Nanomaterials for photoacoustic imaging in the second near-infrared window

Kai Huang abc, Yifan Zhang a, Jing Lin *a and Peng Huang *a
aGuangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, China. E-mail: jingl@szu.edu.cn; peng.huang@szu.edu.cn
bKey Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
cDepartment of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA

Received 11th June 2018 , Accepted 18th September 2018

First published on 18th September 2018


Photoacoustic imaging (PAI) is a rapidly developing imaging technique for both fundamental research and clinical applications. Recent studies revealed that PAI in the second near-infrared (NIR-II) region exhibits enhanced deep-tissue imaging capability, which benefits from reduced photon scattering, minimized background noise and increased applicable power in comparison to PAI in the first near-infrared (NIR-I) region. This review focuses on the latest achievements on PAI in the NIR-II region. The advantages of shifting PAI from NIR-I to NIR-II is first compared, followed by discussions on nanomaterials as contrast agents for NIR-II PAI. In the end, the challenges and perspectives of PAI in the NIR-II region are also elaborated.


image file: c8bm00642c-p1.tif

Kai Huang

Kai Huang obtained his B.Sc. degree in materials chemistry (University of Science and Technology of China) and a Ph.D. degree in biomedical engineering (National University of Singapore) in 2011 and 2016, respectively. After graduation, he was a postdoctoral researcher at the University of Massachusetts Medical School (UMMS). He is now a joint postdoctoral fellow between UMMS and the Laboratory of Evolutionary Theranostics (LET) at Shenzhen University (SZU). His research interest focuses on the design and development of energy conversion nanomaterials for biomedical applications.

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Yifan Zhang

Yifan Zhang received her B.Sc. degree from Nanjing University in 2011, where she obtained her PhD degree in 2016 under the guidance of Prof. Yiqiao Hu. Then she joined the Laboratory of Evolutionary Theranostics (LET) at Shenzhen University (SZU) as a postdoctoral fellow under the supervision of Prof. Peng Huang. Her research interest focuses on developing nanomedicine for cancer diagnosis, treatment and theranostics.

image file: c8bm00642c-p3.tif

Jing Lin

Jing Lin received her Ph.D. degree in organic chemistry from the Donghua University and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, in 2010. Then she joined PharmaResources (Shanghai) Co., Ltd as a group leader. After two years, she moved to the United States of America and spent 4 years as a postdoctoral student at the University of Maryland and the National Institutes of Health (NIH). She joined the faculty of Shenzhen University (SZU) in 2016 and was promoted as a Distinguished Professor in 2018. Her research focuses on the self-assembly of functional nanomaterials for diagnosis, treatment, and theranostics of diseases.

image file: c8bm00642c-p4.tif

Peng Huang

Peng Huang received his Ph.D. degree in biomedical engineering from Shanghai Jiao Tong University in 2012. Then he joined the Laboratory of Molecular Imaging and Nanomedicine (LOMIN) at the National Institutes of Health (NIH) as a postdoctoral fellow. In 2015, he moved to Shenzhen University (SZU) as a Distinguished Professor, Chief of Laboratory of Evolutionary Theranostics (LET), and Director of the Department of Molecular Imaging. His research focuses on the design, synthesis, and biomedical applications of molecular imaging contrast agents, stimuli-responsive programmed targeting drug delivery systems, and activatable theranostics.


1. Introduction

Photoacoustic imaging (PAI) is an emerging hybrid imaging technique that combines the high contrast of optical imaging with the high spatial resolution of ultrasound imaging.1–5 It works based on the photoacoustic effect of endogenous biological substrates (e.g. water, melanin, collagen, and lipids) or exogenous PA contrast agents. The PA effect is a phenomenon where substrates produce broadband acoustic waves at megahertz frequencies due to thermoelastic expansion after absorption of short laser pulses (Fig. 1).1,2 These acoustic waves based on the diverse intrinsic PA effect of different substrates will then be detected by an ultrasound transducer at the surface of the sample and reconstructed into an image. Because acoustic waves suffer less from tissue scattering compared to optical signals, PAI breaks the traditional limits of optical imaging. For instance, the lateral resolution of PAI is scalable with ultrasonic frequency and reaches the order of hundreds of micrometers for deep penetration depths (several centimeters) and tens of micrometers for shallow (<1 cm) penetration depths.2 More attractively, since PAI does not require photons coming out from the tissue, the imaging depth of PAI could reach several centimeters subjected to the penetration of excitation photons, in stark contrast to the penetration depth of optical imaging that usually is limited to no more than 2 centimeters due to the requirement of both in and out photons for imaging constructions.2,6 As a fast-growing non-invasive imaging technique, PAI has been widely applied for biomedical imaging from cells to organs, anatomy to function, and molecules to metabolism.7–14
image file: c8bm00642c-f1.tif
Fig. 1 Scheme of optoacoustic signal generation and detection. Pulse excitation light at selected optical wavelengths is absorbed by endogenous biological substrates or exogenous PA contrast agents, leading to instantaneous thermoelastic expansion and the resulting ultrasound waves to be detected. Reprinted with permission from ref. 1. Copyright 2017 Royal Society of Chemistry.

2. Shifting PAI to the NIR-II region

Shifting PAI from the first near-infrared (NIR-I) window (700–1000 nm) to the second near-infrared (NIR-II) window (1000–1700 nm) could lead to PAI with deeper tissue imaging capability and enhanced imaging contrast, thus attracting burgeoning research interest in the past couple of years.15 The imaging depth of PAI is determined by the penetration depth of the excitation light. During the propagation of light through biological tissues, scattering and absorption play significant roles in attenuating it. The scattering of light proportionally declines as the wavelength increases in most types of tissue (Fig. 2a).16 Thus, using longer wavelength excitation light in the NIR-II region, deeper penetration could be achieved. Meanwhile, this less scattering nature of NIR-II light could also contribute to the enhanced contrast in PAI, since scattering light could cause strong background noise due to its non-focused and random directional distribution. Moreover, major components of biological tissues, such as oxyhemoglobin, deoxyhemoglobin, melanin and fat, exhibit either a valley or decreasing trend of light absorption in the NIR-II region (Fig. 2b).6 It should be noted that, as an important endogenous absorber, water exhibits an increasing absorption above 950 nm and possesses a local maximum around 1450 nm (Fig. 2c).16 Thus for an overall consideration, PAI is more preferable in the short wavelength of the NIR-II region (1000–1400 nm) for deeper penetrating depth, while it is worth noting that there is still a lack of quantitative studies systematically investigating light penetration in different biological tissues considering the overall effect of the scattering and absorption of light at different wavelengths. A possible reason might be that the composition may be very different across different biological tissues and also variations exist across individuals, thus making it difficult for quantitative studies of the overall effect across different biological samples. In spite of the limited quantitative studies, the semi-quantitative studies of each effect, as summarized in Fig. 2, could still provide us with the general indications of the desirable NIR-II region for deep tissue applications. In addition, the higher tolerance of biological tissue to longer wavelength light (from 400 to 1400 nm) is another advantage of shifting PAI to the NIR-II region.17 According to the American National Standards for the Safe Use of Lasers (ANSI), the maximum permissible exposure (MPE) of the early range NIR-II light is much higher compared to NIR-I light (e.g. 1 W cm−2 at 1064 nm light vs. 0.33 W cm−2 at 808 nm light for skin exposure at a duration from 10 to 3 × 104 s) because of the lower energy and less tissue absorption of photons at a longer wavelength.17 The higher MPE of NIR-II light allows that the higher excitation power could be applied for deeper tissue imaging. Taken together, by shifting to the NIR-II region, PAI could be achieved with deeper tissue imaging capability and enhanced contrast due to the (1) less scattering, (2) weaker absorption and (3) higher MPE of NIR-II excitation light, which could promote PAI with better clinical translation possibilities.
image file: c8bm00642c-f2.tif
Fig. 2 Imaging window at the NIR-II region. (a) Reduced scattering coefficients of different biological tissues as a function of wavelength in the range of 400–1700 nm. (b) Effective attenuation coefficients of blood, skin, and fat as a function of wavelength in the range of 200–1800 nm. (c) Absorption spectrum of water through a 1 mm-long path. OD, optical density. Reprinted with permission from ref. 16 and ref. 6. Copyright 2009 and 2017 Nature Publishing Group.

3. Nanomaterials for PAI in the NIR-II region

The development of high-performance PAI contrast agents in the NIR-II region is crucial for shifting PAI to the NIR-II region. Since most endogenous biological substrates have weak interactions with NIR-II light, label-free PAI in the NIR-II region is significantly limited.6 The development of nanomaterials as exogenous contrast agents for PAI in the NIR-II region has thus attracted increasing research interest in the past couple of years. These contrast agents are expected to possess excellent photothermal conversion ability to generate significant acoustic signal due to thermoelastic expansion after light absorption. So far, a few types of NIR-II PAI contrast agents have been developed based on inorganic or organic nanomaterials by endowing them with NIR-II photothermal conversion ability through materials engineering.

3.1 Inorganic nanomaterials

Metal sulfides: Metal sulfides are a type of widely used nanomaterials for PAI.18,19 Conventionally, metal sulfides possess a broadband absorption in the NIR-I region and have been applied for NIR-I PAI and photothermal therapy (PTT).20,21 Their light absorption property is primarily determined by localized surface plasmon resonance (LSPR).18 LSPR describes the confinement of a surface plasmon in a nanoparticle of size smaller than the wavelength of incident light. It produces a collective oscillation of conduction band electrons on the surface of the nanoparticle, which subsequently generates significant wavelength-selective enhancement in light absorption and scattering.22 Recent studies revealed that the LSPR effect was significantly affected by composition variations in nonstoichiometric metal sulfides, such as Cu2−XS.23–27 By adjusting their composition, metal sulfide nanoparticles (NPs) with NIR-II photothermal conversion property could be achieved for NIR-II PAI. For example, Li et al. reported the first demonstration of NIR-II PAI using CuS NPs as the contrast agent in 2012.28 They found that the absorption band of CuS NPs could be tuned from the NIR-I to the NIR-II region by simply adjusting the stoichiometric ratio between CuCl2 and Na2S during their synthetic process. The as-prepared CuS NPs were approximately 11 nm in diameter (Fig. 3a) and possessed an absorption band peak at 990 nm (Fig. 3b). At the wavelength of 1064 nm, which is the valley of water absorption, the extinction coefficient of CuS NPs was calculated to be 2.6 × 107 cm−1 M−1, making it an excellent contrast agent for NIR-II PAI. CuS NPs were applied for NIR-II PAI with excitation under a 1064 nm Nd:YAG laser. An in vitro experiment confirmed that the CuS NPs-contained agarose gel embedded in chicken breast muscle could be imaged at a depth of ∼5 cm (Fig. 3c–f). This contrast agent also allowed visualization of mouse brain after intracranial injection and rat lymph nodes 12 mm beneath the skin after interstitial injection.28 Afterwards, they further red-shifted the absorption peak of nonstoichiometric CuS from 990 nm to 1064 nm, and demonstrated the PAI of tumor vasculature in a 4T1 breast cancer-bearing mice model.29
image file: c8bm00642c-f3.tif
Fig. 3 CuS nanoparticles (NPs) for NIR-II PAI. (a) Transmission electron microscopy image of CuS NPs; inset: size distribution of CuS NPs. (b) Extinction coefficient spectra of 0.5 mM CuS nanoparticle aqueous solution. (c–f) Photoacoustic images of agarose gels containing CuS nanoparticles beneath chicken breast tissue. Photograph of (c) chicken breast muscle blocks stacked, (d) the cross section of chicken breast muscle containing CuS nanoparticles of 100 μg mL−1 (2 OD), 50 μg mL−1 (1 OD), 25 μg mL−1 (0.5 OD), 12.5 μg mL−1 (0.25 OD), 6.25 μg mL−1 (0.125 OD), gel without contrast agent (from No. 1 to No. 6), and No. 7 represents two needle tips at center and 11 o'clock position; two-dimensional photoacoustic image at a depth of (e) ∼2.5 cm and (f) ∼5 cm, from a laser-illuminated surface. OD, optical density. Reprinted with permission from ref. 28. Copyright 2012 American Chemical Society.

In another case, Gao et al. also confirmed that the ratio between Cu and S significantly affects the absorption peak of CuS NPs.30 They adjusted the sulfide/copper ratio from 3[thin space (1/6-em)]:[thin space (1/6-em)]1 to 0.75[thin space (1/6-em)]:[thin space (1/6-em)]1; the absorption peak of CuS NPs was red-shifted from ∼1000 nm to more than 1300 nm. Moreover, they achieved dual-modal NIR-II PA/magnetic resonance imaging by doping magnetic Ni2+ ions into CuS NPs.31 Although the photothermal conversion ability was reduced due to the Ni2+ doping, this strategy of ion doping provides a solution to the design of multifunctional nanomaterials for multimodality imaging. Interestingly, the LSPR absorption peak of CuS NPs could also be controlled by ion doping. Li et al. reported ternary semiconductor nanomaterials (copper bismuth sulfide, Cu3BiS3) with broad LSPR absorption from 300 nm to 1100 nm after nonstoichiometric Bi doping.32 Through the Bi doping, the as-prepared Cu3BiS3 nanorods also exhibited X-ray sensitivity. Finally, nanorods were used for PAI-CT dual-modal guided PTT in the NIR-II region. It should be noted that although two of these studies did not perform NIR-II PAI, the good NIR-II photothermal conversion performance and PAI in the long-end of the NIR-I region suggested the potential of nonstoichiometric metal sulfides in NIR-II PAI.

Noble metals: They are another type of nanomaterials that are promising for NIR-II PAI. They exhibit intensive light absorption also due to the LSPR effect and are usually located in the visible or NIR-I region.33,34 The LSPR of noble metals is significantly affected by their size and morphology of NPs.33 Recent studies revealed that the aggregation of noble metals could red-shift their absorption band.35,36 It is because the broadband LSPR could be generated by a strong plasmonic coupling effect between closely arranged building blocks.37–39 However, the formation of gold ensembles consisting of multiple components could simultaneously reduce absorption efficiency due to strong light scattering resulting from their large sizes.40,41 Recently, Duan et al. developed an Au plasmonic blackbody (AuPB), which contained multiple Au nanoparticle assemblies in polydopamine (Fig. 4a).42 Due to the strong intraparticle plasmonic coupling effect among branches, these AuPBs surprisingly possessed intensive broadband absorption spanning the entire UV-Vis-NIR range from 400 to 1350 nm (Fig. 4b and c).42 This unique plasmonic nanostructure showed an excellent ability for NIR-II PAI (Fig. 4d). During the synthesis of AuPB, dopamine not only served as both a reducing agent and a surface capping ligand, but spontaneous self-polymerization of dopamine also led to the highly adhesive polydopamine coating on the AuPBs, imparting them with robust, readily tailorable surface chemistry and excellent thermal stability. These as-prepared AuPBs demonstrated PAI-guided PTT in the NIR-II region.


image file: c8bm00642c-f4.tif
Fig. 4 AuPB for NIR-II PAI. (a) Schematic illustration of the one-pot synthesis of AuPBs. (b) Simulation results of the heat power density inside the AuPBs illuminated by light at 808 and 1064 nm. The power density of the incident light was 1.0 W cm−2 for both wavelengths. (c) UV–vis–NIR absorbance spectra of dopamine and AuPBs at different stages of synthesis; inset: photographs of dopamine solution (left) and AuPB dispersion (right). (d) In vivo photoacoustic imaging of tumor region (highlighted by yellow circles) acquired at 1064 nm excitation at different times after intravenous injection. Reprinted with permission from ref. 42. Copyright 2018 American Chemical Society.

3.2 Organic nanomaterials

Semiconducting polymers: NPs are the most widely applied organic nanomaterials for NIR-II PAI. These polymers generally consist of alternating electron rich donors (D) and electron deficient acceptors (A), composing D–A pairs. Their absorption band is theoretically determined by the band gap between the highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular orbitals (LUMOs). Conventional semiconducting polymers could have a sharper and strong absorbance in the NIR-I window through rationally selecting the appropriate D–A pairs.43–45 However, it was challenging to further red-shift their absorption to the NIR-II region. Recently studies indicated that increasing the electron deficiency in semiconducting polymers could help to narrow their band gap and shift their absorption into the NIR-II region.46–49 For example, Pu et al. designed semiconducting polymers with NIR-II absorption by introducing an additional D–A pair into a NIR-I semiconducting polymer.46 The original NIR-I semiconducting polymer has a structure of poly[diketopyrrolopyrrole-altthiophene] (SP1) with a D–A alternating backbone structure, while the novel designed NIR-II semiconducting polymer consists of poly(diketopyrrolopyrrole-altthiadiazoloquinoxaline) (SP2) with a D–A1–D–A2 structure, wherein thiophene is the electron donor and both pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione and thiadiazoloquinoxaline are the electron acceptors. The much stronger electron-withdrawing ability of thiadiazoloquinoxaline further narrowed the band gap, shifting the absorption band to the NIR-II region (Fig. 5a and b).46 They applied the NIR-II semiconducting polymer for NIR-II PAI and achieved a 1.4-fold higher signal-to-noise ratio at 1064 nm excitation compared to 750 nm excitation at the tissue depth of 3 cm, benefiting from the decreased background PA signals of biological tissue in the NIR-II window (Fig. 5c and d). They further demonstrated PAI of brain vasculature in living rats, which showed a 1.5-fold increase in the signal-to-noise ratio as compared with NIR-I imaging at the same laser fluence.
image file: c8bm00642c-f5.tif
Fig. 5 Semiconducting polymer for NIR-II PAI. (a) Schematic illustration of SPN-II. (b) UV–vis–NIR absorption spectrum of SPN-II (40 μg mL−1 in tetrahydrofuran). (c) In vitro deep-tissue PAI in NIR-I and NIR-II windows. SPN-II (1 mg mL−1) spots were embedded in an agar gel phantom placed under different depths of chicken breast tissue. SNRs (dB) of SPN-II spots at 750 and 1064 nm were plotted as a function of the depth of chicken breast tissue. Energy density: 5.5 mJ cm−2. (d) 2D NIR-II PA images of the agar gel phantom containing SPN-II spots at different depths of chicken breast tissue. Energy density: 20 mJ cm−2 at 1064 nm. Concentrations of SPN-II spots (from the white asterisk anti-clockwise): 1, 0.5, 0.2, and 0.05 mg mL−1. Reprinted with permission from ref. 46. Copyright 2017 American Chemical Society.

In the meantime, Mei et al. developed another semiconducting polymer based on thienoisoindigo (TII).50 TII has a unique electron-deficient unit with high planarity, leading to the ultranarrow bandgap in TII homopolymers. Thus, TII homopolymers possess a strong absorption in the NIR-II region by themselves. These polymers were further conjugated with triethylene glycol (TEG) side-chains and formulated into NPs. After surface modification with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy[poly(ethylene glycol)]-2000] (DSPE-PEG2000), TII NPs have been applied for PAI at 800, 1000, 1100, 1200 and 1300 nm excitations. They found that PAI of TII NPs at 1300 nm benefited from even less intrinsic blood signal from tissue background, while PAI at a 1100 nm laser may provide higher excitation efficiency in tissue due to the less light attenuation in water. They also achieved PAI of a sample beneath a 5.3 cm-thick chicken-breast tissue at 1064 nm laser excitation. Similarly, Liu et al. used benzodithiophene (BDT), a widely used NIR-I semiconducting polymer, as the electron donor.51 BDT has a symmetrical and planar structure, which possesses a large extinction coefficient. They further introduced benzobisthiadiazole (BBT), a very strong electron-deficient acceptor, to copolymerize with BDT to form poly(benzodithiophene-altbenzobisthiadiazole), thus obtaining an NIR-II sensitive semiconducting copolymer. They applied the designed semiconducting copolymer for imaging orthotopic brain tumors in a mice model in the NIR-II region.

Phosphorus phthalocyanine: This compound was also developed for NIR-II PAI.52 Phthalocyanines (Pcs) are hydrophobic chromophores with delocalized macrocycle electrons, strong NIR absorption, diverse metal coordination capacity and good stability. These chromophores usually possess absorption bands in the NIR-I region.53,54 It was found that by engineering the intra-electron distributions, the absorption band could be shifted. For instance, Lovell et al. applied phosphorus Pc that contained central phosphorus and outer sulfur for both in vitro and in vivo NIR-II PAI.52 By introducing this electron-deficient phosphorus in the center and electron-rich sulfur at the outer part, they narrowed the band gap in the chromophore and shifted its absorption band from the NIR-I to the NIR-II region. They have surprisingly achieved PAI through 11.6 cm of chicken breast tissue and an entire 5 cm arm of a healthy human adult under the excitation of a 1064 nm laser.52

3.3 Other potential nanomaterials for NIR-II PAI

Apart from the above-mentioned nanomaterials, several other nanomaterials also possess strong NIR-II absorption and have been employed for NIR-I PAI guided NIR-II PTT. These nanomaterials are highly promising as potential nanomaterials for NIR-II PAI due to their good photothermal conversion performance in the NIR-II region.

MXenes: They are potential contrast agents for NIR-II PAI. They are two-dimensional (2D) materials composed of transition metal carbides, and either nitrides or carbonitrides.55 Due to their metallic nature, MXenes possess intensive LSPR, which gives them light absorption ability.55 By adjusting the metal elements of MXenes, their broadband absorption could spread to the NIR-I and NIR-II regions. For example, Chen et al. prepared 2D niobium carbide (Nb2C) nanosheets with excellent photothermal conversion property in both NIR-I and NIR-II windows, and demonstrated their highly effective NIR-I PAI-guided photothermal ablation and eradication of tumor in both the NIR-I and NIR-II biowindows.56

Nonstoichiometric titanium/silicon oxides: These are another type of materials with potential for NIR-II PAI. For instance, Li et al. developed nonstoichiometric SiOX NPs for NIR-I PAI-guided NIR-II PTT.57 They synthesized these SiOX NPs via magnesiothermic reduction of ordinary SiO2 NPs under hydrogen (20 vol% in argon). The reduced SiOX NPs exhibited full-spectrum UV-Vis-NIR from 200 to 1100 nm. This unique absorption of SiOX could be attributed to the LSPR effect of oxygen vacancies generated during the reduction process. Similarly, nonstoichiometric titanium oxide TiO2−X NPs obtained through the high-temperature reduction of ordinary TiO2 NPs under a hydrogen atmosphere also exhibited full-spectrum UV-Vis-NIR from 250 to 1300 nm due to the LSPR effect of induced oxygen vacancies.58,59 Both nonstoichiometric titanium oxide and silicon oxide possess good photothermal conversion ability in the NIR-II region and are thus promising for NIR-II PAI applications.

Semimetal Bi NPs: These nanoparticles could also be applied for NIR-II PAI. For example, Li et al. developed ultrasmall Bi NPs through the solvothermal synthesis method.60 The as-prepared Bi NPs exhibited broad absorption and efficient photothermal conversion from 350 to 1100 nm, which could be attributed to their higher charge carriers compared to semiconductors, which narrowed their band gap and thus were applicable for photothermal applications in NIR windows.61 Combined with the highly effective nuclear charge of Bi, PA-CT dual-modal imaging-guided synergistic NIR-II photothermal/radiotherapy of tumors was achieved using these Bi NPs. Therefore, Bi NPs could be used for NIR-II PAI-based multimodal imaging and theranostics.

4. Challenges and opportunities

Although PAI exhibits remarkable advantages in the NIR-II range, several challenges are needed to overcome before its further application in fundamental research and clinical translation. The first issue comes from the limited choices of ideal contrast agents for NIR-II PAI. Up to now, the types of nanomaterials that have already been applied for NIR-II PAI are quite rare. More efforts should be devoted to the discovery and development of NIR-II sensitive photothermal conversion nanomaterials as contrast agents for NIR-II PAI in addition to metal sulfides, noble metals, and semiconducting polymers. The second issue lies in the biosafety of the proposed nanomaterials for PAI in NIR-II. The above studies on nanomaterials for NIR-II PAI primarily emphasized the strategies to enhance the ability of nanomaterials for light absorption and heat conversion in the NIR-II region, thus to enhance their efficiency as contrast agents. However, their biosafety, especially the long-term effects, were not systematically investigated in these studies, which is crucial for future clinical translations. Therefore, more studies on the biosafety of nanomaterials with protective surface modifications for NIR-II PAI, including their biodistributions, excretion pathways, median lethal dose, and long-term effects, should be performed on various animal models to evaluate their feasibility for clinical translations. Thirdly, the access to well-developed equipment for NIR-II PAI is still limited. The commercially available PAI system usually covers excitations shorter than 970 nm, and current attempts on NIR-II PAI are mainly achieved by coupling a commercial 1064 nm Nd:YAG laser in the PAI setup. These home-made NIR-II PAI setups, however, make it difficult to compare PAI efficiency across laboratories. Moreover, since nanomaterials possess maximum absorption at different wavelengths, an excitation light source with a fixed wavelength may not match with the peak wavelength, making it difficult to reflect the real efficiency of different nanomaterials as contrast agents for NIR-II PAI. Thus, a standard NIR-II PAI system, preferably with multiple excitation sources in addition to the 1064 laser, would provide more freedom for the development of novel nanomaterials as NIR-II PAI contrast agents. It is noted that a recent PAI system, Vevo LAZR-X, included a 1200–2000 nm excitation source in addition to its original 680–970 nm excitation source. It would be more desirable if the 1000–1200 nm range with high tissue transparency could also be covered. Fourthly, the biomedical applications of NIR-II PAI are still at the early stage, most of which are proof-of-concept explorations. A number of studies demonstrated in vitro tests, while some others focused on tissue imaging. Therefore, NIR-II PAI with more complex and advanced biomedical applications, such as molecular imaging, metabolism imaging and biosensing, is also worth exploring.

5. Conclusions

The NIR-II region is a desirable window for PAI to achieve a deeper imaging capability with better contrast. Previous studies developed several types of nanomaterials, such as metal sulfides, noble metals, and semiconducting polymers, as contrast agents for NIR-II PAI. These nanomaterials were designed to acquire significantly enhanced PA effects in the NIR-II region through special materials engineering. It should be noted that as NIR-II PAI is still an infant and burgeoning research field, numerous research endeavors could contribute to the development of high-performance NIR-II PAI contrast agents, innovative NIR-II PAI systems and novel biomedical applications.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work is financially supported by the National Natural Science Foundation of China (51703132, 31771036, 51573096, 21807073), the Basic Research Program of Shenzhen (JCYJ20170412111100742, JCYJ20160422091238319 and JCYJ20170818144745087), the Guangdong Province Natural Science Foundation of Major Basic Research and Cultivation Project (2018B030308003), the Fok Ying-Tong Education Foundation for Young Teachers in the Higher Education Institutions of China (161032), and the China Postdoctoral Science Foundation (2018M630987, 2018M633139 and 2018M633138).

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