Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Suppression of the fibrotic encapsulation of silicone implants by inhibiting the mechanical activation of pro-fibrotic TGF-β

Nature Biomedical Engineering volume 5, pages 1437–1456 (2021)Cite this article

Subjects

Abstract

The fibrotic encapsulation of implants involves the mechanical activation of myofibroblasts and of pro-fibrotic transforming growth factor beta 1 (TGF-β1). Here, we show that both softening of the implant surfaces and inhibition of the activation of TGF-β1 reduce the fibrotic encapsulation of subcutaneous silicone implants in mice. Conventionally stiff silicones (elastic modulus, ~2 MPa) coated with a soft silicone layer (elastic modulus, ~2 kPa) reduced collagen deposition as well as myofibroblast activation without affecting the numbers of macrophages and their polarization states. Instead, fibroblasts around stiff implants exhibited enhanced intracellular stress, increased the recruitment of αv and β1 integrins, and activated TGF-β1 signalling. In vitro, the recruitment of αv integrin to focal adhesions and the activation of β1 integrin and of TGF-β were higher in myofibroblasts grown on latency-associated peptide (LAP)-coated stiff silicones than on soft silicones. Antagonizing αv integrin binding to LAP through the small-molecule inhibitor CWHM-12 suppressed active TGF-β signalling, myofibroblast activation and the fibrotic encapsulation of stiff subcutaneous implants in mice.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Soft surface coatings reduce capsule formation at the deep side of subcutaneously implanted silicones.
Fig. 2: Soft implant surfaces suppress implant fibrosis in the wound environment.
Fig. 3: Implanted silicones rapidly adsorb ECM proteins that allow fibroblast attachment.
Fig. 4: Soft implant surfaces supress myofibroblast activation during the FBR.
Fig. 5: Inhibition of αv integrins with CWHM-12 suppresses fibrogenesis at the deep side of stiff silicone implants.
Fig. 6: CWHM-12 treatment reduces cytoskeletal force transmission to LAP and TGF-β activation in vitro.
Fig. 7: High mechanical stress increases the recruitment of β1 integrin to focal adhesions.
Fig. 8: Mechanism of fibrotic encapsulation of implanted stiff materials.

Similar content being viewed by others

Data availability

The main data supporting the results of this study are available within the paper and its Supplementary Information. The data used to produce the figures are available from Figshare with the identifier https://doi.org/10.6084/m9.figshare.14319758. The raw and analysed datasets generated during the study are too large to be publicly shared, but are available for research purposes from the corresponding author upon reasonable request.

Code availability

The custom Fiji (ImageJ) macro used to analyse the recruitment of active β1 integrin to focal adhesions is available on GitHub at https://github.com/NinaNoskovicova/Noskovicova-N.-et-al.-2021-NBE.

References

  1. Majd, H. et al. Novel micropatterns mechanically control fibrotic reactions at the surface of silicone implants. Biomaterials 54, 136–147 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Visscher, L. E. et al. Breast augmentation and reconstruction from a regenerative medicine point of view: state of the art and future perspectives. Tissue Eng. Part B Rev. 23, 281–293 (2017).

    Article  PubMed  Google Scholar 

  3. Veiseh, O. & Vegas, A. J. Domesticating the foreign body response: recent advances and applications. Adv. Drug Deliv. Rev. 144, 148–161 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Klopfleisch, R. & Jung, F. The pathology of the foreign body reaction against biomaterials. J. Biomed. Mater. Res. A 105, 927–940 (2017).

    Article  CAS  PubMed  Google Scholar 

  5. Franz, S., Rammelt, S., Scharnweber, D. & Simon, J. C. Immune responses to implants—a review of the implications for the design of immunomodulatory biomaterials. Biomaterials 32, 6692–6709 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Morris, A. H. & Kyriakides, T. R. Matricellular proteins and biomaterials. Matrix Biol. 37, 183–191 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Borenstein, A. & Friedman, O. Combined breast implant explantation and multilevel mastopexy technique. Plast. Reconstr. Surg. Glob. Open 7, e2429 (2019).

    PubMed  PubMed Central  Google Scholar 

  8. Pakshir, P. & Hinz, B.The big five in fibrosis: macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 68–69, 81–93 (2018).

    Article  PubMed  Google Scholar 

  9. Hinz, B. Myofibroblasts. Exp. Eye Res. 142, 56–70 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Hinz, B., Celetta, G., Tomasek, J. J., Gabbiani, G. & Chaponnier, C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell 12, 2730–2741 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pakshir, P. et al. The myofibroblast at a glance. J. Cell Sci. 133, jcs227900 (2020).

    Article  CAS  PubMed  Google Scholar 

  12. Hinz, B. The extracellular matrix and transforming growth factor-β1: tale of a strained relationship. Matrix Biol. 47, 54–65 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Lodyga, M. & Hinz, B. TGF-β1—a truly transforming growth factor in fibrosis and immunity. Semin. Cell Dev. Biol. 101, 123–139 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Annes, J. P., Chen, Y., Munger, J. S. & Rifkin, D. B. Integrin αvβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J. Cell Biol. 165, 723–734 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shi, M. et al. Latent TGF-β structure and activation. Nature 474, 343–349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Henderson, N. C. et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19, 1617–1624 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Sarrazy, V. et al. Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction. Cardiovasc. Res. 102, 407–417 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGF-β1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Mu, D. et al. The integrin αvβ8 mediates epithelial homeostasis through MT1–MMP-dependent activation of TGF-β1. J. Cell Biol. 157, 493–507 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dong, X. et al. Force interacts with macromolecular structure in activation of TGF-β. Nature 542, 55–59 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wipff, P. J., Rifkin, D. B., Meister, J. J. & Hinz, B. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Buscemi, L. et al. The single-molecule mechanics of the latent TGF-β1 complex. Curr. Biol. 21, 2046–2054 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Hillard, C., Fowler, J. D., Barta, R. & Cunningham, B. Silicone breast implant rupture: a review. Gland Surg. 6, 163–168 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Swezey, E., Shikhman, R. & Moufarrege, R. Breast Implant Rupture (StatPearls, 2020).

  25. Zhu, J. et al. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol. Cell 32, 849–861 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Goffin, J. M. et al. Focal adhesion size controls tension-dependent recruitment of α-smooth muscle actin to stress fibers. J. Cell Biol. 172, 259–268 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Klingberg, F. et al. Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation. J. Cell Biol. 207, 283–297 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hinz, B., McCulloch, C. A. & Coelho, N. M. Mechanical regulation of myofibroblast phenoconversion and collagen contraction. Exp. Cell Res. 379, 119–128 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Li, C. X. et al. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mater. 16, 379–389 (2017).

    Article  CAS  PubMed  Google Scholar 

  30. Achterberg, V. F. et al. The nano-scale mechanical properties of the extracellular matrix regulate dermal fibroblast function. J. Invest. Dermatol. 134, 1862–1872 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Quesnel, K. et al. CCN1 expression by fibroblasts is required for bleomycin-induced skin fibrosis. Matrix Biol. 3, 100009 (2019).

    Article  Google Scholar 

  32. Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Avula, M. N., Rao, A. N., McGill, L. D., Grainger, D. W. & Solzbacher, F. Foreign body response to subcutaneous biomaterial implants in a mast cell-deficient Kitw-Sh murine model. Acta Biomater. 10, 1856–1863 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Duffield, J. S., Lupher, M., Thannickal, V. J. & Wynn, T. A. Host responses in tissue repair and fibrosis. Annu. Rev. Pathol. 8, 241–276 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Wipff, P. J. et al. The covalent attachment of adhesion molecules to silicone membranes for cell stretching applications. Biomaterials 30, 1781–1789 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Werner, S., Lutzkendorf, J., Muller, T., Muller, L. P. & Posern, G. MRTF-A controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models. Sci. Rep. 9, 11725 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Foster, C. T., Gualdrini, F. & Treisman, R. Mutual dependence of the MRTF–SRF and YAP–TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics. Genes Dev. 31, 2361–2375 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bialik, J. F. et al. Profibrotic epithelial phenotype: a central role for MRTF and TAZ. Sci. Rep. 9, 4323 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Klingberg, F. et al. The fibronectin ED-A domain enhances recruitment of latent TGF-β-binding protein-1 to the fibroblast matrix. J. Cell Sci. 131, jcs201293 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Reed, N. I. et al. The αvβ1 integrin plays a critical in vivo role in tissue fibrosis. Sci. Transl. Med. 7, 288ra279 (2015).

    Article  Google Scholar 

  41. Magness, S. T., Bataller, R., Yang, L. & Brenner, D. A. A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations. Hepatology 40, 1151–1159 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Tsukui, T. et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat. Commun. 11, 1920 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Murray, I. R. et al. αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis. Nat. Commun. 8, 1118 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sun, Z., Guo, S. S. & Fassler, R. Integrin-mediated mechanotransduction. J. Cell Biol. 215, 445–456 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hannan, R. T., Peirce, S. M. & Barker, T. H. Fibroblasts: diverse cells critical to biomaterials integration. ACS Biomater. Sci. Eng. 4, 1223–1232 (2018).

    Article  CAS  PubMed  Google Scholar 

  46. Akilbekova, D. & Bratlie, K. M. Quantitative characterization of collagen in the fibrotic capsule surrounding implanted polymeric microparticles through second harmonic generation imaging. PloS ONE 10, e0130386 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Tarpila, E., Ghassemifar, R., Fagrell, D. & Berggren, A. Capsular contracture with textured versus smooth saline-filled implants for breast augmentation: a prospective clinical study. Plast. Reconstr. Surg. 99, 1934–1939 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Stevens, W. G. et al. Risk factor analysis for capsular contracture: a 5-year Sientra study analysis using round, smooth, and textured implants for breast augmentation. Plast. Reconstr. Surg. 132, 1115–1123 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Shin, B. H. et al. Silicone breast implant modification review: overcoming capsular contracture. Biomater. Res. 22, 37 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Harvey, A. G., Hill, E. W. & Bayat, A. Designing implant surface topography for improved biocompatibility. Expert Rev. Med. Devices 10, 257–267 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Wixtrom, R. N., Garadi, V., Leopold, J. & Canady, J. W. Device-specific findings of imprinted-texture breast implants: characteristics, risks, and benefits. Aesthet. Surg. J. 40, 167–173 (2020).

    PubMed  Google Scholar 

  52. Buonomo, O. C. et al. Comparison of round smooth and shaped micro-textured implants in terms of quality of life and aesthetic outcomes in women undergoing breast reconstruction: a single-centre prospective study. Updates Surg. 72, 537–546 (2020).

    Article  PubMed  Google Scholar 

  53. Liu, X. et al. Comparison of the postoperative incidence rate of capsular contracture among different breast implants: a cumulative meta-analysis. PloS ONE 10, e0116071 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Barr, S., Hill, E. W. & Bayat, A. Development, fabrication and evaluation of a novel biomimetic human breast tissue derived breast implant surface. Acta Biomater. 49, 260–271 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. Ramin, M. A., Latxague, L., Sindhu, K. R., Chassande, O. & Barthelemy, P. Low molecular weight hydrogels derived from urea based-bolaamphiphiles as new injectable biomaterials. Biomaterials 145, 72–80 (2017).

    Article  CAS  PubMed  Google Scholar 

  56. Minev, I. R. et al. Biomaterials. Electronic dura mater for long-term multimodal neural interfaces. Science 347, 159–163 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Schweller, R. M., Wu, Z. J., Klitzman, B. & West, J. L. Stiffness of protease sensitive and cell adhesive PEG hydrogels promotes neovascularization In Vivo. Ann. Biomed. Eng. 45, 1387–1398 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Moshayedi, P. et al. The relationship between glial cell mechanosensitivity and foreign body reactions in the central nervous system. Biomaterials 35, 3919–3925 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Sindhu, K. R. et al. New injectable self-assembled hydrogels that promote angiogenesis through a bioactive degradation product. Acta Biomater. 115, 197–209 (2020).

    Article  CAS  PubMed  Google Scholar 

  60. Godbout, C. et al. The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts. PloS ONE 8, e64560 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Curtis, J. & Colas, A. in Biomaterials Science 3rd edn (eds Ratner, B. D. et al.) 1106–1116 (Academic Press, 2013).

  62. Mayesh, J. P. & Vicari, A. R. in Biomaterials Science 3rd edn (eds Ratner, B. D. et al.) 1431–1443 (Academic Press, 2013).

  63. Swarts, E., Kop, A. M., Nilasaroya, A., Keogh, C. V. & Cooper, T. Rupture of poly implant prothese silicone breast implants: an implant retrieval study. Plast. Reconstr. Surg. 131, 480e–489e (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Charalambous, M., Daoud, R. & Karat, I. Advances in Medical and Surgical Engineering (eds Ahmed, W. et al.) 141–147 (Academic Press, 2020).

  65. Merkel, R., Kirchgessner, N., Cesa, C. M. & Hoffmann, B. Cell force microscopy on elastic layers of finite thickness. Biophys. J. 93, 3314–3323 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Buxboim, A., Ivanovska, I. L. & Discher, D. E. Matrix elasticity, cytoskeletal forces and physics of the nucleus: how deeply do cells ‘feel’ outside and in? J. Cell Sci. 123, 297–308 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dutta, B., Goswami, R. & Rahaman, S. O. TRPV4 plays a role in matrix stiffness-induced macrophage polarization. Front. Immunol. 11, 570195 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Scott, R. A., Kiick, K. L. & Akins, R. E. Substrate stiffness directs the phenotype and polarization state of cord blood derived macrophages. Acta Biomater. 122, 220–235 (2021).

    Article  CAS  PubMed  Google Scholar 

  69. Janmey, P. A., Fletcher, D. A. & Reinhart-King, C. A. Stiffness sensing by cells. Physiol. Rev. 100, 695–724 (2020).

    Article  PubMed  Google Scholar 

  70. Discher, D. E. et al. Matrix mechanosensing: from scaling concepts in ‘omics data to mechanisms in the nucleus, regeneration, and cancer. Annu. Rev. Biophys. 46, 295–315 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dondossola, E. et al. Examination of the foreign body response to biomaterials by nonlinear intravital microscopy. Nat. Biomed. Eng. 1, 0007 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Wynn, T. A. & Vannella, K. M. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44, 450–462 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Correa-Gallegos, D. et al. Patch repair of deep wounds by mobilized fascia. Nature 576, 287–292 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. Shook, B. A. et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 362, eaar2971 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Arora, P. D., Narani, N. & McCulloch, C. A. The compliance of collagen gels regulates transforming growth factor-β induction of α-smooth muscle actin in fibroblasts. Am. J. Pathol. 154, 871–882 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li, A. G. et al. Elevation of transforming growth factor beta (TGFβ) and its downstream mediators in subcutaneous foreign body capsule tissue. J. Biomed. Mater. Res. A 82, 498–508 (2007).

    Article  PubMed  Google Scholar 

  77. Kuhn, A. et al. Periprosthetic breast capsules contain the fibrogenic cytokines TGF-β1 and TGF-β2, suggesting possible new treatment approaches. Ann. Plast. Surg. 44, 387–391 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Higgins, D. M. et al. Localized immunosuppressive environment in the foreign body response to implanted biomaterials. Am. J. Pathol. 175, 161–170 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. DiEgidio, P. et al. Biomedical implant capsule formation: lessons learned and the road ahead. Ann. Plast. Surg. 73, 451–460 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Mazaheri, M. K., Schultz, G. S., Blalock, T. D., Caffee, H. H. & Chin, G. A. Role of connective tissue growth factor in breast implant elastomer capsular formation. Ann. Plast. Surg. 50, 263–268 (2003).

    Article  PubMed  Google Scholar 

  81. Park, S. et al. Acute suppression of TGF-β with local, sustained release of tranilast against the formation of fibrous capsules around silicone implants. J. Control. Release 200, 125–137 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Gancedo, M., Ruiz-Corro, L., Salazar-Montes, A., Rincon, A. R. & Armendariz-Borunda, J. Pirfenidone prevents capsular contracture after mammary implantation. Aesthetic Plast. Surg. 32, 32–40 (2008).

    Article  PubMed  Google Scholar 

  83. Travis, M. A. & Sheppard, D. TGF-β activation and function in immunity. Annu. Rev. Immunol. 32, 51–82 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Wipff, P. J. & Hinz, B. Integrins and the activation of latent transforming growth factor β1—an intimate relationship. Eur. J. Cell Biol. 87, 601–615 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Giacomini, M. M., Travis, M. A., Kudo, M. & Sheppard, D. Epithelial cells utilize cortical actin/myosin to activate latent TGF-β through integrin αvβ6-dependent physical force. Exp. Cell Res. 318, 716–722 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hinz, B. It has to be the αv: myofibroblast integrins activate latent TGF-β1. Nat. Med. 19, 1567–1568 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Basta, J. et al. Pharmacologic inhibition of RGD-binding integrins ameliorates fibrosis and improves function following kidney injury. Physiol. Rep. 8, e14329 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Henderson, N. C. & Sheppard, D. Integrin-mediated regulation of TGFβ in fibrosis. Biochim. Biophys. Acta 1832, 891–896 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Kim, K. K., Sheppard, D. & Chapman, H. A. TGF-β1 signaling and tissue fibrosis. Cold Spring Harb. Perspect. Biol. 10, a022293 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Minagawa, S. et al. Selective targeting of TGF-β activation to treat fibroinflammatory airway disease. Sci. Transl. Med. 6, 241ra279 (2014).

    Article  Google Scholar 

  91. Wang, J. et al. Atypical interactions of integrin αvβ8 with pro-TGF-β1. Proc. Natl Acad. Sci. USA 114, E4168–E4174 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Cormier, A. et al. Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension. Nat. Struct. Mol. Biol. 25, 698–704 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Asano, Y. et al. Increased expression of integrin αvβ5 contributes to the establishment of autocrine TGF-β signaling in scleroderma fibroblasts. J. Immunol. 175, 7708–7718 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Asano, Y. et al. Involvement of αvβ5 integrin-mediated activation of latent transforming growth factor β1 in autocrine transforming growth factor beta signaling in systemic sclerosis fibroblasts. Arthritis Rheum. 52, 2897–2905 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Tatler, A. L. et al. Integrin αvβ5-mediated TGF-β activation by airway smooth muscle cells in asthma. J. Immunol. 187, 6094–6107 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Scotton, C. J. et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J. Clin. Invest. 119, 2550–2563 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Zaveri, T. D., Lewis, J. S., Dolgova, N. V., Clare-Salzler, M. J. & Keselowsky, B. G. Integrin-directed modulation of macrophage responses to biomaterials. Biomaterials 35, 3504–3515 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kang, H. et al. Immunoregulation of macrophages by dynamic ligand presentation via ligand–cation coordination. Nat. Commun. 10, 1696 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Jenney, C. R. & Anderson, J. M. Adsorbed serum proteins responsible for surface dependent human macrophage behavior. J. Biomed. Mater. Res. 49, 435–447 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Barr, S., Hill, E. W. & Bayat, A. Functional biocompatibility testing of silicone breast implants and a novel classification system based on surface roughness. J. Mech. Behav. Biomed. Mater. 75, 75–81 (2017).

    Article  CAS  PubMed  Google Scholar 

  101. Zollinger, A. J. & Smith, M. L. Fibronectin, the extracellular glue. Matrix Biol. 60–61, 27–37 (2017).

    Article  PubMed  Google Scholar 

  102. Ringer, P., Colo, G., Fassler, R. & Grashoff, C. Sensing the mechano-chemical properties of the extracellular matrix. Matrix Biol. 64, 6–16 (2017).

    Article  CAS  PubMed  Google Scholar 

  103. Kong, F., Garcia, A. J., Mould, A. P., Humphries, M. J. & Zhu, C. Demonstration of catch bonds between an integrin and its ligand. J. Cell Biol. 185, 1275–1284 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Friedland, J. C., Lee, M. H. & Boettiger, D. Mechanically activated integrin switch controls α5β1 function. Science 323, 642–644 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Van Putten, S. M. et al. Endotoxin contamination delays the foreign body reaction. J. Biomed. Mater. Res. A 98, 527–534 (2011).

    Article  PubMed  Google Scholar 

  106. Spiegel, A. J., Kania, K. & Hamilton, K. L. 2020 special issue: twenty years of breast reconstruction: past, present, and future. Breast J. 26, 39–41 (2020).

    Article  PubMed  Google Scholar 

  107. Yim, H. W., Nguyen, A. & Kim, Y. K. Facial contouring surgery with custom silicone implants based on a 3D prototype model and CT-Scan: a preliminary study. Aesthetic Plast. Surg. 39, 418–424 (2015).

    Article  PubMed  Google Scholar 

  108. Sakai, T. et al. Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis. Nat. Med. 7, 324–330 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Lodyga, M. et al. Cadherin-11-mediated adhesion of macrophages to myofibroblasts establishes a profibrotic niche of active TGF-β. Sci. Signal. 12, eaa03469 (2019).

    Article  Google Scholar 

  110. Balestrini, J. L., Chaudhry, S., Sarrazy, V., Koehler, A. & Hinz, B. The mechanical memory of lung myofibroblasts. Integr. Biol. 4, 410–421 (2012).

    Article  CAS  Google Scholar 

  111. Sawada, Y. & Sheetz, M. P. Force transduction by Triton cytoskeletons. J. Cell Biol. 156, 609–615 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hinz, B., Dugina, V., Ballestrem, C., Wehrle-Haller, B. & Chaponnier, C. Alpha-smooth muscle actin Is crucial for focal adhesion maturation in myofibroblasts. Mol. Biol. Cell 14, 2508–2519 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. O’Reilly, D. R., Miller, L. K. & Luckow, V. A. Baculovirus Expression Vectors—A Laboratory Manual (Oxford Univ. Press, 1992).

Download references

Acknowledgements

We are very grateful to A. Modarressi (Plastic, Reconstructive and Aesthetic Surgery Division, University Hospitals Geneva, Geneva, Switzerland) for providing expert advice on breast implant materials and medical complications. We thank G. Gabbiani (University of Geneva) for kindly providing the α-SMA antibody, H. Ni (St. Michael’s Hospital, Toronto) for the anti-fibrin antibodies, C.-H. Heldin (University of Uppsala, Sweden) for the LTBP-1 antibody and J. Murphy-Ullrich for providing the LAP expression construct. The FN−/− MEFs were a kind gift from M. Costell (Universitat de València, Spain) and R. Fässler (Max Planck Institute of Biochemistry, Munich, Germany). The col1a1 transgenic mice were provided by D. Brenner (University of California, San Diego). We also thank J. Firmino and D. Rajshankar at the Collaborative Advanced Microscopy Labs of Dentistry (CAMiLoD; Faculty of Dentistry, University of Toronto) and S. Plotnikov (Cell and Systems Biology, University of Toronto) for outstanding help with image acquisition and data analysis. We gratefully acknowledge F. Younesi (Hinz laboratory), F. Sarraf and N. Valiquette (Histology service, Faculty of Dentistry, University of Toronto) and the staff of the Centre for Phenogenomics (Mount Sinai Hospital, Toronto) for excellent technical histology support. The research of B.H. is supported by a foundation grant from the Canadian Institutes of Health Research (375597) and support from the John R. Evans Leaders Fund (grant numbers 36050, 38861 and 38430), as well as innovation funds (Fibrosis Network; grant number 36349) from the Canada Foundation for Innovation (CFI) and Ontario Research Fund (ORF). M.E. is supported by an Ontario Graduate Scholarship (OGS). R.S. is supported by a grant from the Mathematics of Information Technology and Complex Systems (MITACS; IT13623).

Author information

Author notes

  1. These authors contributed equally: Ronen Schuster, Sander van Putten.

Authors and Affiliations

  1. Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada

    Nina Noskovicova, Ronen Schuster, Sander van Putten, Maya Ezzo, Anne Koehler, Stellar Boo & Boris Hinz

  2. Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark

    Sander van Putten

  3. Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada

    Nuno M. Coelho & Christopher A. McCulloch

  4. Center for World Health & Medicine, Saint Louis University, St. Louis, MO, USA

    David Griggs & Peter Ruminski

Authors
  1. Nina Noskovicova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronen Schuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sander van Putten
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maya Ezzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Koehler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stellar Boo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nuno M. Coelho
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David Griggs
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peter Ruminski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christopher A. McCulloch
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Boris Hinz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.N., S.v.P., A.K. and B.H. conceived of the study idea. N.N., R.S., S.v.P., M.E., A.K., S.B., N.M.C. and B.H. developed the methodology. N.N., R.S., S.v.P., M.E. and A.K. performed the formal analysis and data visualization. D.G. and P.R. provided resources. B.H. was responsible for project administration, supervision and funding acquisition. N.N. and S.v.P. prepared the original draft of the manuscript. N.N., R.S., S.v.P., S.B., N.M.C., D.G., P.R., C.A.M. and B.H. reviewed and edited the manuscript.

Corresponding author

Correspondence to Boris Hinz.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Noskovicova, N., Schuster, R., van Putten, S. et al. Suppression of the fibrotic encapsulation of silicone implants by inhibiting the mechanical activation of pro-fibrotic TGF-β. Nat Biomed Eng 5, 1437–1456 (2021). https://doi.org/10.1038/s41551-021-00722-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-021-00722-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing