According to a 2013 report from the American Society of Plastic Surgeons, there are more than 200,000 women in the USA who had reconstructive or cosmetic breast augmentations. The medical literature describes that silicone gel-filled breast implants are linked with significant adverse health effects  . The most common local complication associated with silicone gel-filled breast implant is capsular contracture, with a combined overall incidence of 10.6%    . Capsular contracture is a multifactorial fibrotic foreign body reaction that promotes the hardening and tightening of the capsule at the contact site between the tissue and implant, which then causes dissatisfaction and pain after breast augmentation in addition to deformity and device failure . Though the pathogenesis of capsular contracture has not been fully elucidated, a variety of causal associations including surface texture of the breast implant have been proposed to date .
The surface texture of the shell surrounding breast implant acts as the interface between the breast tissue and device  and its understanding is important in the field of implantation. They can markedly alter the pathophysiology and directly influence cellular biology, body tissues, and fibrous capsule development, specially the adherence of the tissue to the breast implant and the alignment of collagen fibers   . Traditionally, there are two main kinds of implants: smooth and textured implants. Smooth-surface implants are used worldwide; however, the prevalence of capsular contracture is higher with the smooth implants than others. Meta-analyses studies showed approximately 5 times increase in the contracture rate on smooth surface with respect to textured surfaces  . Textured-surface implants, which can disrupt the contractile forces, were developed to minimize capsular contracture . However, serious complications such as double capsule formation, late seroma, and anaplastic large cell lymphoma (ALCL) have been appeared for textured implants due to their aggressive texturization  .
Recently, numerous articles have proposed the use of nanometric surface topographies to induce specific cellular behavior like cell proliferation, attachment, migration, and differentiation, which affect the prevalence rate of capsular contracture      . Surfaces with nanoscale roughness closer to cellular dimensions are known to exhibit profound effects on cells and also produce a reduced foreign body response  . BellaGel SmoothFine® implants have a novel nano textured surfaces. The complication rates of BellaGel SmoothFine® were almost 10 times less than any other devices in our practice . Our intuitive aim here is to evaluate the tissue’s reaction to the BellaGel SmoothFine® surface texture with different surfaces using a rat implant model.
2. Materials and Methods
2.1. Breast Implants
Each shell of implants was obtained from 4 different breast implant devices (Table 1).
2.2. Scanning Electron Microscope (SEM)
A 2-cm2 shell sample was obtained from each of BellaGel Smooth®, BellaGel Textured®, BellaGel SmoothFine®, and Motiva SilkSurface® implants. These specimens were cleaned twice in isopropylalcohol and viewed via an SEM (Hitachi, Tokyo, Japan). Analysis was done at accelerating voltage of 5 keV. The electron beam intensity was I = 10 - 11 A.
2.3. 3D Confocal Images
Physical properties of silicone breast implant surfaces including roughness, skewness, and kurtosis were observed by looking at their topographical features using a 3D confocal laser scanning microscope (LEXT OLS5000, Olympus Corporation, Tokyo, Japan). The experiments have been performed on 3 sample areas.
Wettability assessment was carried out using a contact angle meter Phoenix-MT(T) (SEO, Suwon, Gyeonggido, Korea). The experiments were undertaken three times to ensure significance of the tests.
2.5. In Vivo Animal Experiment
Sixty Sprague-Dawley rats with a body weight of about 250 - 300 g (Orientbio, Seongnam, Gyeonggido, Korea) were maintained in an exceedingly 12/12 light/dark cycle under a pathogen-free condition and given water ad libitum. Animal care and experimental procedures were approved from the Institutional Animal Care and Use Committee of Seoul National University Bundang Hospital
Table 1. Breast implant types included in this study.
(approval number: N-1803/454-602).
In this study, 5 rats were allocated to each group and divided into four groups: 1) BellaGel Smooth® implant, 2) BellaGel Textured® implant, 3) BellaGel SmoothFine® implant, and 4) Motiva SilkSurface® implant. Each animal was anesthesed through inhalation using isoflurane (Hana Pharm, Seoul, Korea) and the incision site was made approximately 2 cm long on the dorsal part of rat. Subsequently, silicone breast implants were placed to the subpaniculus pocket. After 1, 2, and 8 weeks with the implant, rats were sacrificed with carbon dioxide.
2.6. Hematoxylin & Eosin Staining
Implants were excised in block with the surrounding tissue. Harvested specimens were fixed with 10% neutral buffered formalin and embedded in paraffin. Sections (5 µm) of tissue samples were stained with hematoxylin and eosin (H & E) before dewaxing and dehydration for histological analysis. Each stained slide was examined at × 100 magnification using a microscope (Carl Zeiss, Germany). The capsular thickness was calculated using Image J software (National Institutes of Health, Bethesda, MD, USA).
2.7. Masson’s Trichrome Staining
Masson’s Trichrome stain was performed according to manufacturer’s instructions (Polysciences, Pennsylvania, USA).
2.8. Western Blot Analysis
The capsule tissue around silicone breast implant was prepared using a RIPA buffer (Sigma Aldrich, MO, USA) that contained phosphatase inhibitor cocktail (BioPrince, Chuncheon, Gangwon, Korea). Samples were then denatured by heating for five min and immediately placed on ice. After centrifugation, aliquots containing approximately 60 μg protein were separated by gel electrophoresis. After electrophoresis, the protein was transferred from the gel onto nitrocellulose membranes and then the membranes were blocked in 5% skim milk for 2 h. After blocking, the membranes were subjected to western blotting with antibodies for iNOS, α-SMA, ARG1 (1:1000; Abcam, Cambridge, UK), Vimentin and β-actin (1:1000; Santa cruz, CA, USA) at 4˚C for overnight. The blot was incubated with secondary antibodies (1:5000 in TBST, rabbit for iNOS and α-SMA; mouse for ARG1 and β-actin) for 1 h for protein detection. Finally, proteins were detected using the enhanced chemiluminescence reagent (Amersham Co. Newark, NJ, USA) following the manufacturer’s instruction. The density of protein bands was measured using the Image J (National Institutes of Health, USA). The relative quantities were normalized by β-actin.
2.9. Statistical Analysis
All values are reported as means ± S.E.M. (standard error of the mean). Statistical analyses were performed using SPSS statistical software (SPSS 11.5, Armonk, NY, USA). For all data, significant differences were determined using an unpaired t-test. For all analyses, P < 0.05 was defined as statistically significant.
3.1. Texturing Analysis of BellaGel SmoothFine® Implant
BellaGel Smooth® texture was found a characteristic relatively flat appearance, with no height or no depth in the texturing and occasional surface irregularity (Figure 1). The BellaGel Textured® has striking surface characteristics and is made up of the pitted irregular cuboid appearance of the pores (“open-cell network”) with sizes ranging from 100 to 400 μm width and depths varying between
Figure 1. Texturing analysis of BellaGel SmoothFine® implant. SEM images of the top view (50×, 100×, and 200×) of BellaGel Smooth®, BellaGel Textured®, BellaGel SmoothFine®, and Motiva SilkSurfaces®.
100 and 400 μm. It has an average well density of six per mm2 and pores composed of 80% of the total surface area (pores with 70 nm diameter). BellaGel SmoothFine® and Motiva SilkSurface® has more physically similar shapes and a more random and bumpy surface topography (Figure 1).
3.2. Surface Characterization of BellaGel SmoothFine® Implant
The surface area per mm2 from 4 breast implant devices ranged from 1.0 mm2 for the BellaGel Smooth® to 4.62 mm2 for the BellaGel Textured® (Table 2). The BellaGel SmoothFine® and Motiva SilkSurface® have the surface area value, with 1.29 ± 0.01 mm2 and 1.32 ± 0.02 mm2, respectively.
Surface roughness is defined as the variance in the surface height with respect to the reference plane. Of the four implant textures tested, the BellaGel Smooth® surface contains a nano-scale roughness value of 0.40 μm ± 0.20 μm (Table 2 and Figure 2). The relatively large increased peak roughness value obtained for
Table 2. 3D surface parameters including surface area, roughness, kurtosis, and skewness.
Figure 2. Surface characterization of BellaGel SmoothFine® implant. Confocal laser 3-D topography of BellaGel Smooth®, BellaGel Textured®, BellaGel SmoothFine®, and Motiva SilkSurfaces®.
the BellaGel Textured® surfaces (100.10 μm ± 10.40 μm), which were about 250 times rougher than the BellaGel Smooth® surfaces (Table 2 and Figure 2). The BellaGel SmoothFine® surface has a roughness value of 5.96 μm ± 0.41 μm, which is relatively less rough than the BellaGel Textured® surface (P < 0.001). Motiva SilkSurface® contains nano-scale features with an average roughness of 3.05 μm ± 0.82 μm, this low roughness therefore would reduce the friction and particle lose (Table 2 and Figure 2).
The positive skewness values (Sk > 0) exhibited by the BellaGel Smooth® (Sk = 0.45 ± 0.53), BellaGel SmoothFine® (Sk = 0.36 ± 0.19), and Motiva SilkSurface® (Sk = 0.89 ± 0.33) implants suggests more peaks than valleys on the surfaces of these samples (Table 2). In contrast, the negative skewness value (Sk < 0) exhibited by the BellaGel Textured® (Sk = −0.65 ± 0.19) indicates the presence of more valleys than peaks on the surfaces (Table 2).
The BellaGel Smooth® surfaces exhibited an excess kurtosis value (Sku = 14.70 ± 12.56) suggesting that a repetitive surface with spikes. The smaller kurtosis values obtained for the BellaGel Textured® (1.90 ± 0.14), BellaGel SmoothFine® (4.23 ± 0.68), and Motiva SilkSurface® (5.03 ± 1.26) implants suggesting that bumpier and random surface.
Contact angle measurement was carried out to investigate the hydrophobicity of the surface texture. All implants were hydrophobic with contact angles all greater than 100˚ (Figure 3). From the measurements it was determined that the BellaGel Smooth® and BellaGel SmoothFine® surface were less hydrophobic than others, exhibiting a lower contact angle of 102.76˚ ± 0.62˚ and 103.14˚ ± 2.06˚, respectively (Figure 3) while the larger contact angle of 125.11˚ ± 2.35˚ and 121.61˚ ± 5.54˚ were obtained for the Motiva SilkSurface® and the BellaGel Textured® surface, respectively (Figure 3). The values indicate that the BellaGel Textured® surface and Motiva SilkSurface® and is less wettable than the BellaGel Smooth® and BellaGel SmoothFine® surface (Figure 3).
3.3. Effect of BellaGel SmoothFine® Implant on Capsule Formation
We compared the fibrous capsule development with respect to the implant surface texture of each implant device based on the contact site of the implant. The capsules wall diameter around the BellaGel Smooth® and BellaGel Textured®
Figure 3. Contact angle analysis of BellaGel SmoothFine® implant. The assessment of contact angle of BellaGel Smooth®, BellaGel Textured®, BellaGel SmoothFine®, and Motiva SilkSurfaces® was carried out using a contact angle meter Phoenix-MT(T) (SEO, Suwon, Gyeonggido, Korea). The experiments were undertaken three times to ensure significance of the tests.
surface appeared significantly thicker than those around the BellaGel SmoothFine® and Motiva SilkSurface®. The average capsular thickness was 964.03 ± 20.05 μm in the BellaGel Smooth group®, compared with 935.9 ± 51.4 μm in the BellaGel Textured® group. This difference was not statistically significant (P = 0.621; Figure 4). Meanwhile, the thickness of capsules to BellaGel SmoothFine® (680.58 ± 46.64 μm) and Motiva SilkSurface® (775.92 ± 49.66 μm) were significantly thinner than those surrounding the BellaGel Smooth® (P < 0.05) and BellaGel Textured® surfaces (P < 0.05). These results clearly indicate a close relationship between implant texture and the capsule thickness.
3.4. Effect of BellaGel SmoothFine® Implant on Collagen Density
To evaluate the collagen density, the sections were subjected to MT staining, there was a significantly greater increased collagen density to both BellaGel Smooth® (62.3% ± 1.18%) and BellaGel Textured® (61.01% ± 0.61%) surface (Figure 5). There were no significant differences in collagen density between the BellaGel Smooth® and the BellaGel Textured® group (P > 0.05; Figure 5). In contrast, a significant reduction in the rate of MT-positive tissue was seen both in the BellaGel SmoothFine® (54.2% ± 3.5%; P = 0.042) and Motiva SilkSurface® (55.3% ± 2.12%; P = 0.011) related to the BellaGel Smooth® (Figure 5).
3.5. Effect of BellaGel SmoothFine® Implant on iNOS and Arg-1 Expression
iNOS levels are crucial to quantify local inflammatory response. As seen in Figure 6, at the 1-week point, the levels of iNOS around the BellaGel Smooth® and BellaGel Textured® surface appeared significantly overexpressed than those around the BellaGel SmoothFine® and Motiva SilkSurface® (Figure 6). The mean relative expression level was 1.27 ± 0.18 in the BellaGel Smooth® group, compared with 0.81 ± 0.11 in the BellaGel Textured® group (Figure 6). This difference was not
Figure 4. The effect of BellaGel SmoothFine® implant on capsule formation. (a) Capsule tissues at the tissue-implant interface at 8 weeks were stained with hematoxylin and eosin (H & E). (b) The capsule thickness was measured. Five randomly selected tissue sections per rat were counted. Data are represented as the mean ± S.E.M. with n = 5 rats per group. #P < 0.05, significantly different from BellaGel Smooth implant. Original magnification ×400, scale bar = 100 μm.
Figure 5. The effect of BellaGel SmoothFine® implant on collagen density. (a) Capsule tissues at the tissue-implant interface at 8 weeks were stained with Masson’s Trichrome (MT). (b) The collagen density was measured. Five randomly selected tissue sections per rat were counted. Data are represented as the mean ± S.E.M. with n = 5 rats per group. #P < 0.05, significantly different from BellaGel Smooth implant (independent t-test). Original magnification ×400, scale bar = 100 μm.
Figure 6. The effect of BellaGel SmoothFine® implant on iNOS and Arg-1 expression. Silicone breast implants were emplaced beneath the panniculus carnosus muscle on the dorsum of Sprague Dawley rats and the fibrous capsule tissues at the tissue-implant interface at 1 week, 2 weeks, 8 weeks were extracted explanted for histological examination. Expressions of iNOS and Arg-1 were detected by immunoblot analysis. Data are represented as the mean ± S.E.M. with n = 5 rats per group.
statistically significant (P = 0.072; Figure 6). Meanwhile, the relative expression level to BellaGel SmoothFine® (0.24 ± 0.03) and Motiva SilkSurface® (0.38 ± 0.04) were significantly lower than those surrounding the BellaGel Smooth® (P < 0.05) and BellaGel Textured® surfaces (P < 0.05). This result provides evidence of a more severe inflammatory reaction against BellaGel Smooth® than against BellaGel SmoothFine® or Motiva SilkSurface®. At the 2-week point, iNOS levels also tended to decrease when compared with the BellaGel Smooth® and BellaGel Textured®, although this decrease was not significant (Figure 6). In contrast, at 8 weeks, the level of iNOS expression peaked in the BellaGel Textured® surface (mean = 1.22). The BellaGel SmoothFine® surface (mean = 0.55) and Motiva SilkSurfaces® (mean = 0.54) showed a significantly lower level of iNOS than the BellaGel Smooth® surface (mean = 1.02) (Figure 6). However, Arg-1 expression was not affected significantly (P > 0.05). In all groups analyzed (1, 2, and 8 weeks), the expression of iNOS was higher in the BellaGel Smooth® and the BellGel Textured® surfaces, it was statistically significant than BellaGel SmoothFine® and Motiva SilkSurfaces®.
3.6. Effect of BellaGel SmoothFine® Implant on Vimentin and α-SMA Expression
Vimentin and SMA are molecular markers of fibrosis. After 1 week, there was a greater increased Vimentin expression to both BellaGel Smooth® and BellaGel Textured® surfaces in comparison to both BellaGel SmoothFine® (BellaGel Smooth® P = 0.12; BellaGel Textured® P = 0.042) and Motiva SilkSurface® (BellaGel Smooth® P = 0.12; BellaGel Textured® P = 0.044) (Figure 7). At the 2-week point, Vimentin levels to BellaGel SmoothFine® also tended to decrease when compared with the BellaGel Smooth®, although this decrease was not significant (P = 0.449; Figure 7). At the 2-week point, we did not observe any difference between them. In contrast, at 8 weeks, the Motiva SilkSurface® group showed a significantly lower level of Vimentin than the BellaGel Smooth® (P = 0.015; Figure 7). However, there was no significant differences in the BellaGel Smooth® in comparison to BellaGel SmoothFine® (P = 0.377). There was a significant increase in myofibrobalsts in the capsule around the BellaGel Smooth® surfaces. Notably, formation of α-SMA-negative stress fibers was also reduced on the Motiva SilkSurface® was completely absent from 1 week to 8 weeks (Figure 7).
The BellaGel SmoothFine® implant is a novel nanotextured breast implant. On a clinical level, BellaGel SmoothFine® demonstrated excellent safety outcomes and reduced serious adverse events such as double capsules, capsular contracture, implant rupture for device failure, or late seromas . In the current study, we investigated the physical properties of BellaGel SmoothFine® surfaces and the effect and underlying mechanisms of BellaGel SmoothFine® on the capsular contracture in vivo animal model.
Figure 7. The effect of BellaGel SmoothFine® implant on Vimentin and α-SMA expression. Silicone breast implants were emplaced beneath the panniculus carnosus muscle on the dorsum of Sprague Dawley rats and the fibrous capsule tissues at the tissue-implant interface at 1 week, 2 weeks, 8 weeks were extracted explanted for histological examination. Expressions of Vimentin and α-SMA were detected by immunoblot analysis. Data are represented as the mean ± S.E.M. with n = 5 rats per group.
BellaGel SmoothFine® has a low surface roughness value at a subcellular level, which implies less particle friction coefficients and no tissue ingrowth  . A skewness value of 0.36 ± 0.19, a kurtosis value of 4.23 ± 0.68 and a contact angle of 103.14˚ ± 2.06˚, are known to show higher biocompatibility. Therefore, we expected that BellaGel SmoothFine® may have led to the blocking of fibrous capsule formation in the current study.
Collagenous capsules formation is an inevitable response to all kind of foreign bodies and is always occur after silicone breast implant insertion into the body. Externally, a capsule develops a relatively undetectable thin membrane surrounding the implant in those undergoing breast augmentations. However, a stronger foreign body reaction to the implant leads to more excessive hypocellular thicker capsule formation, which is rich in collagen and positively related to the contracture formation . This can cause an abnormally hard feel of the implant and pain in the breast. Previous study reported that surface texture may predispose implants to excessive capsular formation  . Smooth surfaces are known to be correlated with high prevalence of capsular contracture, because fibroblasts on the surface of smooth textured implant produce collagen fibers, which are align highly within the capsule next to the implant in response to a shearing motion within the implant pocket  . The continual rubbing between a smooth-surfaced implant and its nonadherent capsule plays a key role in causing a thick capsule and an acute, active tissue response . By contrast, textured surfaces disrupt certain collagen alignment of the surrounding capsule through inhibiting micromotion at the porsthesis/host interface. Therefore, textured surfaces induce decreased malposition and capsular contracture with respect to smooth surfaces       . However, additional studies showed no statistically significant reduction in the capsule formation  - . In the present study, we conducted an experiment in which silicone implants were emplaced beneath the muscle layer in rat, and the capsules that developed surrounding the silicone implants were then investigated. BellaGel SmoothFine® surfaces promoted significantly decreased collagenous capsule thickness in comparison to the BellaGel Smooth® and BellaGel Textured® surfaces. In addition, the collagen densities in the capsules surrounding the BellaGel SmoothFine® and Motiva SilkSurfaces® were significantly decreased with respect to the BellaGel Smooth® and BellaGel Textured®. The hierarchical nano-texutred surfaces of the BellaGel SmoothFine® implant, together with its perceived roughness may lead to the dramatic reduction of capsule thickness and collagen density as well.
Inflammatory reaction occurred when silicone breast implant inserted into the body, plays a vital role in the progression of capsular contracture, because it activates fibroblasts around capsules to cause excessive fibrosis and hypertrophic scar contracture  . iNOS, a degradative enzyme, is an acute phase inflammatory factor and expressed by macrophages. They seem central to degrade the silicone breast implant through the production of nitric oxide. Significantly, iNOS is important in the pathogenesis of breast implant derived capsular contracture  . In this work we found that the expression of iNOS was reduced on BellaGel SmoothFine® and Motiva SilkSurfaces® in comparison to BellaGel Smooth® and Textured® surfaces. The constant rubbing between a smooth surfaces implant and host tissue might induce significantly increased inflammatory response . The reduction in frictional forces between the textured surfaces and host tissues may result in minimal inflammation with respect to smooth surfaces. However, frequent cracking of the collagen fibers on textured surfaces may cause persistent inflammation. BellaGel SmoothFine® is not rough enough to cause friction with the surrounding tissues; therefore, the initial inflammatory response was decreased.
Fibroblasts differentiate into myofibroblasts in contracted fibrous capsules and upregulate the expression of IL-8, TGF-β, TGF-β 1, α-SMA, collagen 1, and MMP12 as they differentiate into capsular myofibroblasts . Myofibroblasts present in some conditions associated with contraction processes, such as tenosynovitis, Dupuytren’s contracture, and fibrous capsules formed around implant . Inside the body, fibroblasts and myofibroblasts are known to make a stiff extracellular matrix that remodels the original healthy tissue. An abundance of vimentin positive fibroblasts and α-SMA positive myofibroblasts were seen in contracted capsules, and were relatively absent in normal breast tissue. Our result showed that the BellaGel SmoothFine® induced decreased expression of Vimentin and α-SMA in comparion to BellaGel Smooth® and BellaGel Textured®. This results indicated that silicone breast implant with nano texture inhibited BI-induced capsular contracture by inhibiting the proliferation of fibroblast and myofibroblasts.
In conclusion, our study showed that variations in surface roughness of breast implant influenced breast implant derived fibrous capsule formation. Of note, surface texture with nano-textured implant such as BellaGel SmoothFine® and Motiva SilkSurfaces® can affect the pathophysiology of the foreign body reaction, causing less capsule formation, inflammation, and influx of fibroblasts, which contributes to the development of capsular contracture.
The study was supported by grant No. 02-2013-121 from SNUBH Research Fund, and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI15C1744).
*Sun-Young Nam and Miji Lee contributed equally to this work.
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