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Nat Biotechnol. 2018 Dec 17. doi: 10.1038/nbt.4281. [Epub ahead of print]

Protection of tissue physicochemical properties using polyfunctional crosslinkers.

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Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
Picower Institute for Learning and Memory, MIT, Cambridge, Massachusetts, USA.
Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA.
Broad Institute of Harvard University and MIT, Cambridge, Massachusetts, USA.
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.
Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, Hong Kong.
Program in Cellular and Molecular Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Department of Chemical Engineering, MIT, Cambridge, Massachusetts, USA.
Department of Chemistry, MIT, Cambridge, Massachusetts, USA.
Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.


Understanding complex biological systems requires the system-wide characterization of both molecular and cellular features. Existing methods for spatial mapping of biomolecules in intact tissues suffer from information loss caused by degradation and tissue damage. We report a tissue transformation strategy named stabilization under harsh conditions via intramolecular epoxide linkages to prevent degradation (SHIELD), which uses a flexible polyepoxide to form controlled intra- and intermolecular cross-link with biomolecules. SHIELD preserves protein fluorescence and antigenicity, transcripts and tissue architecture under a wide range of harsh conditions. We applied SHIELD to interrogate system-level wiring, synaptic architecture, and molecular features of virally labeled neurons and their targets in mouse at single-cell resolution. We also demonstrated rapid three-dimensional phenotyping of core needle biopsies and human brain cells. SHIELD enables rapid, multiscale, integrated molecular phenotyping of both animal and clinical tissues.

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