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In Vitro and in Vivo Analyses of the Effects of Source, Length, and Charge on the Cytotoxicity and Immunocompatibility of Cellulose Nanocrystals

  • Adam M. Weiss
    Adam M. Weiss
    Department of Chemistry, University of Chicago 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
    Pritzker School of Molecular Engineering, University of Chicago 5640 South Ellis Avenue, Chicago, Illinois 60637, United States
  • Nicholas Macke
    Nicholas Macke
    Pritzker School of Molecular Engineering, University of Chicago 5640 South Ellis Avenue, Chicago, Illinois 60637, United States
  • Yefei Zhang
    Yefei Zhang
    Pritzker School of Molecular Engineering, University of Chicago 5640 South Ellis Avenue, Chicago, Illinois 60637, United States
    More by Yefei Zhang
  • Céline Calvino
    Céline Calvino
    Pritzker School of Molecular Engineering, University of Chicago 5640 South Ellis Avenue, Chicago, Illinois 60637, United States
  • Aaron P. Esser-Kahn*
    Aaron P. Esser-Kahn
    Pritzker School of Molecular Engineering, University of Chicago 5640 South Ellis Avenue, Chicago, Illinois 60637, United States
    *Email: [email protected]
  • , and 
  • Stuart J. Rowan*
    Stuart J. Rowan
    Department of Chemistry, University of Chicago 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
    Pritzker School of Molecular Engineering, University of Chicago 5640 South Ellis Avenue, Chicago, Illinois 60637, United States
    Chemical and Engineering Sciences, Argonne National Laboratory 9700 Cass Avenue, Lemont, Illinois 60439, United States
    *Email: [email protected]
Cite this: ACS Biomater. Sci. Eng. 2021, 7, 4, 1450–1461
Publication Date (Web):March 9, 2021
https://doi.org/10.1021/acsbiomaterials.0c01618
Copyright © 2021 American Chemical Society

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    Abstract

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    Cellulose nanocrystals (CNCs) are an emergent, sustainable nanomaterial that are biosourced, abundant, and biodegradable. On account of their high aspect ratio, low density, and mechanical rigidity, they have been employed in numerous areas of biomedical research including as reinforcing materials for bone or tissue scaffolds or as carriers in drug delivery systems. Given the promise of these materials for such use, characterizing and understanding their interactions with biological systems is an important step to prevent toxicity or inflammation. Reported herein are studies aimed at exploring the in vitro and in vivo effects that the source, length, and charge of the CNCs have on cytotoxicity and immune response. CNCs from four different biosources (cotton, wood, Miscanthus x Giganteus, and sea tunicate) were prepared and functionalized with positive or negative charges to obtain a small library of CNCs with a range of dimensions and surface charge. A method to remove endotoxic or other impurities on the CNC surface leftover from the isolation process was developed, and the biocompatibility of the CNCs was subsequently assayed in vitro and in vivo. After subcutaneous injection, it was found that unfunctionalized (uncharged) CNCs form aggregates at the site of injection, inducing splenomegaly and neutrophil infiltration, while charged CNCs having surface carboxylates, sulfate half-esters, or primary amines were biologically inert. No effect of the particle source or length was observed in the in vitro and in vivo studies conducted. The lack of an in vitro or in vivo immune response toward charged CNCs in these experiments supports their use in future biological studies.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsbiomaterials.0c01618.

    • Discussions of FT-IR spectroscopy, conductometric titration, ζ potential, thermogravimetric analysis, NMR spectroscopy, WAXS deconvolution, in vitro LDH assay, in vitro BrdU assay, and in vitro cytokine assays, figures of length distributions of CNC samples, Kapton spectrum, representative spectrum of MxG-CNC–OH, WAXS diffraction patterns, crystallinity index, thermogravimetric analysis, FT-IR spectra, AFM images, 1H NMR spectra, correlation functions obtained, ζ potentials calculated, LDH cytotoxicity assay, TNF-α ELISA assay, IL-6 ELISA assay, effect of CNCs on cellular differentiation in vitro, light microscopy images, systemic IFN-γ production, images of subcutaneous tissue, and hematoxylin and eosin staining images (PDF)

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    This article is cited by 26 publications.

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