PURPOSE: Capsular contracture is the most common complication of implant-based breast surgery in the United States, leading to abnormal breast contour, increased firmness, and pain to touch. It is well established that smooth implants have higher rates of capsular contracture than textured implants. Assessing the effect of implant texture on contracture pathogenesis may help identify therapeutic targets for this disease process. The purpose of this study is to elucidate the pathogenesis of capsular contracture by examining RNA expression in a rat model of capsular formation around textured and smooth silicone implants, with pathologic correlation.
METHODS: A small animal model of capsular contracture was developed using Fischer rats. Ten animals underwent miniature smooth or textured silicone implant insertion in the submammary gland position. Six weeks postoperatively, implant capsules were harvested for histologic and molecular analysis. RNA sequencing was performed to identify target genes expressed in extracted capsules. Selected gene expression levels were confirmed with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry (IHC). Additionally, implant capsules collected from patients with and without capsular contracture were analyzed and correlated with results from our animal model.
RESULTS: RNA sequencing data were subjected to the Probability of Positive Log Ratio (PPLR) algorithm. Transcripts were identified for further characterization using cutoff values of PPLR ≥0.975 (2-fold increase) or a PPLR ≤0.025 (2-fold decrease). We identified 18,555 transcripts that met PPLR inclusion criteria. Quantitative reverse transcriptase polymerase chain reaction was performed for matrix metalloproteinase-3 (MMP-3), troponin T3 (TNNT-3), and neuregulin-1 (NRG-1). Expression of MMP-3 and TNNT-3 was upregulated in textured implant capsules compared to smooth implant capsules with a mean relative fold change of 8.79 (P = 0.0059) and 4.81 (P = 0.0056), respectively. Expression of NRG-1 was downregulated in textured implant capsules with a mean relative fold change of 0.40 (P < 0.0001) compared to smooth implant capsules. IHC staining of capsules extracted from our animal model was consistent with differential expression patterns, with smooth implant capsules expressing less MMP-3 and TNNT-3, and more NRG-1 than textured implant capsules. Similarly, IHC staining of human specimens revealed that contracted capsules had lower expression of MMP-3 and TNNT-3 and greater expression of NRG-1 compared to healthy capsules.
CONCLUSION: We demonstrated that capsules around smooth and textured implants have different histologic appearances and different patterns of gene expression. Importantly, pathologic correlation reveals that contracted capsules have expression patterns for MMP-3, TNNT-3, and NRG-1 that are consistent with capsules derived from smooth implants, which are known to have higher contracture rates. These results may help elucidate the mechanism of capsular contracture and identify potential genes for the development of future therapeutic targets for this condition.