Innovation and Partnerships Office

Small, Photostable, Non-blinking Upconverting Nanocrystals for Imaging IB-3130


  • Luminescent tags for biological imaging – single molecule to whole animal
  • High-throughput screening for drug discovery
  • Nanocrystal lasers
  • Photovoltaics
  • Digital displays
  • LEDs
  • Infrared and chemical sensors
  • Optoelectronic communications


  • Efficiently upconverts infrared to visible light
  • Responds to inexpensive infrared laser excitation
  • No autofluorescent background signal in cells
  • Photostable: non-blinking, non-bleaching
  • 5 –15 nm particle size is comparable to proteins
  • Biocompatible
  • Inexpensive materials


A team of Berkeley Lab researchers led by Bruce Cohen has developed a technique to produce tiny bioimaging tags using nanocrystals able to absorb infrared light and then emit higher energy visible light through the property of upconversion. These lanthanide-doped nanocrystals range in size from 4.5 to 15 nm, and are phosphorescent rather than fluorescent. Unlike conventional fluorophores, they do not degrade under strong light, nor do they blink, a quality that can severely complicate imaging experiments. Because their size is comparable to the macromolecules they tag, they are far less likely to interfere with the function of these target proteins than many of the larger nanocrystals that have been reported.

The Berkeley Lab team used combinatorial chemistry and exhaustive screening to find the right-sized particles with the upconversion property. Photoluminescent materials typically absorb photons and then re-emit them at a lower energy state — that is, at longer wavelengths. Upconverting materials absorb two or more photons and re-emit a single photon at a higher energy state — a shorter wavelength. Because biological materials such as cells and proteins simply do not upconvert, the signals from these nanocrystals cannot be drowned out by cellular autoflurorescence.

Upconverting nanocrystals have been commercially available, but the smallest ever previously produced are larger than 20 nm, and this size can perturb the target proteins. The Berkeley Lab team developed a process to fabricate their extremely small upconverting nanocrystals made of β-phase NaYF4, which is the most efficient host material for upconversion. The size of the nanocrystals was controlled during fabrication by varying the concentration of surfactants, reaction temperature, and the ratio of yttrium to fluoride ions. Yielding a bright, unblinking signal, these nanocrystals are ideally suited for single-particle imaging. Significantly, they can be activated by modest infrared lasers costing in the vicinity of $2,000, while competing multiphoton fluorescent imaging products require pulsed lasers costing 100-fold more.

The bright, upconverting properties of these crystals could have significant applications beyond medical imaging. If they can be applied economically to photovoltaic panels, for example, they could convert the infrared light —uncaptured in most solar panels — into visible light, which can subsequently can generate electric power, boosting the efficiency of the process. They also hold potential for use in LEDs and integrated optoelectronic circuitry used in telecommunications and, possibly, optical computers.

Fluorescent dyes and stains have been important tools in biological research for more than a century. Dyes such as fluorescein attached to a specific protein in a cell will fluoresce under exposure to light, signaling the presence and behaviors of that target protein. However, fluorescent tags have inherent limitations for modern bioimaging: a tendency to degrade, or photobleach, under the bright-light conditions required to image molecular targets, and a tendency to blink on and off, which can severely complicate imaging experiments. The faint glow of a fluorescent tag may also be lost in the background noise from surrounding biological materials that naturally absorb and emit light, a phenomenon known as autofluorescence. This new Berkeley Lab technology overcomes these limitations.

DEVELOPMENT STAGE:  Bench-scale prototype.

STATUS: Issued U. S. Patent # 9,556,379.  Available for licensing or collaborative research.


Ostrowski, A.D., Chan, E.M., Gargas, D.J., Katz, E.M., Schuck, P.J., Milliron, D.J., Cohen, B.E., “Controlled synthesis and single particle imaging of bright, sub-10 nm lanthanide-doped upconverting nanocrystals,” ACS Nano 6 (3), 2686–2692 (2012).


High Throughput Nanoparticle Delivery to the Cytosol of Living Cells, IB-2849