Upconversion nanoparticles for bioimaging

Chenxi Song; Shubiao Zhang; Quan Zhou; Hua Hai; Defeng Zhao; Yunze Hui

doi:10.1515/ntrev-2016-0043

Artikel Open Access

Upconversion nanoparticles for bioimaging

Chenxi Song
Chenxi Song received his BSc degree in applied chemistry from Liaoning Normal University in 2012. He is currently working towards his PhD degree in the department of Chemistry at Dalian University of Technology. His research interests focus on the study about nonviral vectors for gene delivery and bio-imaging nanoparticles.
, Shubiao Zhang
Shubiao Zhang is a distinguished professor at Dalian Minzu University and a doctor supervisor at Dalian Institute of Chemical Physics and Dalian University of Technology. He received his PhD in applied chemistry at Dalian University of Technology in 2000, after that he worked as a postdoctoral fellow at Dymatic Chemical Inc. for over 2 years. From then on he works as a teacher at Dalian Minzu University and is involved in the study about nonviral vectors for gene delivery and bioactive materials.
, Quan Zhou
Quan Zhou received her doctorate degree at Dalian University of Technology in 2014. She is currently a lecturer of chemical engineering and technology, working in SEAC-ME Key Laboratory of Biochemistry Engineering at Dalian Minzu University. Her current research interest is the development of novel graphene-based nanocomposites for biosensors and bio-imaging agents.
, Hua Hai , Defeng Zhao und Yunze Hui

Veröffentlicht/Copyright: 20. Oktober 2016

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Abstract

Fluorescent labeling is a widely used indispensable tool in biology. Conventional downconversion fluorescence labels with ultraviolet or short-wavelength excitation suffer from autofluorescence, low signal-to-noise ratio, and incident photo damage to living organisms. However, upconverting fluorescent nanoparticles emit detectable photons of higher energy in the near-infrared (NIR) or visible range upon irradiation with a NIR light in a process termed upconversion. They overcome some of the disadvantages faced by conventional downconversion labels with the advantages including very low autofluorescence, absence of photo damage to living organisms, high detection sensitivity, and high depth of light penetration, thus making them an ideal fluorescent label for bioimaging. The present review focuses on the features of upconversion nanoparticles, the applications of upconversion nanoparticles in bioimaging, and the bioimaging equipments and methods and discusses the obstacles and development trend of upconversion nanoparticles in bioimaging; we hope this work will provide insights into the study of relevant fields. Upconversion nanoparticles have special photoluminescent properties. Substantial advancements have been made in the field of upconversion nanoparticles for bioimaging. A large number of modifications of upconversion nanoparticles are studied to make them more hydrophilic and biocompatible. At the same time, the safety and toxicity of nanoparticles have caused wide public concern.

Keywords: bioimaging; biomaterials; rare-earth; upconversion nanoparticles

1 Introduction

Most biomolecules lack sensitively detectable fluorescent signal; hence, there is a need for fluorescent labels to study their molecular interactions. Fluorescent probes emit florescence at certain wavelengths which can be detected using florescence microscope under in vitro and in vivo conditions. Exogenous labels for biological analysis were first introduced by American scientists, Yalow and Berson, in the form of radioimmunoassay. Apart from its high sensitivity (10⁻⁹~10⁻¹²) and wide application, it suffers from radioactivity and inherently short half-life. This has led to the introduction of various nonradioactive labeling techniques based on enzyme-catalyzed reactions, bio/chemiluminescence, and fluorescence. Among the three, fluorescent labeling is widely used in biology and medicine.

Fluorescence is generated by luminescence phenomenon that occurs in fluorophores. It is a process by which a fluorophore absorbs a particular wavelength of light and excites to higher energy state with emission of light. This emission energy corresponds to the energy difference between excited state and ground state. The optical properties of fluorophores such as fluorescence intensity, excitation spectrum, emission spectrum, and fluorescence lifetime help to encode the happenings around the molecule that is monitored. For example, labels which are environmentally sensitive can be used as molecular reporters. Information on what is happening in their molecular environment can thus be derived from their florescence signals, and their exact locations can be monitored using florescence microscopy. Most of the conventional florescent labels follow the principle of Stokes law. They are excited under ultraviolet (UV) or short-wavelength excitation. The main problems in using them are autofluorescence (noise) from analytes under UV and short-wavelength excitation which decreases the signal-to-noise ratio (SNR), low light penetration depth, and severe damage to living organisms [1], [2], [3]. Organic dyes, fluorescent proteins, lanthanide chelates, semiconductor quantum dots (QDs), lanthanide doped inorganic nanoparticles, and fluorophore tagged latex/silica nanobeads are some conventional fluorescent labels. Among them, the most commonly used are organic dyes and QDs.

Organic dyes, though popular owing to their low cost, availability, and easy usage, also pose some challenges such as short Stokes shift, poor photo-chemical stability, susceptibility to photobleaching, and decomposition under repeated excitation. Some commonly used organic dyes are florescein, rhodamine, cyanine, and Alexa dyes. QDs are semiconductor nanoparticles composed of atoms from groups II–VI or III–V of the periodic table. They are generally defined as particles with physical dimensions smaller than the exciton Bohr radius, typically 1–5 nm. This small size leads to a quantum effect, which endows nanoparticles with unique optical and electronic properties. The advantages of using QDs over other fluorescent labels include great assay sensitivity and stability and better emission selectivity. QDs with different sizes and compositions can be excited simultaneously with a single wavelength of light to produce emissions at different wavelengths useful in multiplex detection studies. Some problems involve water dispersibility and biocompatibility. These obstacles in the application of conventional labels have forced the development of labeling materials.

Upconversion nanoparticles (UCNPs) with near-infrared (NIR) excitation show the best performance. The process in which the emission energies are found to exceed excitation energies by 10–100 times kinetic theory (KT) violating Stokes law in its basic statement is called upconversion (UC). UCNPs convert low-energy exciting photons to visible emissions. They have various advantages such as low autofluorescence and no photo damage to living organisms, as exciting NIR light does not excite the biological samples; deep tissue penetration, as NIR light shows low scattering effect; high emission signals, as the UC process occurring inside the host materials is not affected by external environment such as pH, temperature, etc; and multiplex imaging, as under the same excitation, the emission wavelengths of UCNPs can be varied by changing their doping ions [4], [5], [6]. Therefore, it is necessary to give an overview of UCNPs and their bio-applications.

2 Advantages of UCNPs in bioimaging

2.1 Improving penetration depth

Suitable penetration depth of UCNPs for bioimaging could be obtained by using different upconversion materials. Upconversion materials based on the triplet-triplet annihilation (TTA) have emerged as a promising method to improve the efficiency of the upconversion process. The TTA is an important process that involves photon absorption by a sensitizer with a large absorption cross-section in the visible and/or NIR and a high triplet quantum yield. This strategy can maintain high translational mobility of the chromophores, avoid luminescence quenching by aggregation, and improve penetration depth in bioimaging, leading to the increase of the upconversion process efficiency. Bogdan et al. reported a TTA upconversion material with the excitation wavelength of 635 nm for in vivo imaging, whereby an emission at 530±25 nm was collected. Though the penetration depth was only 2 mm, by using these TTA-based upconversion materials under excitation at a low power density (12.5 mW cm⁻²) [7], they proved to be a useful tool for monitoring the binding interaction with lectins in aqueous samples.

Recently, the 980–800 nm UCNPs doped with Tm³⁺ has been used for in vivo bioimaging. Because the excitation and emission wavelengths of the upconversion process are located within the optical transmission window of biological tissues, upconversion in vivo bioimaging based on lanthanide UCNPs provides a higher penetration depth. For example, Chen et al. reported that upconversion images from a suspension of NaYbF₄:Yb,Tm@CaF₂ core shell nanoparticles (27 nm) can be successfully acquired through 3.2 cm of pork tissue [8]. Liu et al. demonstrated that high-contrast upconversion imaging of a whole black mouse was achieved using hexagonal phase NaLuF₄:Yb,Tm (7.8 nm) as a probe. The penetration depth was approximately 2 cm [9]. Though great progress has been made, the penetration depths need to be improved for some in vivo bioimaging applications.

2.2 Low photobleaching

When lanthanide-based and TTA-based UCNPs are used as luminescent probes, they show low photobleaching. Yu et al. had reported direct experimental evidence to prove this point [10]. HeLa cells co-stained with 4′,6-diamidino-2-phenylindole and NaYF₄:Yb,Er were illuminated with an excitation radiation of 1.6 μW (405 nm), 0.13 μW (633 nm), and 19 mW (980 nm). Only the luminescence from NaYF₄:Yb,Er was preserved. The nature of the inorganic host lattice of lanthanide UCNPs brought about its high photostability. When a relatively longer-wavelength excitation is used for TTA-based upconversion systems, higher photostability is observed with the fluorescence of the nihilator as the detection signal.

On the other hand, rapid photobleaching of 9,10-diphenylanthracene was seen in normal fluorescence imaging with excitation at 405 nm (0.15 mW) [11]. For the TTA-based UCNPs, excitation with shorter wavelength (higher energy) light than that used for common fluorescence will damage the structure of the corresponding annihilator molecules and hence give rise to the photobleaching phenomenon.

2.3 Low detection limitations in whole-body animal imaging

The minimum number of cells detected in living animals by upconversion luminescence imaging is an important parameter in the evaluation of the sensitivity of an in vivo imaging technique. Sun et al. demonstrated that when human nasopharyngeal epidermal carcinoma cell (KB cell )labeled with sub-10 nm β-NaLuF₄:Yb,Tm nanoparticles were injected into a mouse subcutaneously or intravenously, low detection limits were achieved for in vivo whole-body bioimaging with upconversion emission SNR of >3 and >10, respectively [9]. Xu et al. [12] reported that around ten mesenchymal stem cells labeled with NaYF₄:Yb,Er nanoparticles could be detected by in vivo imaging with 50 nm lanthanide UCNPs. Interestingly, high-contrast whole-body TTA-based upconversion in vivo bioimaging can be achieved with an SNR of 25, although the blue upconversion emission at 430 nm was used as the detection channel [11]. Such short-wavelength photoluminescence as a detection signal had not previously been achieved in conventional fluorescence in vivo bioimaging. Unfortunately, no data concerning detection limits for TTA-based upconversion imaging of small animals has been reported to date.

2.4 Multiplex upconversion in vivo bioimaging

Multiplex upconversion in vivo bioimaging can be easily achieved; thus, lanthanide UCNPs show sharp emission lines, and upconversion emission can cover UV, blue, green, red, and NIR spectral ranges by changing the doping activator ions. For example, Chatterjeea et al. [13] demonstrated multiplexed lymphangiography of three groups of lymph nodes using three different lanthanide UCNPs with multiwavelength emissions. To date, however, no example of multiwavelength TTA-based upconversion in vivo bioimaging has been reported.

The advantages of UCNPs, including excellent photostability, no autofluorescence of biological samples, good tissue penetration depth, and less tissue damage during the imaging, all make them suitable bioimaging probes. Meanwhile, there are some distinct differences in upconversion bioimaging as labels.

3 Equipments and methods of bioimaging

In this part, the bioimaging equipments and methods are introduced. For upconversion bioimaging of lanthanide UCNPs, Chen et al. constructed a laser scanning upconversion luminescence confocal microscope (LSUCLM) by introducing a stop-pass excitation dichroic mirror and using the confocal pinhole technique to block out-of-focus light (Figure 1) [8]. This instrument was built on a reversed microscope with a confocal scanning unit. A 980 nm continuous-wave (CW) laser was directed and focused onto the specimen. Light was deflected by the galvanometer mirrors and separated by a reverse excitation dichroic mirror and then crossed a confocal pinhole and a filter before entering a photomultiplier tube as the detector.

Figure 1:

Schematic layout of a LSUCLM system setup; the excitation beam path from a CW laser is shown in green, and the upconversion emission pathway is shown in blue. Reprinted with permission from Ref. [10].

They further developed another confocal microscope based on a similar principle [8], [9], [11]. However, the excitation wavelengths can be rationally tuned for TTA-based upconversion systems. Therefore, when a different sensitizer/annihilator was adopted and paired with tunable excitation/emission wavelengths, the mirror, reverse excitation dichroic mirror, and filters can be judiciously selected so as to operate at specific wavelengths. Usually, TTA-based upconversion bioimaging requires lower laser excitation power than lanthanide UCNPs probes.

Xiong et al. have introduced the use of a small-animal upconversion luminescence imaging system for Yb³⁺-sensitized UCNPs. Two external CW fiber 980 nm lasers with adjustable power as the excitation sources was used (Figure 2) [7]. In this system, beam expanders converted the radiation into beams of larger diameters, which then homogeneously illuminated the whole body of the small animal. An electron-multiplying charge-coupled device (EMCCD) was used to collect weak upconversion emission. The short-pass filter was tuned according to the different excitation and emission wavelengths of the upconversion materials. Upconversion emission signals could be collected in different channels by changing the optical filters between the sample and the EMCCD. This small-animal upconversion luminescence imaging system setup could also be modified for TTA-based upconversion systems by introducing CW lasers at 543 or 633 nm to replace the 980 nm laser as excitation source [8], [9], [11].

Figure 2:

Diagram depicting the experimental setup for the small-animal upconversion luminescence imaging system. Reprinted with permission from Ref. [10].

To date, some commercial systems are available for upconversion luminescence in vivo imaging with similar modifications. Benefiting from the working light in the NIR range, such a small-animal upconversion luminescence imaging system also worked well with the existence of ambient illumination light [11]. This is extremely important for potential applications such as imaging-guided surgery because doctors need proper illumination during surgery process while the upconversion imaging system is working.

Fluorescence diffuse optical tomography is a 3D visualization method used to reconstruct the internal fluorophore distribution inside a highly scattering material by acquiring the boundary fluence using multiple source-detector pairs. Recently, Xu et al. developed an optical tomography system to reconstruct the upconversion emission image by utilizing CCD cameras to capture the image for every scanned position under excitation at 980 nm [11], [12], [14]. The tomographic reconstruction images from lanthanide UCNPs had higher quality than those from conventional organic dyes due to the excellent upconversion SNR arising from the ultralow autofluorescence background.

4 Application in bioimaging

Upconversion materials can be used for photostable biological labels and cell imaging. They can also be used for photodynamic therapy (PDT) of cancer and other diseases. Under irradiation of infrared light, a biological system itself does not show fluorescence and only upconversion produces luminescence; this markedly reduces background and improves accuracy and sensitivity of biological detection. At the same time, UCNPs possess high chemical stability, high SNR, low potential biological toxicity, etc. They are more desirable as biological imaging markers.

4.1 Targeted upconversion materials

Huang et al. from Fudan University did much research on small-animal imaging with the targeted upconversion materials probes. The amino-functionalized surface of NaYF₄:Yb,Er was hydrothermally synthesized and functionalized with folic acid (FA). This was used to measure the folate receptor expression of FR (+) cervical carcinoma (HeLa) cells with FR (−) human breast cancer cells (MCF-7) as control. Excitation at 980 nm showed red light (500–560 nm) and green light (495–570 nm light) that overlap substantially in HeLa cells. Thus, it is confirmed in the bright-field and dark-field photographs. Subsequently, they injected UCNPs-FA and UCNPs-NH₂in vivo via tail vein. The same mouse had the HeLa tumor on the right flank. After 24 h, the tumor showed signal from UCNPs-FA; the untargeted probe did not accumulate confirming molecular imaging of the folate [15], [16].

Similar work has been done with the RGD peptide and α_vβ₃with NaYF₄: 20% Yb, 1.8% Er, 0.2% Tm as a fluorescent probe, and U87 MG tumor model. The UCNPs RGD peptide has good tumor targeting behavior. Tissue slice imaging showed a depth of 600 μm with little autofluorescence interference. The ROI (region of interest) analysis showed that the SNR between tumor and background lighting signal conversion was 24. Li and colleagues evaluated toxicity of polyacrylic acid (PAA)-modified NaYF₄:Yb,Tm by intravenous injection into mice. The results showed that PAA-UCNPs mainly targeted the liver and spleen [17], [18].

4.2 Upconversion materials with core-shell structure

Recently, a silicon-layer core-shell structure of nanocrystalline NaYF₄: Yb, Tm @ Fex Oy (core 20 nm, shell 5 nm) was synthesized. The core-shell nanocrystals had a strong NIR emission at 800 nm with continuous 980 nm laser excitation shown by a magnetization intensity of 12 emu g⁻¹. This material has been successfully applied to KB cells and mouse lymphatic system upconversion imaging [19].

At the same time, Ohulchanskyy et al. reported [20], [21] a core-shell structured NaYbF₄:Tm/NaGdF₄ with the size of 12 nm. Compared with the pure NaYbF₄:Tm core, the emission intensity increased 3 times after being coated with NaGdF₄ on its outside surface.

The UCNPs were coated with SiO₂ and amino modified to form core-shell nanoparticles. After functionalization on the surface, the rabbit antibodies were connected to the UCNPs to form conjugates. This antibody-UCNP conjugates were applied in the detection of a cancer biomarker carcinoembryonic antigen. Certain attachment of the UCNPs onto the HeLa cells due to the connection of antibody and UCNPs facilitated fluorescent imaging and detection of the HeLa cells. These results indicate that the amino-functionalized UCNPs can be used as fluorescent probes in cell immunolabeling and imaging [22], [23].

4.3 Bifunctional upconversion materials

In addition, Zhang et al. [24], [25], [26], [27], [28], [29], [30], [31], [32] provided an approach to activate caged small interfering RNAs (siRNAs) using NIR-to-UV upconversion process to achieve high spatial and temporal gene interference patterns. siRNA molecules against the anti-apoptotic gene survivin were caged by light-sensitive molecules (4,5-dimethoxy-2-nitroacetophenone, DMNPE). NIR-to-UV NaYF₄:Yb,Tm UCNPs here were used as delivery and activators [33], [34], [35], [36], [37], [38], [39], [40], [41], [42]. Liu reports the synthesis of tetragonal-phase LiYF₄ nanoparticles doped with upconverting lanthanide ions [43], [44], [45]. It is found that microwave hydrothermal method can be used to synthesize NaYF₄:Yb³⁺,Tm³⁺ microtubes faster, and the upconversion fluorescent intensity is also enhanced. The authors also concluded possible reasons and mechanisms for the enhancement of the fluorescent intensity [46], [47], [48], [49]. These bifunctional nanoparticles have potential application in florescence imaging [50], targeting [51], bioseparation, cancer diagnosis and treatment, DNA separation, and magnetic resonance imaging [52], [53], [54], [55], [56]. Significant advancements have been made in the last decade, but therapeutic application of UCNPs is still hampered by safety and toxicity issues [57], [58], [59], [60], [61], [62], [63], [64], [65], [66].

5 Opinion on bioimaging in the future

Upconversion luminescent materials have received great attention for several decades and have been considered as the next generation of photoluminescent probes for sensing and bioimaging due to their special photoluminescent properties, especially that they can convert a longer wavelength radiation (e.g. NIR light) into a shorter wavelength fluorescence (e.g. visible light). Upconversion fluorescence imaging technique with excitation in the NIR region possesses several advantages like being less harmful to living organisms, low autofluorescence, high sensitivity, and better penetration in biological tissues.

The applications of UCNP are limited due to its low water dispersibility despite its advantages. Therefore, surface modification of UCNPs plays a crucial role in improving their hydrophilicity and biocompatibility before employing them in biological studies [5], [67], [68], [69], [70], [71]. There are two main types of modifiers: one is organic surfactants such as cetyl-trimethyl ammonium bromide or ethylene diamine tetraacetic acid that are often used as ligands to control the particle growth and stabilization against aggregation; the other is hydrophilic, biocompatible, and bifunctional polymers such as polyvinylpyrrolidone [72], chitosan [73], [74], polyethylenimine [42], polyacrylic acid sodium salt [75], and polyethylene glycol [76], [77], [78], [79], [80] that are often used as chelating and stabilizing agents for UCNPs in order to render the UCNPs hydrophilic and provide functional groups for bio-conjugations.

Furthermore, hierarchical structure shows superior properties compared to traditional nanoparticles, especially when the design and controllable fabrication of core-shell composites have received extensive scientific and technological interest. The commonly used strategy is to encapsulate the hydrophobic UCNPs with a thin layer of SiO₂, as its surface chemistry is well documented [39], [81]. The silica-coated NaYF₄ upconversion nanocrystals displayed good in vitro and in vivo biocompatibility, demonstrating their potential applications in both cellular and animal imaging systems. The surface silica prevents nanoparticles from flocculation and provides room for decoration with functional groups such as thiol, amino, and carboxyl groups, which allow greater control in conjugation protocols [82], [83]. However, the precise control of the thickness and uniformity of SiO₂ layer is rather difficult, and thus several UCNPs may be packed together in a single layer of SiO₂, which will result in aggregation.

So far, though great progress has been made in the past few years in the biomedical field, there are still many challenges which hinder potential applications of UCNPs as therapeutic and bioimaging agents. Among them, nanotoxicology studies and safety assessment are absolutely essential for clinical application. Previous studies have shown that the UCNPs have no obvious toxicity in the in vitro and in vivo toxicity assessments, but the effects of UCNPs on small animals over an even longer time and the interaction between the UCNPs and the immune systems are still unknown; meanwhile, the interaction of UCNPs with proteins in blood is still unclear. Therefore, much more systematic investigations are still needed.

Meanwhile, the biggest payoff of nanomedicine lies in the realization of theranostics, the combined function of therapy and diagnostics by a single nanoformulation. However, limited promising research was reported on this topic, which restricts real-time monitoring of therapeutic action [84], [85]. Development of theranostic agents for see-treat-see action will be appealing, as it will be of tremendous value to a patient who does not have to wait for posttreatment evaluation to determine the outcome [86].

Biosensing and bioarrays using various nanocarriers can be the next thrust in this field, which provides numerous opportunities for point-of-care diagnostics, without the need to refer to the demanding clinical assessments. What is more, new single-cell molecular assays using Raman molecular probes will be a valuable approach in the development of personalized molecular medicine [87], [88], [89], [90].

In summary, UCNPs are promising nanomaterials for bioimaging; however, challenges will remain before much progress can be made in their biocompatibility and toxicity. Future work will involve targeted localization of these particles to tumors in vivo in small animals as a prelude to use in primate animals and humans.

6 Conclusion

Conventional downconverting fluorescent labels suffer from autofluorescence, low light penetration, and severe photodamage to living organisms. UCNPs with NIR laser excitation are a good alternative because they have strong anti-Stokes emission of discrete wavelengths, great contrast in biological specimens due to the low autofluorescence upon excitation with NIR light, and simultaneous detection of multiple target analytes. With these advantages, UCNPs have potential applications in immunoassays, bioimaging [91], and PDT [92], [93], [94]. There is still room for improvement in UCNPs because of their large size, absence of functional groups for bioconjugation, and instability when dispersed in aqueous solutions. In addition, the synthesis of bifunctional UCNPs with surface modification has raised a significant interest in the field of biolabeling [95], [96]. Thus, we hope this review could provide insights into the study strategy of UCNPs in bioimaging.

About the authors

Chenxi Song

Chenxi Song received his BSc degree in applied chemistry from Liaoning Normal University in 2012. He is currently working towards his PhD degree in the department of Chemistry at Dalian University of Technology. His research interests focus on the study about nonviral vectors for gene delivery and bio-imaging nanoparticles.

Shubiao Zhang

Shubiao Zhang is a distinguished professor at Dalian Minzu University and a doctor supervisor at Dalian Institute of Chemical Physics and Dalian University of Technology. He received his PhD in applied chemistry at Dalian University of Technology in 2000, after that he worked as a postdoctoral fellow at Dymatic Chemical Inc. for over 2 years. From then on he works as a teacher at Dalian Minzu University and is involved in the study about nonviral vectors for gene delivery and bioactive materials.

Quan Zhou

Quan Zhou received her doctorate degree at Dalian University of Technology in 2014. She is currently a lecturer of chemical engineering and technology, working in SEAC-ME Key Laboratory of Biochemistry Engineering at Dalian Minzu University. Her current research interest is the development of novel graphene-based nanocomposites for biosensors and bio-imaging agents.

Acknowledgments

This research is financially supported by the National High-Tech Research and Development Program of China (863 Program, 2014AA020707), the National Natural Science Foundation of China (21176046), and the Fundamental Research Funds for the Central Universities (DC201502020205, DC201501076).

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Received: 2016-6-2

Accepted: 2016-7-12

Published Online: 2016-10-20

Published in Print: 2017-4-1

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/ntrev-2016-0043

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bioimaging; biomaterials; rare-earth; upconversion nanoparticles

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