Full Citation
Doloff JC, Veiseh O, de Mezerville R, Sforza M, Perry TA, Haupt J, Jamiel M, Chambers C, Nash A, Aghlara-Fotovat S, Stelzel JL, Bauer SJ, Neshat SY, Hancock J, Romero NA, Hidalgo YE, Leiva IM, Munhoz AM, Bayat A, Kinney BM, Hodges HC, Miranda RN, Clemens MW, Langer R. The surface topography of silicone breast implants mediates the foreign body response in mice, rabbits and humans. Nature Biomedical Engineering. 2021;5:1115–1130. DOI: 1038/s41551-021-0073-4 [1] [2] [3].
Disclosure
Dr. Epstein is a paid investigator in the Motiva U.S. FDA clinical trial and is compensated by Establishment Labs to train surgeons on the Preservé breast augmentation technique. He discloses this relationship in all public communications involving Motiva or Preservé. Dr. Epstein owns stock in Establishment Labs.
Authors and Affiliations
- Joshua C. Doloff, Omid Veiseh, Robert Langer: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA [3] [4].
- Jessica L. Stelzel, Stuart J. Bauer, Sarah Y. Neshat: Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA [4].
- Amanda Nash, Samira Aghlara-Fotovat, H. Courtney Hodges: Department of Bioengineering, Rice University, Houston, TX, USA [4].
- Roberto de Mezerville, Tracy Ann Perry, John Hancock, Natalia Araujo Romero, Yessica Elizondo Hidalgo, Isaac Mora Leiva: Establishment Labs Holdings, Alajuela, Costa Rica [4].
- Marcos Sforza: Division of Plastic Surgery, Dolan Park Hospital, Birmingham, UK [4].
- Jennifer Haupt, Morgan Jamiel: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA [4].
- Courtney Chambers, H. Courtney Hodges: Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX, USA [4].
- Alexandre Mendonça Munhoz: Breast Surgery Group, Plastic Surgery Division, University of São Paulo School of Medicine, São Paulo, Brazil; Plastic Surgery Department, Hospitals Sirio-Libanês and Moriah, São Paulo, Brazil [4].
- Ardeshir Bayat: Plastic and Reconstructive Surgery Research, NIHR Biomedical Research Centre, University of Manchester, Manchester, UK [4].
- Brian M. Kinney: Division of Plastic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA [4].
- Courtney Hodges: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA [4].
- Roberto N. Miranda: Department of Hematopathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [4].
- Mark W. Clemens: Department of Plastic Surgery, University of Texas, MD Anderson Cancer Center, Houston, TX, USA [4].
- Robert Langer: Harvard-MIT Division of Health Sciences Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA [4].
Study Design and Evidence Level
- Study Type: Preclinical animal study (mice and rabbits) combined with a retrospective human clinical pilot study [1] [5] [6].
- IRB/Ethics Approval: Animal protocols were approved by the MIT Committee on Animal Care (IACUC) [7]. Human clinical specimens were collected following Institutional Review Board (IRB) approval at MD Anderson Cancer Center and the Scientific Ethical Committee of the Costa Rican Institute for Research and Teaching in Nutrition and Health Foundation [8].
- Sample Size:
- Rabbits: $n = 5$ per group per time point [5].
- Mice: $n = 5$ per group per time point [6].
- Humans: 21 female recipients (15 healthy individuals and 6 patients with BIA-ALCL) [9].
- Groups:
- Rabbits: 6 commercial breast implant topographies: Smooth, SmoothSilk, VelvetSurface, Siltex, Microcell, and Biocell [5].
- Mice: Miniaturized implants with roughnesses of 0, 4, 15, 30, and 90 $\mu$m [6].
- Humans: Traditional Smooth, SmoothSilk, and Biocell [9].
- Follow-up:
- Rabbits: 3 weeks and 6 months [5].
- Mice: 3 weeks and 6 weeks (up to 6 months for long-term kinetics) [6].
- Humans: Implants in place for 1 to 11 years [9].
- Level of Evidence: Level V (Preclinical / Bench and Animal Study / Case-Control Pilot Series).
Objectives
- To systematically understand host immune responses to six commercial breast implants with varied surface topographies [10].
- To test the hypothesis that a specific surface topography (SmoothSilk, 4 $\mu$m roughness) alters the kinetics and composition of foreign body reactions to suppress inflammation and fibrous encapsulation [11].
Background Context
- Silicone is widely used in chronic implants, but textured breast implants are associated with immune-related complications, including capsular contracture and malignancies [1].
- Approximately 400,000 women in the US receive silicone breast implants annually, and a majority will require replacement within 10 to 20 years due to capsular contracture [12].
- Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), a cancer of immune T cells, has only been observed in response to textured surface implants [13].
- In 2019, the US FDA requested a class I recall of textured breast implants and tissue expanders from one manufacturer due to elevated BIA-ALCL risk [14].
Methods
- Patient Population: 21 female recipients undergoing revision surgery (15 healthy, 6 with BIA-ALCL) [9].
- Inclusion/Exclusion: Not fully reported.
- Interventions: Subcutaneous implantation of human-scale implants in rabbits [5] and miniaturized implants in wild-type and T-cell-deficient (nude) mice [6] [15].
- Outcome Measures: Capsule thickness (H&E and Masson's trichrome staining), immune cell profiling (FACS, scRNA-seq, NanoString multiplexed gene expression), and surface characterization (SEM, non-contact profilometry, XPS) [5] [6].
- Statistical Methods: One-way ANOVA with Bonferroni multiple-comparisons correction, two-tailed t-tests, and Fisher's exact test [6].
Results
- Capsule Thickness: SmoothSilk (4 $\mu$m) elicited the thinnest capsule in rabbits and mice [16]. Siltex, Microcell, and Biocell implants showed double capsule formation [17].
- Topography Effects: In mice, 4 $\mu$m and 15 $\mu$m roughness significantly reduced capsule thickness compared to smooth controls, whereas 90 $\mu$m roughness increased capsule thickness at 3 weeks [18].
- T-cell Dependency: In T-cell-deficient nude mice, the anti-fibrotic effect of the 4 $\mu$m surface was lost, resulting in thicker capsules similar to smooth controls [15].
Conclusions
- Surface topography is a critical mediator of the foreign body response to silicone implants [19].
- Implants with an average roughness of 4 $\mu$m (single-cell scale) provoke the least amount of inflammation and fibrotic encapsulation across mice, rabbits, and humans [19].
Key Terminology and Definitions
- Foreign Body Response (FBR): An immune-driven fibrotic response to implanted biomaterials leading to fibrous encapsulation [12].
- BIA-ALCL: Breast implant-associated anaplastic large cell lymphoma, a cancer of immune T cells associated with textured implants [13].
Limitations
- The study notes that the emergence of autoimmune diseases increases as patients age, which was not investigated in this study [20].
- Potential species-specific differences exist between mouse and rabbit models.
Funding and Conflicts of Interest
- Conflicts of Interest: Several authors (J.H., A.B., B.K., T.A.P., R.L., M.S., A.M.M.) are advisory board members or hold equity in Establishment Labs Holdings [21]. R.D.M., N.A.R., Y.E.H., and I.M.L. are employees of Establishment Labs S.A. [21].
Plain-Language Patient Summary
This study investigated how the surface texture of silicone breast implants affects the body's immune response and scar tissue formation [1]. By testing different textures in animals and analyzing human tissue samples, the researchers found that a specific, finely tuned texture (4 $\mu$m roughness) caused the least amount of inflammation and scar tissue [19]. These findings could help design safer breast implants with fewer long-term complications [19].
References
[1]“File: 50. The surface topography of silicone breast mediates foreign body response_Doloff_Nature_2021 (1).pdf,” File.
