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Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates

Nature Materials volume 14, pages 643–651 (2015)Cite this article

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Abstract

The efficacy of implanted biomedical devices is often compromised by host recognition and subsequent foreign body responses. Here, we demonstrate the role of the geometry of implanted materials on their biocompatibility in vivo. In rodent and non-human primate animal models, implanted spheres 1.5 mm and above in diameter across a broad spectrum of materials, including hydrogels, ceramics, metals and plastics, significantly abrogated foreign body reactions and fibrosis when compared with smaller spheres. We also show that for encapsulated rat pancreatic islet cells transplanted into streptozotocin-treated diabetic C57BL/6 mice, islets prepared in 1.5-mm alginate capsules were able to restore blood-glucose control for up to 180 days, a period more than five times longer than for transplanted grafts encapsulated within conventionally sized 0.5-mm alginate capsules. Our findings suggest that the in vivo biocompatibility of biomedical devices can be significantly improved simply by tuning their spherical dimensions.

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Figure 1: Increasing alginate sphere size results in reduced cellular deposition and fibrosis formation on the spheres.
Figure 2: Increasing the spherical diameter of a variety of materials, including, hydrogels, ceramics, metals and plastics, results in reduced foreign body responses.
Figure 3: Comparing the size- and shape-dependent effects of fibrosis formation on alginate hydrogels implanted in the subcutaneous dorsal region of non-human primates.
Figure 4: Comparison of 0.5 and 1.5-mm alginate capsules encapsulating rat islets (500 IEs) in curing STZ-induced C57BL/6 diabetic mice.
Figure 5: Kinetic profiling of host response to SLG20 alginate microspheres of diameter 0.5 and 1.5 mm.

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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 (Grant 09PG-T1D027), the National Institutes of Health (Grants EB000244, EB000351, DE013023 and CA151884), the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute, and also by a generous gift from the Tayebati Family Foundation. 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. J.M-E. is supported by the American Diabetes Association (ADA) Clinical Scientist Training Award (7-12-CST-03) and the American Society of Transplant Surgeons (ASTS) Presidential Student Mentor Award. The authors would like to acknowledge the use of resources at the Koch Institute Swanson Biotechnology Center for technical support, specifically, the Hope Babette Tang Histology, Microscopy, Flow Cytometry, and Animal Imaging and pre-clinical testing core facilities. We acknowledge the use of imaging resources at the W. M. Keck Biological Imaging Facility (Whitehead Institute) and assistance from W. Salmon. We thank R. Bogorad and K. Whitehead for helpful discussions and feedback on the manuscript.

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Author notes

  1. Minglin Ma

    Present address: Present address: Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, USA.,

  2. Omid Veiseh, Joshua C. Doloff and Minglin Ma: These authors contributed equally to this work.

Authors and Affiliations

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

    Omid Veiseh, Joshua C. Doloff, Minglin Ma, Arturo J. Vegas, Hok Hei Tam, Andrew R. Bader, Jie Li, Erin Langan, Jeffrey Wyckoff, Siddharth Jhunjhunwala, Alan Chiu, Sean Siebert, Katherine Tang, Stephanie Aresta-Dasilva, Danya M. Lavin, Michael Chen, Nimit Dholakia, Raj Thakrar, Robert Langer & Daniel G. Anderson

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

    Omid Veiseh, Hok Hei Tam, Whitney S. Loo, Robert Langer & Daniel G. Anderson

  3. Department of Anesthesiology, Boston Children’s Hospital, 300 Longwood Ave, Boston, Massachusetts 02115, USA,

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

  4. Research Division, Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA

    Minglin Ma, Jennifer Hollister-Lock & Gordon C. Weir

  5. Division of Transplantation, Department of Surgery, University of Illinois at Chicago, 840 South Wood Street, Chicago, Illinois 60612, USA,

    Matthew Bochenek, Joshua Mendoza-Elias, Yong Wang, Merigeng Qi & Jose Oberholzer

  6. Department for Biomaterials Research, Polymer Institute of the Slovak Academy of Sciences, Dubravska cesta 9, 845 41 Bratislava, Slovakia,

    Igor Lacík

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

    Dale L. Greiner

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

    Robert Langer & Daniel G. Anderson

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

    Robert Langer & Daniel G. Anderson

  10. Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,

    Robert Langer & Daniel G. Anderson

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  1. Omid Veiseh
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Contributions

O.V., J.C.D., M.M. and D.G.A. conceived the idea, designed experiments, analysed data, and wrote the manuscript. O.V., J.C.D., M.M. A.J.V., A.R.B., J.L., E.L., J.W., W.S.L., S.J., A.C., S.S., K.T., J.H-L., S.A-D., M.B., J.M-E., Y.W., M.Q., D.M.L., M.C., N.D., R.T., I.L., G.C.W. and J.O. performed experiments. H.H.T. performed statistical analyses of data sets and aided in the preparation of displays communicating data sets. G.C.W., 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.

Corresponding author

Correspondence to Daniel G. Anderson.

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The authors declare no competing financial interests.

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Veiseh, O., Doloff, J., Ma, M. et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nature Mater 14, 643–651 (2015). https://doi.org/10.1038/nmat4290

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