Platinum in silicone breast implants

Silicone elastomers are widely used in implantable devices, including silicone breast implants. These rubbers are generally formed/cured using platinum-catalyzed hydrosilylation. The current scientific literature on the chemistry of platinum is reviewed, as it applies to the use of platinum catalysts for cure of silicone elastomers destined for use in silicone breast implants. These discussions serve as a basis to examine the recent literature describing release of platinum into tissues adjacent to silicone breast implants, the chemical nature of the platinum present in breast implants and the possible association between platinum and clinical outcomes.     

A formal risk assessment of silicone breast implants.

In 1992, the United States Food and Drug Administration (FDA) announced that breast implants filled with silicone gel would be available only through controlled clinical studies despite the fact that they had been used for mammoplasty in millions of women around the world for more than 30 years. The safety of silicone gel breast implants had come into question after several reports on a possible association between the implants and subsequent development of connective-tissue diseases. Risk assessment refers to the systematic, scientific characterization of potential adverse effects of human exposures to hazardous agents or activities. The following risk assessment is intended to review the current scientific evidence for the safety of silicone gel-filled breast implants since the FDA's decision in 1992. There now appears ample evidence from the scientific literature for the safety of these prostheses.     

In vivo tissue reactivity of radiation-cured silicone rubber implants.

Silicone rubber implants are clinically used in large numbers and elicit a milk tissue reaction. An occasional patient develops an accentuated reaction, an observation which has stimulated clinicians to try to understand this process more fully. The chemistry of medical silicone implants, including quantitative composition, is reviewed. This in vitro laboratory study show less tissue reaction-cured silicone with SiO2 filler. A proposed system for fabrication and curing of a silicone implant, with the qualities of strength and diminished tissue reactivity, is discussed.     

Silicone-specific blood lymphocyte response in women with silicone breast implants.

A blinded cross-sectional study was carried out with 99 women, 44 of whom had silicone breast implants. Group I consisted of 55 healthy volunteer women without breast implants; group II comprised 13 volunteer women with breast implants or explants who felt healthy; group III comprised 21 volunteer women with breast implants who had chronic fatigue, musculoskeletal symptoms, and skin disorders; and group IV comprised 10 women who had their prostheses explanted but still presented with clinical symptoms similar to those of the women in group III. Proliferative responses of peripheral blood mononuclear cells from all 99 women were measured by [3H]thymidine uptake after exposure to SiO2 silicon, or silicone gel. The levels of proliferative responses were expressed as stimulation indices, which were obtained by dividing the counts per minute of stimulated cells by the counts per minute of unstimulated cells. Abnormal responses to SiO2, silicon, or silicone gel were defined as a stimulation index of > 2.8, > 2.1, or > 2.4, respectively. Abnormal responses were observed in 0% of group I, 15% of group II, 29% of group III, and 30% of group IV (P < 0.0005 for group I versus groups II and IV). Thirty-one percent of symptomatic women with silicone gel breast implants had elevated serum silicon levels ( > 0.18 mg/liter); however, there was no significant correlation between abnormal cellular responses and silicon levels in blood serum, type of implant, time since first implantation, prosthesis explantation, number of implants, or report of implant leakage or rupture.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term exposure to silicone breast implants does not induce antipolymer antibodies

The focus of our studies was to determine whether the antipolymer antibody assay (APA) as an objective laboratory assay could contribute to the diagnosis in women with a silicone breast implant (SBI) and complaints/symptomatic disease. We investigated whether a population of symptomatic SBI recipients exists with a high prevalence of APA in the Netherlands. The study participants were selected based on self-reported complaints. In one study their physician was approached for additional information on their disease status. Two groups of 42 women were included in the studies, with a mean SBI exposure of 17 and 16 years, respectively. The participants were clinically examined, and the APA level in serum samples determined. The study population of SBI recipients was categorised in severity subgroups based on the functional capacity, and the study physicians general assessment of pain and disease activity. Positive APA levels were found in 10% of the SBI recipients. Also in control groups 8% showed a positive APA response. After categorisation most (65 of 84) SBI recipients belonged to the limited severity subgroup on an increasing scale of limited, mild, moderate and advanced. Eight were categorised in the mild, four in the moderate, and seven in the advanced severity subgroup. None of the APA positive women were found to belong to the moderate or advanced severity subgroup. Seven of the APA positive women belonged to the limited, and one woman to the mild severity subgroup. In conclusion, we were unable to include a large proportion of severely symptomatic SBI recipients in our study populations. So, we cannot confirm the results of Tenenbaum et al. [1] on the presence of APA in symptomatic SBI recipients. However, our failure in two separate studies to recruit symptomatic SBI recipients suggests that the population of severely symptomatic SBI recipients in the Netherlands is rather small. The number of APA positive responses in our study population was low. In addition, also in the normal population a similar low percentage of positively reacting women were observed. Hence, we cannot recommend the use of the APA assay for diagnostic purposes in the clinical evaluation of SBI recipients with severe complaints/symptoms.     

Counterfactual thinking and quality of life among women with silicone breast implants

This study examined the relationship of counterfactual thinking (thoughts about how one's current situation might have turned out differently) with psychosocial adjustment and quality of life in a sample of women with silicone breast implants. Seventy-four women who were concerned about or who were experiencing problems with their implants were recruited following magnetic resonance imaging (MRI) evaluation. Participants completed measures of counterfactual thinking, psychosocial adjustment, and quality of life (QOL). Results indicated that counterfactual thinking was significantly associated with more psychosocial adjustment difficulties, more perceived implant-related health problems, and poorer QOL in the physical health domain. These findings provide additional insight into the factors that may influence adjustment in a complex and poorly understood population and also have implications for understanding the adjustment process to other types of illnesses.     

In vitro interaction between silicone gel and human monocyte-macrophages

Controversy remains regarding the ability of silicone materials to induce a specific immune reaction versus a nonspecific inflammatory response. Histopathological analysis of the tissue around failed breast implants reveals chronic inflammation with silicone gel droplets either surrounded by giant cells or engulfed by macrophages, areas of fibrosis, and necrosis. Macrophages are the key cells engulfing or forming foreign body giant cells. To address the mechanisms of silicone-induced inflammation a model of human monocyte-derived macrophages (MDMs) was developed. After sonication of silicone gel, the silicone droplets were embedded in Type I collagen and used to coat glass coverslips; human MDMs were subsequently seeded on the coverslips and maintained in culture for up to 7 days. The advantage of the model was that human macrophages could be studied histologically, and cytochemically as they interacted with well-characterized silicone materials. Initial analysis of the human macrophages shows phagocytosis of the silicone gel within hours of exposure to the material. Analysis for pro-inflammatory cytokines reveals significant transient secretion of IL-1 (p < 0.01) over controls by human macrophages upon exposure to silicone gel at 24 h.     

Meta-analyses of the relation between silicone breast implants and the risk of connective-tissue diseases

BACKGROUND: The postulated relation between silicone breast implants and the risk of connective-tissue and autoimmune diseases has generated intense medical and legal interest during the past decade. The salience of the issue persists, despite the fact that a great deal of research has been conducted on this subject. To provide a stronger quantitative basis for addressing the postulated relation, we applied several techniques of meta-analysis that combine, compare, and summarize the results of existing relevant studies. METHODS: We searched data bases and reviewed citations in relevant articles to identify studies that met prestated inclusion criteria. Nine cohort studies, nine case-control studies, and two cross-sectional studies were included in our meta-analyses. We conducted meta-analyses of the results of these studies, both with and without adjustment for confounding factors, and a separate analysis restricted to studies of silicone-gel-filled breast implants. Finally, we estimated the annual number of new cases of connective-tissue disease that could be attributed to breast implants. RESULTS: There was no evidence that breast implants were associated with a significant increase in the summary adjusted relative risk of individual connective-tissue diseases (rheumatoid arthritis, 1.04 [95 percent confidence interval, 0.72 to 1.51]; systemic lupus erythematosus, 0.65 [95 percent confidence interval, 0.35 to 1.23]; scleroderma or systemic sclerosis, 1.01 [95 percent confidence interval, 0.59 to 1.73]; and Sj?gren's syndrome, 1.42 [95 percent confidence interval, 0.65 to 3.11]); all definite connective-tissue diseases combined (0.80; 95 percent confidence interval, 0.62 to 1.04); or other autoimmune or rheumatic conditions (0.96; 95 percent confidence interval, 0.74 to 1.25). Nor was there evidence of significantly increased risk in the unadjusted analyses or in the analysis restricted to silicone-gel-filled implants. CONCLUSIONS: On the basis of our meta-analyses, there was no evidence of an association between breast implants in general, or silicone-gel-filled breast implants specifically, and any of the individual connective-tissue diseases, all definite connective-tissue diseases combined, or other autoimmune or rheumatic conditions. From a public health perspective, breast implants appear to have a minimal effect on the number of women in whom connective-tissue diseases develop, and the elimination of implants would not be likely to reduce the incidence of connective-tissue diseases.     

Laser-Raman microprobe identification of inclusions in capsules associated with silicone gel breast implants.

Raman spectroscopy (the analysis of scattered photons after excitation with a monochromatic light source) provides a nondestructive method for identifying organic and inorganic materials on the basis of the molecule's characteristic spectrum of vibrational frequencies. Although the technique has been predominantly applied in sciences other than pathology, the recent advent of high-quality microscope optics coupled to optical Raman spectrometers (a variation known as a Raman microprobe) rendered this technique amenable to applications in human pathology. In the Raman microprobe, a laser beam is focused on a spot approximately 1 microm in diameter on the surface of the sample, e.g., tissue, and the scattered light is collected and analyzed. In this investigation, we used the Raman microprobe for the identification of foreign materials in breast implant capsular tissues. The characteristic silicone group frequencies associated with the silicon-oxygen stretch, the silicone-carbon stretch, the silicon-methyl and the methyl carbon-hydrogen stretch frequencies were used to identify polydimethylsiloxane and to define chemical differences among the various other implant-related inclusions. All of the inclusions were positively identified in a series of 44 capsules from silicone gel-filled implants: polydimethylsiloxane was found in 44 of 44 capsules surrounding silicone gel-filled implants; polyurethane was seen in 4 of 4 capsules around polyurethane foam-coated gel-filled implants; 4 of 4 capsules enveloping Dacron patch gel-filled implants revealed Dacron; and talc was identified in 8 of these 44 capsules. Raman microspectroscopy provides a rapid, accurate, and sensitive method for identifying inclusions associated with silicone and other implant materials in tissue.     

Phenotype of lymphocytes associated with the inflammatory reaction to silicone gel breast implants.

The tissue response to silicone gel breast implants typically includes an inflammatory infiltrate that consists of macrophages, foreign body-type giant cells, and a variable number of lymphocytes and plasma cells. The phenotype of the lymphocytic component was investigated with three-color flow cytometry. Lymphocytes were obtained by collecting fluid from the space between the implant and the fibrous capsule or by washing cells from the fibrous capsule at the time of implant removal with total capsulectomy. Eighty-nine percent of the implant-associated lymphocytes were T cells. Twenty-five percent of the CD3+ T cells coexpressed HLA-DR compared with only 7.9% of matched peripheral blood lymphocytes. Sixty-eight percent of the implant-associated T cells coexpressed CD4 and CD29, while only 3% of the T cells coexpressed CD4 and CD45RO. The expression of HLA-DR and the predominance of CD29+ CD4+ T cells indicate that there is immune activation with the potential for stimulating antigen-specific antibody production. The role of silicone gel breast implants in immune activation and its clinical significance require further investigation.     

In vitro leucocyte adhesion to modified polyurethane surfaces. I. Effect of ionizable functional groups.

To study the effect of ionizable functional groups on the adhesion of leucocytes to surfaces, both poly(ethyleneimine) and poly(acrylic acid) were immobilized on polyurethane films, resulting in the introduction of amine and carboxylic acid groups, respectively. This was confirmed by contact angle measurements and XPS analysis. In vitro adhesion of granulocytes and lymphocytes on untreated and modified surfaces was compared. The number of adherent cells on modified surfaces as a function of time was significantly higher than on untreated surfaces. This effect was most pronounced for the adhesion of lymphocytes to surfaces modified with amine groups. In this case, the number of adherent cells after 1 h of exposure was three times higher than on untreated surfaces. A moderate enhancement of leucocyte adhesion was observed in the case of surfaces modified with carboxylic acid groups. There is evidence that these groups were not ionized under the experimental conditions used. The modification procedures described may be used to improve polyurethane filters for the removal of leucocytes from blood.     

In vitro evaluation of bio-functional performances of Ghimas titanium implants

Titanium is the most widely used material for dental implants. The natural formation, in presence of oxygen, of different oxide films (passivation films) is correlated to titanium implant biocompatibility, resistance to corrosion and is responsible for implant bacteriostatic action. Surface roughness is another surface property of Ti-implants that, affecting implant-to-bone contact, improves integration. In the present study data concerning composition, surface roughness and biocompatibility of Ghimas implants and mini-implants undergoing sandblasting with Calcium Magnesium Carbonate (CaMg(CO3)2) are reported. AFM, SEM/EDX, XRD analyses and morpho-functional tests (MTT and ALP) were performed. Cell actin cytoskeletal modification (fluorescence phalloidin staining) was also observed with confocal laser microscopy (CLSM). Data related to surface geometry and chemical properties, associated with evidence of high purity of all the tested materials (XRD and EDX), highlighted the elevated biocompatibility of tested implants and mini-implants. CLSM investigation confirmed osteoblast features of an active cell behavior able to fit cell to chemico-mechanical stimuli present at the bone/implant interface and suggests an effective implant/alveolar bone integration in vivo.     

First observation of hope?te and parascholzite in fibrous capsules surrounding silicone breast implants

We observed mineralization in 32.6% of the capsular tissue of 97 mammary prostheses recovered after surgical excision. Three distinct mineralogical phases were identified. The first was composed of common hydrated carbonate hydroxylapatite, a well-known physiological and pathological mineral. Hope?te and parascholzite constituted the second and third phases. They are zinc and calcium hydrate phosphates that have not been observed previously in human tissues. Statistical analysis of the data showed relationships between the presence of mineralizations and the manufacturers on the one hand, and the presence of Dacron fixation patches at the surface of the prostheses on the other.     

The association of matrix Gla protein isomers with calcification in capsules surrounding silicone breast implants

Implanted silicone medical prostheses induce a dynamic sequence of histologic events in adjacent tissue resulting in the formation of a fibrotic peri-prosthetic capsule. In some cases, capsular calcification occurs, requiring surgical intervention. In this study we investigated capsules from silicone gel-filled breast prostheses to test the hypothesis that this calcification might be regulated by the small vitamin K-dependent protein, matrix Gla protein (MGP), a potent inhibitor of arterial calcification, or by Fetuin-A, a hepatocyte-derived glycoprotein also implicated as a regulator of pathologic calcification. Immunolocalization studies of explanted capsular tissue, using conformation-specific antibodies, identified the mineralization-protective γ-carboxylated MGP isomer (cMGP) within cells of uncalcified capsules, whereas the non-functional undercarboxylated isomer (uMGP) was typically absent. Both were upregulated in calcific capsules and co-localized with mineral plaque and adjacent fibers. Synovial-like metaplasia was present in one uncalcified capsule in which MGP species were differentially localized within the pseudosynovium. Fetuin-A was localized to cells within uncalcified capsules and to mineral deposits within calcific capsules. The osteoinductive cytokine bone morphogenic protein-2 localized to collagen fibers in uncalcified capsules. These findings demonstrate that MGP, in its vitamin K-activated conformer, may represent a pharmacological target to sustain the health of the peri-prosthetic tissue which encapsulates silicone breast implants as well as other implanted silicone medical devices.     

In vitro biocompatibility assessment of sulfonated polyrotaxane-immobilized polyurethane surfaces

Sulfonated polyrotaxanes (PRx-SO(3)'s), in which sulfonated alpha-cyclodextrins (alpha-CDs) were threaded onto the poly(ethylene glycol) (PEG) segments in a PEG-b-poly(propylene glycol) (PPG)-b-PEG triblock copolymer (Pluronic) capped with benzyloxycarbonyl (Z)-L-phenylalanine (Z-L-Phe), were prepared as a novel surface-modifying biomaterial. Surface modification of the polyurethane (PU) was carried out by blending the PRx-SO(3)'s with a PU solution, followed by solution casting. The incorporated PRx-SO(3)'s led to the enhanced hydrophilicity by changing the surface properties of the PU matrix. Modified PUs showed the stable entrapment of the PRx-SO(3)'s with little extraction into water and enhanced mechanical properties after exposure to water compared to the PU control. The incorporated PRx-SO(3)'s repelled the proteins and kept them from closely approaching the surface areas, prevented platelet activation by thrombin, and effectively repelled bacteria. These results suggest that both the supramolecular structure of the polyrotaxanes and exposure of the sulfonated groups onto the surfaces contribute to these phenomena. Thus, surface modification with PRx-SO(3)'s is suggested to be useful for the fabrication of biocompatible medical devices.     

Effect of surgical insertion on the local shell properties of SILASTIC II silicone gel breast implants

The reasons for the failure of silicone gel breast implants are unclear. One potential failure mechanism is the weakening of the implant shell during its insertion into the breast. Such local weakening could eventually lead to implant failure. We recently reported on the effect of implant surgery on the overall mechanical properties of SILASTIC II gel-filled implants. In the earlier study, the mechanical properties of 34 Dow Corning SILASTIC II gel-filled breast implants from the same manufacturing lot were measured. Twenty of the thirty four implants were not implanted but were evaluated to establish a baseline of control data. The other fourteen lot-matched implants were inserted into a subglandular pocket through an inframammary incision in a cadaver breast and then removed. The experimental augmentation scenario was designed to represent actual breast implantation as closely as possible. The mechanical properties of the anterior and posterior sides of the control implants (not implanted) and explants (implanted in a cadaver) were measured and compared to determine whether differences existed between the explant and control groups. We found that the implantation surgery process did slightly reduce the average tensile strength. Although not as statistically significant, other mechanical properties such as breaking energy and moduli were less for the explants than the controls. The reduction was a relatively small percentage in the context of overall shell properties. Elongation and tear resistance were unaffected. Our findings suggested that the surgical act of implanting a breast implant has a small but detectable weakening effect on the average tensile strength, breaking energy and moduli of the elastomeric shell of the device. The present study is an extension of the previous investigation. Here we have analyzed the explant shell region where the surgeon's fingers forced the implant through the incision. Our results indicate that the implant shell can be locally damaged due to the implantation process.