Province [2017J05019], Young Scientist Natural Science
nanoparticles, the design and synthesis of the degradation of Foundation of Universities in Fujian, and Chinese Scholarship
NIR-II dye probe is the best. Thirdly, dye is endowed with specific Council granted fund [No: 201700930062].
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published: 30 January 2020

Recent Progress in NIR-II Contrast

INTRODUCTION difference is found for the light scattering coefficients in NIR-I

TABLE 1 | NIR-II contrast agent and its biomedical application.

Fluorophore Fluorescence property Biomedical applications References

Fluorophore Fluorescence property Biomedical applications References

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