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Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations

Nature Materials volume 18, pages 892–904 (2019)Cite this article

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Abstract

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled-release formulations for local anti-inflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sites—subcutaneous, intraperitoneal and intramuscular. In particular, incorporation of GW2580, a colony stimulating factor 1 receptor inhibitor, into a range of devices, including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials.

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Fig. 1: Anti-fibrotic drug screen testing agents largely targeted to macrophage biology.
Fig. 2: Crystal development and characterization.
Fig. 3: In vitro release and in vivo anti-fibrotic efficacy.
Fig. 4: Long-term anti-fibrotic efficacy in NHPs.
Fig. 5: Long-term glycemic control with crystalline GW2580.
Fig. 6: Long-term drug depot effects of GW2580 crystals.

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Data availability

The data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request.

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Acknowledgements

Work was supported by: JDRF-Juvenile Diabetes Research Foundation Grant 17-2007-1063, National Institutes of Health Grants: DE013023, EB000244, CA151884 and EB000351, Leona M. and Harry B. Helmsley Charitable Trust Foundation Grants: 2015PG-T1D063 and 09PG-T1D027, and through a gift from the Tayebati Family Foundation. J.C.D. was supported by postdoctoral fellowship from JDRF (Fellowship: 3-PDF-2015-91-A-N). J.O. is supported by the Chicago Diabetes Project and the National Institutes of Health (NIH/NIDDK) R01DK091526. G.C.W. is supported by the National Institutes of Health Diabetes Research Centers Grant P30 DK 36836. D.L.G. is supported by the National Institutes of Health (NIH/NIDDK) UC4 DK104218. We acknowledge the use of resources at Core Facilities (Swanson Biotechnology Center, David H. Koch Institute for Integrative Cancer Research at MIT) and W. M. Keck Biological Imaging Facility for Flow Cytometry, Histology, in situ Accelerated Release Microscopy (Wendy C. Salmon, Whitehead Institute), Animal Imaging, and Scanning Electron Microscopy.

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Author notes

  1. Joshua C. Doloff

    Present address: Department of Biomedical and Materials Science Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute and the Institute for NanoBioTechnology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

  2. These authors contributed equally: Shady Farah, Joshua C. Doloff.

Authors and Affiliations

  1. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Shady Farah, Joshua C. Doloff, Atieh Sadraei, Hye Jung Han, Katy Olafson, Keval Vyas, Hok Hei Tam, Piotr S. Kowalski, Marissa Griffin, Ashley Meng, Malia McAvoy, Robert Langer & Daniel G. Anderson

  2. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Shady Farah, Joshua C. Doloff, Katy Olafson, Piotr S. Kowalski, Robert Langer & Daniel G. Anderson

  3. Department of Anesthesiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Shady Farah, Joshua C. Doloff, Hye Jung Han, Katy Olafson, Hok Hei Tam, Robert Langer & Daniel G. Anderson

  4. X-Ray Diffraction Facility, MIT Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA

    Peter Müller

  5. Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA

    Katy Olafson

  6. Section on Islet Cell and Regenerative Biology, Research Division, Joslin Diabetes Center, Boston, MA, USA

    Jennifer Hollister-Lock & Gordon C. Weir

  7. Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Malia McAvoy, Robert Langer & Daniel G. Anderson

  8. Center for Nanoscale Systems, Harvard University, Cambridge, MA, USA

    Adam C. Graham

  9. Department of Surgery, Division of Transplantation, University of Illinois at Chicago, Chicago, IL, USA

    James McGarrigle & Jose Oberholzer

  10. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Dale L. Greiner

  11. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Robert Langer & Daniel G. Anderson

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  1. Shady Farah
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Contributions

S.F., J.C.D., and D.G.A. designed the studies, analysed data and wrote the paper. S.F., J.C.D., P.M., A.S., H.J.H., K.O., K.V., H.H.T., J.H.-L., P.S.K., M.G., A.M., M.M., A.C.G., J.M. and J.O. conducted the experiments. S.F. and J.C.D. carried out the statistical analyses and prepared displays communicating data sets. G.C.W. and D.L.G. provided advice and technical support throughout. R.L. and D.G.A. supervised the study. All authors discussed the results and the preparation of the paper.

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Correspondence to Daniel G. Anderson.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–21, Supplementary Video captions 1–3, Supplementary Discussions 1–4 and Supplementary references

Reporting Summary

Supplementary Video 1

In situ monitoring MII and MIII crystals stability and release with fluorescent microscope

Supplementary Video 2

Laparoscopic evaluation and 4-week retrievals of implanted ~0.5 mm capsule without drug in non-human primates

Supplementary Video 3

Laparoscopic evaluation and 4-week retrievals of implanted ~0.5 mm capsule with GW2580 crystals in non-human primates

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Farah, S., Doloff, J.C., Müller, P. et al. Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations. Nat. Mater. 18, 892–904 (2019). https://doi.org/10.1038/s41563-019-0377-5

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