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The surface topography of silicone breast implants mediates the foreign body response in mice, rabbits and humans

Abstract

Silicone is widely used in chronic implants and is generally perceived to be safe. However, textured breast implants have been associated with immune-related complications, including malignancies. Here, by examining for up to one year the foreign body response and capsular fibrosis triggered by miniaturized or full-scale clinically approved breast implants with different surface topography (average roughness, 0–90 μm) placed in the mammary fat pads of mice or rabbits, respectively, we show that surface topography mediates immune responses to the implants. We also show that the surface surrounding human breast implants collected during revision surgeries also differentially alters the individual’s immune responses to the implant. Moreover, miniaturized implants with an average roughness of 4 μm can largely suppress the foreign body response and fibrosis (but not in T-cell-deficient mice), and that tissue surrounding these implants displayed higher levels of immunosuppressive FOXP3+ regulatory T cells. Our findings suggest that, amongst the topographies investigated, implants with an average roughness of 4 μm provoke the least amount of inflammation and foreign body response.

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Fig. 1: Roughness and chemical composition of human-scale implants versus miniaturized implant mimics.
Fig. 2: Breast implant surface topography affects host response and fibrosis in rabbits.
Fig. 3: Breast implant surface topography affects host responses and fibrosis in mice.
Fig. 4: Acute immune effects two weeks after implantation revealed by scRNA-seq.
Fig. 5: Long-term kinetics of host immune response to 0 and 4 μm implants in wild-type mice, and testing in nude mice implicating a T-cell-regulated mechanism.
Fig. 6: Human breast tissue explant histology and immune profiling.

Data availability

The main data supporting the findings of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request. High-throughput sequencing data have been deposited in the Gene Expression Omnibus (GEO) database, with series accession number GSE164645.

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Acknowledgements

This work was supported by Establishment Labs. We thank members of the Establishment team for help with sourcing full-scale, commercial implants and manufacturing the miniaturized implants used in this study; M. C. Quiros for his clinical contributions; and D. Wolfram for critique on the presented data that went into this manuscript. The laboratory of H.C.H. is supported by Gabrielle’s Angel Foundation for Cancer Research. We acknowledge the use of resources at Core Facilities (Swanson Biotechnology Center, David H. Koch Institute for Integrative Cancer Research at MIT), W. M. Keck Biological Imaging Facility for Flow Cytometry and Histology, as well as the Division of Comparative Medicine for animal work, and the Sidney Kimmel Comprehensive Cancer Center (SKCCC) Immune Monitoring Core for additional NanoString analysis (at Johns Hopkins).

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Authors

Contributions

J.C.D., O.V. and R.L. designed the studies, analysed data and wrote the paper. J.C.D., O.V., M.S., J. Haupt, M.J., C.C., A.N., S.A.-F., J.L.S., S.J.B., S.Y.N., N.A.R., Y.E.H., I.M.L., H.C.H., R.N.M. and M.W.C. conducted the experiments. J.C.D., H.C.H. and O.V. carried out the statistical analyses and prepared displays communicating datasets. R.d.M., M.S., T.A.P., J. Hancock, A.M.M., A.B., B.M.K. and R.L. provided advice and technical support throughout, and J.C.D., O.V. and R.L. contributed with supervision of the study. All authors discussed the results and the preparation of the paper.

Corresponding authors

Correspondence to Joshua C. Doloff or Omid Veiseh or Roberto de Mezerville or Robert Langer.

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Competing interests

J.H., A.B., B.K., T.A.P and R.L. are members of the Scientific Advisory Board of Establishment Labs Holdings and each hold equity in the company. M.S. and A.M.M. are members of the Medical Advisory Board and each hold equity in Establishment Labs Holdings. M.W.C. and B.M.K. are Investigators on the US IDE Clinical Trial for the Study of Safety and Effectiveness of Motiva Implants. R.D.M., N.A.R., Y.E.H. and I.M.L. are employees of Establishment Labs S.A., and hold equity in Establishment Labs Holdings. J.C.D. and O.V. are paid consultants for Establishment Labs S.A. For a list of entities with which R.L. is involved, compensated or uncompensated, see the listing in the Supplementary Information.

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Peer review information Nature Biomedical Engineering thanks Pamela Moalli and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary figures, tables, video captions, references and additional detailed competing interests.

Reporting Summary

Supplementary Video 1

Double capsules for Mentor Siltex.

Supplementary Video 2

Double capsule for Allergan Microcell, with Velcro effect.

Supplementary Video 3

Double capsule for Allergan Biocell, with Velcro effect.

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Doloff, J.C., Veiseh, O., de Mezerville, R. et al. The surface topography of silicone breast implants mediates the foreign body response in mice, rabbits and humans. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-021-00739-4

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