Vibeke Breiting

Adverse Reactions to Injectable Soft Tissue Permanent Fillers

BackgroundSynthetic injectable facial fillers with a permanent effect are widely atoxic and nonimmunogenic, but they differ with respect to composition and in chemical and biologic characteristics. Yet, they all act as foreign bodies in the tissues eliciting a host response that try to remove the gel. Inflammatory nodules may develop at the sites of injection-for some fillers, many years later, for others, not. Why is that?MethodsBiopsies were contributed by various plastic surgeons from Europe and Australia after requests were made at international congresses and workshops. The study was based on (a) 5 biopsies from unreactive tissue obtained at different times after injection of polyacrylamide hydrogel (Aquamid); (b) 28 biopsies from intermediate or late inflammatory nodules after injection of polyacrylamide hydrogel (Aquamid) (20 cases), a hyaluronic acid-polyhydroxyethylmethacrylate/ethylmethacrylate gel (Dermalive) (2 cases), and a gel consisting of polylactic acid in mannitol/carbomethoxycellulose (New-Fill) (6 cases); and (c) a review of the literature on adverse reactions after injection with permanent fillers.ResultsClinically unreactive tissues after injection with Aquamid showed modest or no host reaction. Inflammatory nodules showed an increased foreign body reaction and a bacterial infection after injection with Aquamid, and a combination of moderate foreign body reaction, fibrosis, and in some cases also bacterial infection after injection with Dermalive and New-Fill. According to the literature, inflammatory nodules occur no later than 1 year after injection with polyacrylamide hydrogel, but up to 6 years after injection of combination gels (Artecol), and up to 28 years after injection of silicone gel.ConclusionsInflammatory nodules are likely to be caused by a low-grade infection maintained within a biogfilm surrounding the hydrophobic silicone gel and the combination gels. Aquamid gel may prevent formation of a biofilm through its high water-binding capacity, explaining why late inflammatory nodules are not seen after injection of this polyacrylamide hydrogel product.

Long-term effects of polyacrylamide hydrogel on human breast tissue.

&NA; Polyacrylamide hydrogel is an atoxic, stable, nonresorbable sterile watery gel consisting of approximately 2.5% cross‐linked polyacrylamide and nonpyrogenic water. Polyacrylamide hydrogel is widely used in ophthalmic operations, drug treatment, food packaging products, and water purification. In the former Soviet Union, polyacrylamide hydrogel has been used in plastic and aesthetic surgery for more than 10 years, and Kiev City Hospital treats approximately 300 women a year for breast augmentation using the polyacrylamide hydrogel Interfall (Contura SA, Montreux, Switzerland). Capsule shrinkage following these injections has never been observed. The authors examined breast tissue samples from a total of 27 women who had polyacrylamide hydrogel injected at Kiev City Hospital up to 8 years and 10 months earlier. Age at operation, duration of polyacrylamide hydrogel implantation, history of possible side effects to the gel injection, other intercurrent diseases, the reason for present open breast operation, and breast palpation findings before operation were in each case compared with the histological findings on samples taken from breast tissue bordering the gel. The gel presented itself as a dark violet, homogenous mass with a rounded or ragged outline in large or medium‐size deposits and as elongated strands, which mimicked the extracellular matrix, in small deposits. Histological findings of the breast tissue bordering the gel showed three different patterns: large collections of gel gave rise to a thick, soft‐looking cellular membrane of macrophages and foreign‐body giant cells; medium‐size deposits were surrounded by just a thin layer of macrophages; and small deposits were not associated with any reaction in the surrounding tissue. Projections of the cellular soft membrane, known as granulomas, were seen in six patients. The granulomas were composed of macrophages, foreign‐body giant cells, lymphocytes, and blood cells. A thin layer of fibrous connective tissue was occasionally present around the foreign‐body membrane, but the thick fibrous capsule, which has been described in connection with silicone implants, was completely absent. The gel changes could be correlated to neither time since gel injection nor a history of recent injury or inflammation. It is concluded that the polyacrylamide hydrogel Interfall, which has been used in the former Soviet Union, is stable over time, nondegradable, confined to the breast, and diffusion and migration resistant. When the hydrogel is injected in medium‐size or large quantities a cellular foreign‐body reaction occurs, but in small amounts it is capable of splitting up individual connective tissue fibers and fat cells, substituting for the extracellular connective tissue matrix without eliciting any foreign‐body reaction. As far as these data are concerned, polyacrylamide hydrogel is well tolerated by the breast and does not give rise to severe fibrosis, pain, or capsule shrinkage. However, to determine safety with more certainty, a larger sample size would be necessary. (Plast. Reconstr. Surg. 111: 1883, 2003.)

Histologic changes and silicone concentrations in human breast tissue surrounding silicone breast prostheses.

Using a previously developed method for quantitative measurements of silicone concentrations in breast tissue, material from 86 biopsies from 67 breasts in 55 patients who had silicone implants was examined. In the 49 breasts with unruptured prostheses, there was a positive relation between the concentrations and inflammatory reactions, the only exception being the amount of plasma cells, which showed a negative relation. It is concluded that silicone prostheses provoke an inflammatory response not only because they act as foreign bodies, but also because of silicone seepage through intact membranes.

A Study on Patients Treated with Polyacrylamide Hydrogel Injection for Facial Corrections

Polyacrylamide hydrogel (PAAG) has been used as a tissue filler in facial corrective surgery and for breast augmentation in Kiev, Ukraine, for more than 10 years with reportedly very good results. These results, however, have not been published in peer-reviewed journals. A Danish/Swedish group of plastic surgeons with special interest in facial corrective surgery did a retrospective, systematic, pre-planned investigation of 104 patients treated at the center in Kiev. All data were entered into a pre-programmed database for data processing. The mean age of this population was 37.4 years and the mean time since the gel injection was 3.9 years. An average of 5.7 ml of PAAG was injected prior to the investigation. The gel was well tolerated and assessment of the outcome was judged to be very good by 78% and good by 22%, by both physicians and patients. It is concluded that PAAG is well tolerated and seems to be a promising product for facial corrective surgery. Currently, the product (Aquamid®) is being studied in several prospective clinical trials, one of which is completed and in the process of preparation for publication.

Adverse reactions following injection with a permanent facial filler polyacrylamide hydrogel (Aquamid): causes and treatment

BackgroundPolyacrylamide hydrogel (Aquamid), an atoxic non-immunogenic gel of the non-resorbable type, has gained widespread popularity as an injectable filler for facial augmentation. However, adverse events (AEs) have occurred, the nature of which seems obscure because of negative findings on culture and a pattern of foreign-body response on microscopy.DesignThis is a prospective study of case reports provided by physicians injecting Aquamid during the period 21 May 2001 to 15 September 2003.MaterialsAmong 40,000 persons injected, 55 were reported to have experienced AEs. Information from questionnaires distributed along with the product and follow-up information from involved physicians was collected into a database.ResultsAEs occurring mainly in lips and nasolabial folds were reported in 55 patients, with 51 requiring treatment. The time from the last gel injection to the debut of the AE varied from 2 to 364 days, with a median of 12 days. Seventeen patients presented with different types of reaction to the injection, and the exact cause of the AE was established in another 19. A complete follow-up until full recovery was available in only 43 cases (84%). A broad-spectrum antibiotic in high dosage was effective for a short time. Steroids and non-steroidal anti-inflammatory drugs (NSAIDs) tended to aggravate symptoms and to prolong treatment time.ConclusionsAEs presenting clinically as nodules or swellings later than 1 week and less than 1 year after the injection of polyacrylamide hydrogel (Aquamid) should be treated immediately with a broad-spectrum antibiotic (quinolone) in high dosage. Steroids or NSAIDs are contraindicated.

Cancer occurrence after cosmetic breast implantation in Denmark

Most studies on cancer incidence after breast implantation have focused on breast cancer, while the risk of cancers at other sites has been less well investigated. We examined cancer incidence among 1,653 women who underwent cosmetic breast implant surgery at private clinics of plastic surgery in Denmark and 1,736 women attending the same clinics for other reasons during the period 1973–1995. Furthermore, we updated previously reported results among 1,114 women who received implants for cosmetic indications at public hospitals. All women were followed for cancer through the Danish Cancer Registry. In comparison with the general female population, the overall standardized incidence ratio (SIR) for cancer among women who received implants in private clinics was 1.65 [95% confidence interval (CI) = 1.17–2.27]. This elevated SIR reflected increased incidence ratios for almost all major cancer sites; however, only for non‐melanoma skin cancer was there an excess of more than 2 cases. No significant excess of cancer was observed among women who received implants in public hospitals (SIR = 1.10, 95% CI = 0.76–1.52) or among women attending the private clinics for other problems (SIR = 1.10, 95% CI = 0.78–1.52). The SIRs for breast cancer after breast implantation were 1.1 (95% CI = 0.5–2.2) among private clinic patients and 0.9 (95% CI = 0.4–1.7) among public hospital patients. The overall findings of these 2 implant cohorts and results from other investigations suggest that cancer risk is probably not increased among women receiving cosmetic breast implants. The inconsistent results for private clinics and public hospitals are likely related to selection bias and confounding among the private clinic patients, but our data did not permit exploration of these possibilities. Further research into the determinants of these inconsistencies is warranted. Int. J. Cancer 88:301–306, 2000.

Self-reported diseases and symptoms by rupture status among unselected Danish women with cosmetic silicone breast implants.

&NA; Epidemiologic evidence does not support an association between silicone breast implants and connective tissue or other rheumatic diseases. However, a recent study has suggested that women with ruptured implants may be at increased risk of developing fibromyalgia. An analysis of adverse health outcomes according to breast implant rupture status was conducted in 238 unselected Danish women with cosmetic silicone breast implants. Ninety‐two of the women had definite implant rupture, and 146 had intact implants as determined by magnetic resonance imaging. Before undergoing imaging, the women provided blood samples and completed a self‐administered questionnaire. Women with ruptured implants overall, and the subgroup with extracapsular ruptures (n = 23), were compared with women with intact implants regarding a number of self‐reported diseases and symptoms and the presence of specific autoantibodies, such as antinuclear antibodies, rheumatoid factor, and cardiolipin immunoglobulin G and M antibodies. Overall, there were no differences in the occurrence of self‐reported diseases or symptoms or in the presence of autoantibodies between women with intact implants and women with ruptured implants, including extracapsular rupture. The only exception was capsular contracture, which was reported six times more frequently by women with extracapsular ruptures than by women with intact implants (OR, 6.3; 95 percent CI, 1.7 to 23.5). In conclusion, this study of unselected women with silicone breast implants could establish no association between silicone implant rupture and specific diseases or symptoms related to connective tissue disease or other rheumatic conditions, except for an excess of capsular contracture among women with extracapsular rupture. (Plast. Reconstr. Surg. 111: 723, 2003.)

Bacterial Infection as a Likely Cause of Adverse Reactions to Polyacrylamide Hydrogel Fillers in Cosmetic Surgery

BACKGROUND The etiology of long-lasting adverse reactions to gel fillers used in cosmetic surgery is not known. Bacterial infection and immunological reaction to the product have been suggested. METHODS We performed a case-control study, with 77 biopsies and 30 cytology specimens originating from 59 patients with adverse reactions to polyacrylamide gel, and 54 biopsies and 2 cytology specimens from 28 control subjects with no adverse reactions. Samples from 5 patients and 4 controls could not be investigated for presence of bacteria owing to limited material. Samples from the remaining 54 patients and 24 controls were systematically examined for the presence of bacteria by culture, 16S rRNA gene sequencing, Gram stain, and fluorescence in situ hybridization. RESULTS Bacteria, mostly normal skin bacteria such as Staphylococcus epidermidis and Propionibacterium acnes, were identified in bacteriologically investigated samples from 53 of 54 patients (98%), and in none of the 24 controls (0%). The bacteria were lying in small clusters, which in symptomatic lesions were detected up to 5 years postinjection. CONCLUSIONS Commensal bacteria of low virulence are capable of producing long-term infection in the presence of polyacrylamide filler in cosmetic surgery, possibly due to a biofilm mode of growth. Adequate skin preparation and use of sterile technique in these procedures are mandatory, but antibiotic prophylaxis prior to injection of nondegradable gels like polyacrylamide should be explored as well.

Primary mucinous carcinoma of the skin: a population-based study.

Background  Primary mucinous carcinoma of the skin (PMCS) is a rare malignant tumor deriving from the sweat glands. It is typically located on the head and is often mistaken for a metastasis from a more common primary tumor of the breast or gastrointestinal tract. We present the first population‐based study of PMCS.

Management of postoperative complications of breast augmentation by injected polyacrylamide hydrogel.

In response to the recent paper by Dr. Qiao and colleagues, we comment as follows. In agreement with Qiao et al. [4] we found in our series of 27 women [3], who had polyacrylamide hydrogel injected into the breast up to 81⁄2 years previously, that lumpiness, disfigurement, and asymmetry were common reasons for having the gel removed surgically. We also saw, as did Qiao and colleagues, that the firmness and lumpiness of the breasts disappeared when the gel was removed. What we did not find, however, was the presence of a thick acellular fibrous capsule similar to the one seen around silicone breast prostheses. Histologically, a fine rim of fibrous tissue was sometimes seen around a cellular membrane composed of macrophages and foreign body giant cells, especially in connection with large gel deposits, but the white fibrous capsule produced around silicone prostheses was never seen, neither macroscopically nor microscopically. Our subsequent studies [1] have shown that polyacrylamide hydrogel becomes an integrated part of connective and fat tissue, probably because its water molecules (95 97.5%) are exchanged with those of the surrounding tissue fluid. We also have seen that the introduction of bacteria into a gel-injected site elicits an intense foreign body response,whichmaygive rise to granulation tissue formation and ensuing fibrosis [2]. All the women in our series had been injected originally at the clinic of Dr. Kebuladze with a sterile Interfall gel produced in Ukraine [3]. The gel had always been injected in a subglandular location in many small deposits (5-10 ml), and the maximum amount of injected gel per breast at each visit never exceeded 80 ml. For prophylaxis, a broad-spectrum antibiotic at a high dosage had always been applied both locally and orally for 5 days after each injection visit. It may be that bacterial infection with ensuing fibrous scarring was a more common complication in the series of women described by Qiao and colleagues than in ours. This would plausibly explain why so many of the women in their series experienced pain, a complaint that was not heard from any of our women.