The Impact of Smad3 Loss of Function on TGF-β Signaling and Radiation-Induced Capsular Contracture

Department of Biomedical Engineering (School of Engineering), University of Rochester, Rochester, New York, United States
Plastic and Reconstructive Surgery (Impact Factor: 2.99). 06/2011; 127(6):2263-9. DOI: 10.1097/PRS.0b013e3182131bea
Source: PubMed


Capsular contracture remains a major problem following prosthetic breast implantation, especially in patients undergoing irradiation. Recent studies suggest that such radiation injuries are a cascading process of cytokine activation, with transforming growth factor (TGF)-β acting as the "master switch." Because TGF-β signals through phosphorylation of Smad3, a plausible approach to abate TGF-β-induced capsular contracture would be to interrupt Smad3 signaling. To test this hypothesis, capsular contracture formation in wild-type and Smad3 knockout mice was compared using micro-computed tomographic and histologic examination.
On day 0, 48 mice were implanted with bilateral silicone gel implants. Postoperatively, animals were imaged using live-scan micro-computed tomographic scanning. Animals in the radiation arm then received a 10-Gy directed radiation dose. On postoperative days 21, 28, 35, and 42, animals were imaged again. Histologic evaluation was performed at necropsy.
Irradiated implants in the wild-type mice demonstrated shape and contour deformation on micro-computed tomographic scanning beginning on postoperative day 21 and progressing through day 42. Conversely, micro-computed tomographic scanning of irradiated implants in knockout mice demonstrated few changes from day 0 through day 42. Corresponding histologic specimens from wild-type mice demonstrated irregular capsules composed of disorganized collagen that became thicker from day 21 to day 42. Irradiated knockout specimen maintained thin capsules from day 21 through day 42.
In this work, inhibiting TGF-β signaling led to a reduction in radiation-induced capsular contracture as measured by micro-computed tomographic and histologic evaluation. The results of this study suggest a promising target for the prevention of capsular contracture through the development of anti-Smad3/TGF-β-based therapies.

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    • "Reported techniques include copious irrigation with sterile normal saline, in situ irrigation with saline followed by antibiotic instillation,4–6 and in situ glucocorticoid instillation.7 Current research focuses on the texturing of implants,8–11 using in situ biogels and collagen scaffolds to reduce the rate of capsular contraction,9 and limiting the body’s immune response to the implants.10 Additional studies have been reported using rabbits as a model for capsule formation to guide the development of more efficacious breast implants.12 "
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    ABSTRACT: Background: Capsular contracture is the most common complication following primary augmentation mammoplasty. It remains poorly understood but is attributed to subclinical infection, immunologic response to breast implants, and chronic inflammatory changes caused by the presence of the implants. The infectious theory of contracture has lead to the practice of irrigating implant pockets with a triple antibiotic solution. The purpose of this study was to determine if antibiotic irrigation reduced the incidence and severity of capsular contracture compared with saline irrigation. Methods: A cohort study enrolling all patients having undergone primary augmentation mammoplasty performed by surgeon A and surgeon B between 2011 and 2012 for all women satisfying inclusion and exclusion criteria was conducted. The only difference in surgical technique was the use of antibiotic irrigation by surgeon B. A chi-square test and analysis of variance with predetermined 95% confidence intervals were performed. Results: Fifty-five patients were operated on. Twenty-eight of surgeon A’s patients were included, ranging in age from 22 to 50 with a mean follow-up time of 1.8 years. Twenty-seven of surgeon B’s patients were included, ranging in age from 22 to 56 with a mean follow-up time of 1.6 years. Rate of capsular contracture was 3.6% (surgeon A) and 3.7% (surgeon B). Chi-square statistic was found to be 0.0014 (P = 0.97) and analysis of variance F value was 1 (P = 0.39). Conclusions: Triple antibiotic breast irrigation is not associated with a significant reduction in the incidence or severity of capsular contracture compared with sterile saline when high-quality surgical technique is used.
    10/2013; 1(7):e55. DOI:10.1097/GOX.0b013e3182aa8760
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    Clinics in plastic surgery 04/2012; 39(2):127-36. DOI:10.1016/j.cps.2012.02.005 · 0.91 Impact Factor
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    ABSTRACT: The authors compared clinical outcomes to determine whether acellular dermal matrix altered the capsular tissue architecture in irradiated and nonirradiated breasts following matrix-assisted expander reconstruction. Part I included all 27 patients who underwent bilateral tissue expander reconstruction with acellular dermal matrix between 2007 and 2012 and subsequent unilateral radiation therapy. Part II included a subset of patients with capsular biopsy specimens taken at the time of implant exchange for histologic analysis. Specimens included irradiated and nonirradiated acellular dermal matrix and irradiated and nonirradiated native capsule. Clinical outcomes were analyzed in relation to capsule architecture and acellular dermal matrix performance. In part I, mean follow-up was 28 months. Grade III/IV contractures were identified in nine patients (all on the irradiated side), and 12 developed noncontracture complications (75 percent on the irradiated side). Nine patients were unable to continue with implant reconstruction and required salvage with autologous tissue. In part II, postirradiation biopsy specimens were taken of the peri-implant capsule in six patients at the time of secondary surgery. Elastin content and the total cellular infiltrate were significantly greater in the irradiated versus nonirradiated native capsules (p = 0.0015). Conversely, the irradiated matrix capsule was composed of similar amounts of cellular infiltrate and collagen as the nonirradiated matrix capsules and nonirradiated native capsules. Irradiated acellular dermal matrix showed the least amount of alpha-smooth actin staining but a similar number of blood vessels. Acellular dermal matrix appears to limit the elastosis and chronic inflammation seen in irradiated implant reconstructions and is potentially beneficial in these patients. Therapeutic, III.
    Plastic and Reconstructive Surgery 02/2014; 133(2):214-21. DOI:10.1097/01.prs.0000437255.01199.42 · 2.99 Impact Factor
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