Luminescence interference-free lifetime nanothermometry pinpoints in vivo temperature

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  • ReceivedDec 10, 2020
  • AcceptedJan 25, 2021
  • PublishedMar 30, 2021


Funded by

the National Key R&D Program of China(2017YFA0205100)

the National Natural Science Foundation of China(21937003,21527801,21722101)


We are grateful for the discussion from Dr. Xingjun Zhu, and we sincerely thank Prof. Lingdong Sun for the kind help with imaging systems and discussions. This work was supported by the National Key R&D Program of China (2017YFA0205100), and the National Natural Science Foundation of China (21937003, 21527801, 21722101).

Interest statement

The authors declare no conflict of interest.

Contributions statement

These authors contributed equally to this work.


The supporting information is available online at http://chem.scichina.com and http://link.springer.com/journal/11426. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.


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  • Figure 1

    The quest to a more accurate approach to quantitively detect temperature in biological fluids. (a–c) Luminescence thermal sensing scheme based on single peak, double peak (ratio metric) and lifetime; (d, e) illustration of the design of an interference free lifetime-based thermometry. Three main aspects contribute to the accurate thermal sensing in vivo: (1) an endogenous thermal sensing scheme (not related to surface) and proper shielding in the nanoscale; (2) lifetime-based sensing, which provides a calibration in the temporal domain; (3) a high collection efficiency and high quantum efficiency imaging system beyond 900 nm, which allows deep-tissue penetrable NIR II light be efficiently collected and analyzed (color online).

  • Figure 2

    The energy transfer interplay and thermal response in Nd-Yb co-doped nanocrystals. (a) Structural illustration and proposed energy transfer ways in a Nd-Yb co-doped core-shell nanocrystal. The solid arrow is back energy transfer from Yb3+ to Nd3+, the dashed arrow is energy transfer from Nd3+ to Yb3+. (b) Time-gated spectroscopy illustrates the energy transfer is mutual. α-NaNdF4: Yb@CaF2 nanocrystal was excited by 785 and 975 nm, and normalized by the peak intensity of 975 nm emission. The excitation laser was filtered by a time-gate. (c) TEM images of NaNdF4: Yb@CaF2 nanocrystal with different doping ratio. The insert shows the size distribution of the nanocrystals. (d, e) Luminescence and lifetime profiles of the NaNdF4: Yb@CaF2 nanocrystal with different doping ratios at room temperature. The excitation was a 785 nm diode laser. (f) Energy diagram of Nd3+ and Yb3+ energy transfer process. (g) The normalized lifetime change in biological temperature range (excited at 785 nm and collected at 975 nm). The lifetime was divided by the maximum value. (h) Thermal sensitivity of NaNdF4: Yb@CaF2 nanocrystals. The lifetime-thermal relationship was fitted by y=y0+Aet/x and calculated accordingly (see Methods Section) (color online).

  • Figure 3

    Energy transfer from 2F5/2 in Yb3+ to 4F3/2 in Nd3+ leads to thermal response in well-protected Nd-Yb doped core-shell nanocrystals. (a) Simplified energy transfer scheme shows a temperature-induced enhancement of Nd3+ to Yb3+ energy transfer rate (WNd-Yb). (b) Experimental energy transfer rate of Nd3+ to Yb3+ calculated from lifetime of Nd-Yb and pure Nd doped core-shell nanocrystals. (c) Simulated luminescence decay curves of NaNdF4: 25%Yb@CaF2 nanocrystals with increased energy transfer rate WNd-Yb. (d) Simplified energy transfer scheme shows a temperature-induced enhancement of Yb3+ to Nd3+ energy transfer rate (WYb-Nd). (e) Experimental energy transfer rate of Yb3+ to Nd3+ calculated from Yb-Nd and pure Yb3+ doped core-shell nanocrystals. (f) Simulated luminescence decay curves of NaNdF4: 25%Yb@CaF2 nanocrystals with increased energy transfer rate WYb-Nd (the simulated decay curves in (c, f) correspond to 2F5/2-2F7/2 transition of Yb3+) (color online).

  • Figure 4

    Interference-free lifetime thermometry helps pinpointing temperature in complex media. (a) Schematic comparison of luminescence thermometry (single peak, intensity ratio and lifetime) in complex biological media. Illustration of single peak detection (b), ratio metric detection (c), lifetime-based detection with no interference-free design (d, with energy transfer to the environment), and (e) interference-free design between ideal (water, in cuvette) and biological environment (blood). (f, g, h, i) Experimental results using the above-mentioned methods in different solvents, respectively. (f) The intensity was integrated from 900 to 1050 nm; (g) the intensity ratios were compared from peaks integrated from 850 to 915 nm and 915 to 1040 nm; (h) Rhodamine B was excited at 510 nm and collected at 575 nm; (i) the α-NaNdF4: 25%Yb@CaF2-PAA-PEG was excited at 785 nm and collected with 850 nm longpass and 980 nm bandpass filters. The error bars represent standard deviation of the test (n=12 per group). **** p<0.00001, * p<0.05, n.s. means not significant (color online).

  • Figure 5

    Chopper-based frequency domain luminescence lifetime imaging reveals in vivo temperature during hot stress. (a) Illustration of a chopper-based frequency domain time-resolved system. (b) Working principle of the frequency domain imaging system. (c) Images of phase contrast of PAA-PEG NaNdF4: 25%Yb@CaF2 nanocrystals at different temperature. (d) Intensity image of a nude mouse intravenously injected with thermal dots (NaNdF4:Yb@CaF2-PAA-PEG). The sketch shows the imaging area and the heating area. The footpad of the mouse was fixed to a ceramic heating pad and set to 45°C during heating process. (e) Thermal images show the vascular temperature in a living mouse. The image was segmented by adaptive threshold, and the white circle indicates significative area. The temperature of the low-intensity regions out of the white circle is inaccurate. (f) Locally enlarged image of (e). (g) Temperatures of the cross sections of the resting, cooling and recovered stage shown in white arrow in (e), respectively. (h, i) ROI analysis and the different recovering dynamics of the vascular temperature during the recovering process (ROI 4‒10 in blue, green, yellow and orange, indicate the artery. ROI 1‒3 in purple and blue and ROI 11 in red circles indicate the vein). To better show the relative temperature change, temperature values were normalized by the original temperature at 0 s (color online).


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