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Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates

Nature Materials volume 16, pages 671–680 (2017)Cite this article

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Abstract

Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization. Interestingly, colony stimulating factor-1 receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, reactive oxygen species production and phagocytosis. Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.

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Figure 1: Numerous immune populations respond to implanted alginate spheres.
Figure 2: The immune response to implanted biomaterial alginate is long-lived.
Figure 3: Innate immune macrophage function is required for fibrosis of alginate.
Figure 4: Macrophages, and not neutrophils, are required for fibrosis of alginate.
Figure 5: CSF1R-dependent macrophages recruit fibrosis-potentiating B cells via CXCL13.
Figure 6: Essential fibrotic cascade players are also increased in non-human primates.

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Acknowledgements

This work was supported by the Juvenile Diabetes Research Foundation (JDRF) (Grant 17-2007-1063), the Leona M. and Harry B. Helmsley Charitable Trust Foundation (Grants 09PG-T1D027 and 2015PG-T1D063), the National Institutes of Health (Grants EB000244, EB000351, DE013023 and CA151884), and through a generous gift from the Tayebati Family Foundation. J.C.D. was supported by JDRF postdoctoral fellowship (Grant 3-PDF-2015-91-A-N). O.V. was supported by JDRF and DOD/CDMRP postdoctoral fellowships (Grants 3-2013-178 and W81XWH-13-1-0215, respectively). J.O. is supported by the National Institutes of Health (NIH/NIDDK) R01DK091526 and the Chicago Diabetes Project. D.L.G. is supported by the National Institutes of Health (NIH/NIDDK) UC4 DK104218. The authors would like to acknowledge the use of resources at W. M. Keck Biological Imaging Facility (Whitehead Institute), and Microscopy, Histology, Whole Animal Imaging, and Flow Cytometry Core Facilities (Swanson Biotechnology Center, David H. Koch Institute for Integrative Cancer Research at MIT).

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  1. Omid Veiseh, Arturo J. Vegas & Minglin Ma

    Present address: Present addresses: Sigilon, Inc., 161 First Street, Cambridge, Massachusetts 02142, USA (O.V.); Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA (A.J.V.); Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, USA (M.M.).,

Authors and Affiliations

  1. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, USA

    Joshua C. Doloff, Omid Veiseh, Arturo J. Vegas, Hok Hei Tam, Shady Farah, Minglin Ma, Jie Li, Andrew Bader, Alan Chiu, Atieh Sadraei, Stephanie Aresta-Dasilva, Marissa Griffin, Siddharth Jhunjhunwala, Matthew Webber, Sean Siebert, Katherine Tang, Michael Chen, Erin Langan, Nimit Dholokia, Raj Thakrar, Robert Langer & Daniel G. Anderson

  2. Department of Anesthesiology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA

    Joshua C. Doloff, Omid Veiseh, Arturo J. Vegas, Shady Farah, Minglin Ma, Jie Li, Andrew Bader, Alan Chiu, Stephanie Aresta-Dasilva, Siddharth Jhunjhunwala, Sean Siebert, Katherine Tang, Michael Chen, Erin Langan, Nimit Dholokia, Raj Thakrar, Robert Langer & Daniel G. Anderson

  3. Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    Joshua C. Doloff, Omid Veiseh, Hok Hei Tam, Shady Farah, Matthew Webber, Robert Langer & Daniel G. Anderson

  4. Division of Transplantation, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois 60607, USA

    Meirigeng Qi & Jose Oberholzer

  5. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

    Dale L. Greiner

  6. Division of Health Science Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    Robert Langer & Daniel G. Anderson

  7. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    Robert Langer & Daniel G. Anderson

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Contributions

J.C.D. and D.G.A. designed experiments, analysed data and wrote the manuscript. J.C.D., O.V., A.J.V., H.H.T., S.F., M.M., J.L., A.B., A.C., S.A.-D., M.G., A.S., S.J., M.W., S.S., K.T., M.C., E.L., N.D., R.T., M.Q. and J.O. performed experiments. J.C.D. and H.H.T. performed statistical analyses of data sets and aided in the preparation of displays communicating data sets. J.O. and D.L.G. provided conceptual advice and technical support. R.L. and D.G.A. supervised the study. All authors discussed the results and assisted in the preparation of the manuscript.

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Correspondence to Daniel G. Anderson.

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Doloff, J., Veiseh, O., Vegas, A. et al. Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Nature Mater 16, 671–680 (2017). https://doi.org/10.1038/nmat4866

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