Abstract Background Silicone elastomer, a ubiquitous biomaterial and main constituent of breast implants, has been used for breast augmentation and reconstruction for over 50 years. Breast implants have direct local and purported systemic effects on normal tissue homeostasis dictated by the chemical and physical presence of the implant. Objectives Protein adsorption has been demonstrated to be a key driver of local reactions to silicone. We sought to develop an assay and identify the proteins that coat implants during breast implantation. Methods Wound fluid was salvaged from women who had undergone breast reduction and incubated in contact with the surface of 13 commercially available implant surfaces. An in situ digestion technique was optimized to elute bound proteins. Samples were analyzed on an Orbitrap elite analyser, proteins identified in Mascot Demon and analyzed in Progenesis. Results A total of 822 proteins were identified, bound to the surfaces of the implants. Extracellular proteins were the most abundant ontology, followed by intracellular proteins. Fibrinogen, a proinflammatory protein and Albumin, an anti-inflammatory protein had significant (P < 0.0001) binding differences between the surfaces studied. Complement C3, C5, and factor H were also shown to have significantly different binding affinities for the implants included in the study (P < 0.05). Conclusions We have developed a novel assay of breast implant protein binding and demonstrated significant binding affinities for relevant proteins derived from breast tissue wound fluid. Level of Evidence: 5 Silicone breast implants are widely used throughout the world for both aesthetic and reconstructive purposes. Despite their common use, breast implants have been linked with a range of complications, which date back to their early development in the 1960s.1 The local complications of breast implants include rupture,2 seroma3 (both early and late), and capsular contracture formation.4 These complications have been shown to have a direct relationship with the implant itself, its surface, infection at the biomaterial surface, and in its ability to interact with the body appropriately.5,6 All biomaterials, of which breast implants are one, elicit an immediate foreign body response as their physical and chemical presence in the wound disturbs the normal wound healing process.7 It is the ability of this biomaterial to minimize the deleterious responses that cause a poor host response that dictates its biocompatibility.8 An understanding of this biomaterial/host interplay is therefore critical in the thorough evaluation of the interaction between implant surfaces and the human body. The very first step in the foreign body reaction to the biomaterial is the adsorption of a protein monolayer.9 Protein adsorption occurs within the first nanoseconds of contact between the biomaterial and the wound.10 The process of protein adsorption and the protein coating that results is determined by the biomaterial, its hydrophobicity, surface charge, topography, curvature, and its chemically reactive sites.11 The protein layer that results from this process determines the integrated response of the coagulation cascade, complement system, and the immune response, which ultimately governs the implant’s biocompatibility.12 Previous studies have largely focused on haemocompatibility, referring to the interaction of biomaterials with blood, serum, and associated specific proteins.13-15 This approach is borne out of the recognition that the complex interplay between proteins is complex in nature and simplifying the experimental mixture in contact with the biomaterial makes for easier recognition of protein adhesion differences. Whilst this simplistic approach is informative, as these protein mixtures are not comparable to the in vivo environment, these approaches are of limited benefit in assessing actual protein adsorption on the surface of implants. Blood serum for example, a fraction of coagulated blood, does not contain fibrinogen, an important protein which is displaced by other proteins like haemoglobin and vitronectin, which have higher affinities for implant surfaces, an effect known as the Vroman effect.16 As a consequence of the Vroman effect, the implant/protein interface is in a constant state of flux.17 Other proteins are less affected by the Vroman effect, such as vitronectin, which adheres strongly to implant surfaces and is not displaced readily by other proteins.18 We recognized that our time point of 4 days gave us a snapshot of this complicated process. Protein denaturing and relative protein quantity are also important considerations when assessing biomaterial surface interaction. Protein denaturing occurs when the protein comes in contact with the implant and this can help to expose adhesion ligands, although excessive protein denaturing can also lead to an inflammatory response.19 Protein quantity is also significant as this can mask the implant surface. Hydrophobic surfaces like breast implant surfaces are more likely to adhere large quantities of proteins and have a large protein footprint.20 When the implant is inserted into the body, it comes in contact with a mixture of proteins, “wound fluid.” Wound fluid has been shown to be 90% similar to blood serum, but there are important distinctions, as it has been found to contain other proteins like heat shock proteins and proteins from necrotic cells that are otherwise not present in serum.21 Wound fluid has been used before to assess the protein adsorption on the surface of silicone, however, no study, to date has assessed the actual protein adsorption on the surface of commercially available implants from site specific wound fluid.21 This aim of this novel study is to assess the protein adsorption on the surface of a range of commercially available implants in order to recognize differences between them in order to predict implant integration and ultimately to begin to understand the physiology of the interface between breast implants and their surroundings. METHODS Tissue samples used in this work were obtained through the Plastics and Reconstructive Surgery Research Skin and Tissue Bank ethics (North West Research Ethics Committee Ethics Code—11/NW/0638). Informed consent was obtained from patients for the use of their tissue in this study. All breast tissue processing was done at the Plastics and Reconstructive Surgery Research Group Human Tissue Authority licensed laboratory in Manchester, England, United Kingdom. Samples were collected between August 6, 2013 and January 29, 2014 and processed and analyzed by May 20, 2015. Wound Bed Fluid Adhesion Three consecutive female patients undergoing breast lift surgery (mastopexy) were recruited for this study with similar demographics (Table 1). These women were recruited and operated on by the same surgeon who used the same technique for each patient. Wound drains were left in situ postoperatively as part of their surgical procedure. Drains were collected at 12 hours postoperatively and the wound fluid removed from the vacuum container and centrifuged at 2500 rpm for 15 minutes to remove any debris and frozen at −80°C until required. We took measures to minimize the loss of proteins in this fluid by keeping the movement of the protein mixture to as few pieces of laboratory equipment as possible. Table 1. Demographics of Patients Included in This Study Sample Gender Ethnicity Age (years) BMI (kg/m2) Smoking history Reason for surgery Patient 1 Female White Caucasian 58 30.8 Nil Mastopexy Patient 2 Female White Caucasian 47 25.3 Nil Mastopexy Patient 3 Female White Caucasian 57 39.4 Nil Mastopexy Sample Gender Ethnicity Age (years) BMI (kg/m2) Smoking history Reason for surgery Patient 1 Female White Caucasian 58 30.8 Nil Mastopexy Patient 2 Female White Caucasian 47 25.3 Nil Mastopexy Patient 3 Female White Caucasian 57 39.4 Nil Mastopexy View Large Table 1. Demographics of Patients Included in This Study Sample Gender Ethnicity Age (years) BMI (kg/m2) Smoking history Reason for surgery Patient 1 Female White Caucasian 58 30.8 Nil Mastopexy Patient 2 Female White Caucasian 47 25.3 Nil Mastopexy Patient 3 Female White Caucasian 57 39.4 Nil Mastopexy Sample Gender Ethnicity Age (years) BMI (kg/m2) Smoking history Reason for surgery Patient 1 Female White Caucasian 58 30.8 Nil Mastopexy Patient 2 Female White Caucasian 47 25.3 Nil Mastopexy Patient 3 Female White Caucasian 57 39.4 Nil Mastopexy View Large Wound fluid from these women were combined in equal volumes. The wound fluid mixture was then sterilized by passing it through a 0.2 µm syringe filter (Minisart, Sartorius, Germany). A protease inhibitor (halt protease inhibitor, Thermo Fisher Scientific, Waltham, MA) was added to this mixture at a 1:100 dilution which contained no ethylenediaminetetraacetic acid (previously shown to alter the binding of proteins), before 100 µL of this wound fluid and protease mixture was added to each experimental well of a 96 well plate which was low bind (Corning, Inc., Corning, NY) to minimize binding of proteins to the walls of each well. Each experimental well contained an implant surface adhered to its bottom with a drop of MED-6216 silicone (Nusil, CA) cured overnight and sterilized with 80% ethanol for 5 minutes prior to use. Experiments were performed in replicates of n = 5. Two controls, one with MED-6215 silicone adhered to the bottom and one with no implant contained within it were included in the analysis. Implants were incubated at 37°C and 5% CO2 for 4 days, a time point which corresponded with the inflammatory phase of wound healing. At the end of this period, the wound fluid was removed from the surface of the implants and they were washed four times with phosphate buffered saline and twice with distilled water. Samples were reconstituted in 6 M urea in 25 mM ammonium bicarbonate, reduced using 200 mM dithiothreitol in 25 mM ammonium bicarbonate and these mixtures and samples were vortexed gently, before being incubated for 1 hour at 37°C. A total of 200 mM iodoacetamide was then added to the mixture and samples were alkylated for 1 hour at room temperature in the dark. Reducing agent was added to neutralize any remaining alkylating agent before samples were diluted using ammonium bicarbonate solution and digested in trypsin at a ratio of 1:30 protein by weight. Samples were incubated overnight at 37°C. On the second day samples were desalted using POROS R3 beads (Corning). Desalting of Samples Using POROS Beads Three solutions were used during this process. “Solution 1” a 30% acetonitrile solution, “solution 2” a 0.1% formic acid solution, “solution 3” a mixed 30% Acetonitrile, and 0.1% formic acid solution. Between each of the following steps the plate was centrifuged at 1400 rpm for 1 minute. A total of 1mg of POROS beads suspended in solution 1 were added to each well of a polyvinylidene fluoride (PVDF) membrane plate (Corning) placed upon a regular 96-well plate. The PVDF plate was washed with 100 µL of solution 1 and then twice with solution 2. The protein solution was added to each well of the PVDF plate in increments of 100 µL and then washed twice with solution 2. The base 96-well plate was then exchanged for a new plate and 50 µL of solution 3 was added to each well. Flow through was transferred to chromatography sample vials and dried in a vacuum concentrator. Mass Spectrometry Samples were reconstituted in water and analysed on a nano-ACUITY Ultraperformance liquid Chromatography system (Waters, Milford, MA) coupled to an Orbitrap Elite analyser (Thermo Fisher Scientific). Data was analysed using extract msn (Thermo Fisher Scientific) in Mascot Daemon version 2.5.1 (Matrix Science, London, UK). Samples were then analysed in Progenesis LC-MS (Non-linear Dynamics, Durham, NC) and aligned. Proteins with fewer than three unique peptides were excluded and the sample intensity was used to determine relative protein abundance. Processing of Commercially Available Implant Surfaces The following implants were included in this study, coded as described: SL1 Biocell (Allergan, Dublin, Ireland) SL2 Sebbin (Zurich, Switzerland) SL3 CUI (Allergan, Dublin, Ireland) SL5 Poly Implant Prothèse (PIP) (Paris, France) CM1 Cereplas Cereform (Sailly lez Cambrai, France) CM3 Establishment Velvet Surface (Coyol de Alajuela, Costa Rica) SM Smooth (Mentor, Santa Barbara, CA) AT1 True Texture (Silimed, Rio de Janeiro, Brazil) POLYM Siltex (Mentor) Breast implants have previously been shown to be manufactured using a range of different techniques and proprietary silicones, which has resulted in a range of chemically and texturally different breast implant surfaces being available on the market.6 Our analysis was aimed at identifying protein binding differences between these surfaces. These implant surfaces were kept in their packaging until required and compared to the low bind (Corning) surface. RESULTS A total of 822 proteins were identified, bound to the surface of breast implant surfaces by mass spectroscopy. Figure 1 illustrates the gene ontology of the adhered proteins on the surface of breast implant surfaces analyzed in this study, demonstrating that the main ontologies adhering to these surfaces are extracellular matrix (ECM) proteins, with a smaller group of intracellular proteins identified. Further details of each node are included in Supplementary Figure 1. Figure 1. View largeDownload slide Gene ontology of proteins isolated on the surface of breast implants. Node dimensions relate to the number of proteins in each ontology and color indicates significance. Ontologies are clustered into related groups (details of each node in Supplementary Figure 1). Figure 1. View largeDownload slide Gene ontology of proteins isolated on the surface of breast implants. Node dimensions relate to the number of proteins in each ontology and color indicates significance. Ontologies are clustered into related groups (details of each node in Supplementary Figure 1). Adhesive Proteins Vary in Abundance on Breast Implant Surfaces Adhesive proteins identified on the surface of implants included fibrinogen, fibronectin, and vitronectin. Figures 2 and 3 illustrate the relative quantities of fibrinogen alpha and gamma on the surfaces of the implants included in the study. It can be seen that the highest quantities of fibrinogen are actually found on the “low-bind” surface which illustrates that this surface is not immune from protein fouling. The CM3 and SL3 surfaces promoted the lowest levels of fibrinogen binding whilst the AT1 surface promotes the highest levels of fibrinogen binding. Figure 2. View largeDownload slide Relative Fibrinogen Alpha quantities (* signifies P < 0.05). Figure 2. View largeDownload slide Relative Fibrinogen Alpha quantities (* signifies P < 0.05). Figure 3. View largeDownload slide Relative Fibrinogen Gamma quantities (* signifies P < 0.05). Figure 3. View largeDownload slide Relative Fibrinogen Gamma quantities (* signifies P < 0.05). Fibronectin adhesion was most abundant on the AT1 surface when compared to all others (P < 0.0001) (Figure 4). The AT1 surface also had the highest levels of serum albumin on its surface (P < 0.0001) but no significant differences in vitronectin binding was recognized across all of the implants included in the study (Figures 5 and 6). Figure 4. View largeDownload slide Relative Fibronectin quantities (* signifies P < 0.05). Figure 4. View largeDownload slide Relative Fibronectin quantities (* signifies P < 0.05). Figure 5. View largeDownload slide Relative Albumin quantities (* signifies P < 0.05). Figure 5. View largeDownload slide Relative Albumin quantities (* signifies P < 0.05). Figure 6. View largeDownload slide Relative Vitronectin quantities (* signifies P < 0.05). Figure 6. View largeDownload slide Relative Vitronectin quantities (* signifies P < 0.05). Complement Our results demonstrate significant differences in binding affinity of complement C3 to the CM1 surface when compared to the CM3, AT1, SL3, and SL2 surfaces (Figure 7). Results also demonstrate significantly higher levels of C3 binding on the SL5 surface when compared to the CM3 and SL3 surfaces (Figure 7). Complement C5 levels were also significantly lower on the SL3 and AT1 surfaces when compared to the SM, POLYM, SL5, and CM1 surfaces (Figure 8). Factor H was less abundant on the CM3 surface when compared to the CM1 and SL1 surfaces (Figure 9). These results do not illustrate the folding or the epitopes exposed on binding of the C3 protein with the implant surfaces which has been shown to change the complement activation of these proteins.22 Figure 7. View largeDownload slide Relative Complement C3 quantities (* signifies P < 0.05). Figure 7. View largeDownload slide Relative Complement C3 quantities (* signifies P < 0.05). Figure 8. View largeDownload slide Relative Complement C5 quantities (* signifies P < 0.05). Figure 8. View largeDownload slide Relative Complement C5 quantities (* signifies P < 0.05). Figure 9. View largeDownload slide Relative Complement factor H quantities (* signifies P < 0.05). Figure 9. View largeDownload slide Relative Complement factor H quantities (* signifies P < 0.05). DISCUSSION In this study, we sought to develop an assay and identify the proteins that coat implants during breast implantation in an in vitro model as we recognized that it would be unfeasible to do so in an in vivo model. A total of 822 proteins were identified, bound to the surfaces of the implants using the methodology described. Extracellular proteins were the most abundant ontology, followed by intracellular proteins. This reflects the important in vitro difference between wound fluid and blood serum and strengthened our decision to perform this analysis using wound fluid. Blood serum does not contain some of the important determinants of the in vivo environment that have been shown to have effects on integration of biomaterials.21 Fibrinogen, a proinflammatory protein and Albumin, an anti-inflammatory protein had significant (P < 0.0001) binding differences between the surfaces studied. Complement C3, C5, and factor H were also shown to have significantly different binding affinities for the implants included in the study (P < 0.05). Adhesion of cells to the ECM is key to wound healing, tissue homeostasis, and modelling.23 Adhesion processes anchor cells, provides tissue structure, and mediates the signals that determine cell cycle progression and cell survival.24 The alternative to cell adhesion is anoikis or programmed cell death.25 Platelet, macrophage, neutrophil, and fibroblast adhesion is mediated by integrin receptors which bind to attachment sites on proteins and cell surfaces.26 ECM proteins fibrinogen and fibronectin act as ligands to bind cell surface integrin receptors.27 Fibrinogen is one of the most abundant and extensively studied proteins found adsorbed on the surface of biomaterials.26 It is a hydrophobic protein with an affinity to hydrophobic surfaces of which breast implant have been shown to be. It is a proinflammatory protein through its promotion of the accumulation of macrophages on biomaterial surfaces and it does so in a dose related manner.10,26,28 The MAC-1 integrin present in the gamma chain of fibrinogen has been shown to be the main mediator of this effect and has also been shown to increase platelet binding.12,29 The CM3, SL3, and SL5 surfaces provoked the lowest levels of binding of this protein in our analysis (Figures 2 and 3). Fibronectin has at least 20 different variants, which all perform similar functions in humans.30 These variants exist in 2 forms, one which circulates in plasma and one which is bound to cell surfaces.31 It has been shown to exist in high levels in the capsules of breast implants in vivo at the implant/tissue interface,32 and has also been shown to have a high affinity for PolyDiMethylSiloxane (PDMS).32 It has an inflammatory effect on macrophages through its α5β1 integrin receptor, which provokes a proinflammatory cytokine release in macrophages.33 Fibronectin also increases binding of fibroblasts which are one of the main cell types in the capsule that surrounds breast implants,34 in a dose related manner.35 Once bound to fibronectin, this leads to the development of adhesion complexes and signaling molecules, like focal adhesion kinase, ras, and src.36 For adherent cells such as fibroblasts, this promotes optimal cell function.27 It has a function in attracting immune cells37 and supports the activation of T-cells.38 The AT1 surface had the highest levels of fibronectin when compared to all other surfaces in our analysis. However, the AT1 surface also promoted the highest attachment of serum albumin. Albumin has been shown to have a masking effect on fibronectin and reduce mammalian cell attachment and provoke a reduced inflammatory response (Figure 5).39 Vitronectin has been shown to be one of the important ECM proteins which mediates biomaterial interactions with fibroblasts in a dose related manner.35 Vitronectin seems to be able to counter the competitive binding of other proteins to surfaces and binds with high affinity without the interruption from other proteins therefore it may dictate adhesion of cells in vivo more so than any other ECM adhesion protein.18,40 However, vitronectin levels did not seem to be differentially adsorbed onto the implants included in this study (Figure 6). It is possible that vitronectin was adsorbed onto the apparatus used to collect and store the wound fluid. This is a potential confounding effect that we countered by standardizing our wound fluid mixture between the implant surfaces studied. The complement system consists of more than 20 plasma bound proteins, which aim to eliminate microorganisms and foreign substances from the body.41 These proteins are activated by either the classical, lectin, or the alternative pathway and these pathways assimilate to produce their terminal humoral effect via the membrane attack complex C5b-9 which binds specific receptors on neutrophils, monocytes, mast cells, and smooth muscle cells causing cell lysis and inflammation.42 Complement activation is a negative factor when assessing a biomaterial surface as it interacts with coagulation and cytokine pathways to provoke an inflammatory response.41 Whilst the classical pathway is triggered by antigen-antibody complexes, the alternative pathway is activated by foreign substances.43 The main proponent of these three pathways is C3, which is the keystone between their activation and is a member of the Alpha 2 Macroglobulin superfamily which also contains C5 and C4.44 C3 convertase C3bBb cleaves C3 into C3a, an anaphylatoxin and C3b which forms the C3b,Bb convertase and cleaves C3 further, creating a powerful amplification loop of the alternative pathway.45 C3b links to other complement factors and promotes the adhesion of immune cells.46 C3 convertase also causes C5 cleavage to produce C5a anaphylatoxin, which is also a chemoattractant of inflammatory cells.47 C3 is blocked from adhering to biomaterials by fibrinogen and Complement H, the second most abundant protein in the plasma and which also acts to regulate the C3 convertase and is the primary regulator of the alternative pathway.48 The SL5 surface showed significantly increased levels of C3 and C5 binding with comparison to the majority of other surfaces analyzed in this study (Figures 7 and 8). Taken together with the protein adhesion results, this surface consistently produced a proinflammatory protein environment. In summary, the initial protein adsorption on the surface of the biomaterial when implanted is a complex process that is poorly understood and has important effects on the response to these materials. For the first time, commercially available implants have been shown to provoke significantly different adsorptions of crucial adhesion and complement proteins. Wound fluid derived from the breast which coats the implant in vivo has been used to make this assessment, a novel analysis and approach that will potentially allow further future assessment of breast implant surfaces. The number of proteins identified on the surfaces included in this study indicates how complex this process is and how readily the binding affinities of these proteins is affected by a range of varying parameters. These effects are one of many elements of the complex interactions that ultimately dictate implant biocompatibility whose effects can manifest as capsular contracture.49 Investigating the complex protein interactions that occur at the biomaterial surface on implantation may inform implant and protein coating choices in the future and reduce these complications, helping breast implants to evolve into smart biomaterials capable of instructing and positively influencing the foreign body response. CONCLUSIONS In this novel study, for the first time, we have successfully developed a novel assay of breast implant protein binding and demonstrated significant binding affinities for relevant proteins derived from breast tissue wound fluid adsorbed onto the surface of commercially available silicone implants. Supplementary Material This article contains supplementary material located online at www.aestheticsurgeryjournal.com. Disclosures Mr Barr’s PhD study was sponsored by Establishment Labs. Drs. Hill and Bayat are recipients of grant funding by Establishment Labs. Funding This work was funded by Establishment Labs (Alajuela, Costa Rica) as part of Establishment Labs’ sponsorship of Mr Barr’s PhD study (including lab and stipend costs), which was supervised by Drs Hill and Bayat. Acknowledgments We would like to acknowledge David Knight and the team at The Manchester University Biological Mass Spectrometry facility and our clinical colleagues and collaborators who have contributed and supported this work. REFERENCES 1. Berry MG , Cucchiara V , Davies DM . Breast augmentation: part II—adverse capsular contracture . J Plast Reconstr Aesthet Surg . 2010 ; 63 ( 12 ): 2098 - 2107 . Google Scholar CrossRef Search ADS PubMed 2. Hölmich LR , Friis S , Fryzek JP , et al. Incidence of silicone breast implant rupture . Arch Surg . 2003 ; 138 ( 7 ): 801 - 806 . Google Scholar CrossRef Search ADS PubMed 3. Spear SL , Rottman SJ , Glicksman C , Brown M , Al-Attar A . 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Aesthetic Surgery Journal – Oxford University Press
Published: Sep 1, 2018
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