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J Am Chem Soc. 2017 Jul 26;139(29):9961-9971. doi: 10.1021/jacs.7b04022. Epub 2017 Jul 13.

Three-Dimensional Imaging of Transparent Tissues via Metal Nanoparticle Labeling.

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Institute of Biomaterials and Biomedical Engineering, University of Toronto , Rosebrugh Building, Room 407, 164 College Street, Toronto, Ontario M5S 3G9, Canada.
Department of Immunology, University of Toronto , Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , Room 230, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
Department of Chemical Engineering, University of Toronto , 200 College Street, Toronto, Ontario M5S 3E5, Canada.
Department of Material Science and Engineering, University of Toronto , Room 450, 160 College Street, Toronto, Ontario M5S 3E1, Canada.


Chemical probes are key components of the bioimaging toolbox, as they label biomolecules in cells and tissues. The new challenge in bioimaging is to design chemical probes for three-dimensional (3D) tissue imaging. In this work, we discovered that light scattering of metal nanoparticles can provide 3D imaging contrast in intact and transparent tissues. The nanoparticles can act as a template for the chemical growth of a metal layer to further enhance the scattering signal. The use of chemically grown nanoparticles in whole tissues can amplify the scattering to produce a 1.4 million-fold greater photon yield than obtained using common fluorophores. These probes are non-photobleaching and can be used alongside fluorophores without interference. We demonstrated three distinct biomedical applications: (a) molecular imaging of blood vessels, (b) tracking of nanodrug carriers in tumors, and (c) mapping of lesions and immune cells in a multiple sclerosis mouse model. Our strategy establishes a distinct yet complementary set of imaging probes for understanding disease mechanisms in three dimensions.

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