Influence of mechanotransduction on capsular fibrosis

• Applicant: Dr. Britta Kühlmann
• Subject Area: General and Visceral Surgery
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 375076668

Capsular fibrosis is the most common long-term complication after breast implant-based augmentation. Breast cancer affects one in eight women worldwide. In most instances mastectomy is necessary, followed by breast reconstruction with breast implants. With 1.649.271 surgeries, breast augmentation with implants was the most frequently performed cosmetic surgical procedure worldwide in 2016. According to the International Society of Aesthetic Plastic Surgery there were more than 52.209 breast augmentations with implants in Germany (a 12% increase from 2015). Despite this tremendous clinical impact, capsular fibrosis remains the most severe complication. Often, surgical revision is the only available treatment. Its cellular alterations and molecular signaling are still barely understood and no clinical therapies for fibrosis have been discovered yet. The identification of cell types can provide clues in determining the pathophysiology of the fibrotic changes to find a medical cure. To elucidate the gene expression patterns associated with this foreign body response, we analyzed genes of human capsular fibrosis. Additionally, an in vivo-mouse model with silicone implants was used to analyze cell types present in the capsule over time as well as single cell analysis to characterize these cells to determine their involvement in fibrotic capsule development.For the first time this studies reveal that the most prominent cells at every time-point in the capsule are macrophages as a subset of immune cells. Most importantly, CD45+/CD11b-/F4/80- cells increase in the capsule over time and have fibrogenic potential. For the first time in translational research, this cell subpopulation was discovered. Interestingly, this unique cell type is able to produce collagen. Additionally, our previous investigations show that genes from mechanotransductional pathways, especially the WNT signaling pathway with WNT11 and FAK, have significant impact on capsular fibrosis in breast implants. These central hypotheses will be examined in several upcoming experiments. The role of WNT11 will be further investigated in WNT11-knockout mice to show that this in vivo-model produces a much thinner and less severe capsule. To explore the role of FAK we employed a selective small molecule inhibitor of FAK (FAK-I) in an in vivo-model. Miniature implants will be coated with FAK-I to reduce capsular fibrosis tremendously. Additionally, the role of CD45+/CD11b-/F4/80- cells in increased production of capsular fibrosis and their unique ability to produce collagen will be investigated. Our hypothesis is that CD45+/CD11b-/F4/80- as well as WNT11 and FAK contribute to the aggravation of fibrotic capsules.These investigations represent innovative future strategies in the therapy of capsular fibrosis and might help to develop novel therapeutic interventions for the treatment of capsular fibrosis.

• DFG Programme: Research Fellowships
• International Connection: USA