Soft tissue augmentation is a momentous procedure in aesthetic and reconstructive surgery. The demand for soft tissue augmentation is growing due to increased interest in procedures such as facial contouring, breast augmentation, cheek reshaping, and the like. In the quest for soft tissue fillers, different biologic and nonbiologic materials have been introduced, but none have provided ideal results.

Polyacrylamide hydrogel (PAAG), a polymer of the acrylamide monomer, is a kind of jellylike colorless substance that is nontoxic and thought to be nonimmunogenic, with cohesive, viscous-elastic, and biocompatible properties [1–3]. Composed of 2.5% polyacrylamide and 97.5% non pyrogenic water, PAAG has been shown to have promising outcomes as an injectable implant [4]. These characteristics, in addition to its hydrophilic property, render PAAG an appropriate filler for use in aesthetic surgery.

Polyacrylamide hydrogel was first introduced to aesthetic surgery in the former Soviet Union countries, mainly in the Ukraine, in the 1980s. Since then, it has been applied increasingly for the purpose of soft tissue augmentation. It was approved by the European Community (Conformite Europeene) for authorized use in facial correction under the trademark of Aquamid [5–7].

There are different subtypes of polyacrylamide gel such as Aquamid, Interfall, Outline, Formacryl, Bioformacryl, Bio-alcamid, Amazing Gel, and Argiform [8, 9]. Among the various subtypes of PAAG, Interfall, Aquamid, and Esteform have been available and widely used in Iran since the introduction of the gel. It is estimated that more than 10,000 injections with PAAG are performed in Iran annually.

Although PAAG has long enjoyed an outstanding safety record and promising outcomes in aesthetic and plastic surgery, especially in breast augmentation and facial contouring, as reported in many studies [4–7, 10–12], recent reports point out some complications with its use that are not concordant with the excellent results of PAAG reported previously as a soft tissue filler [8, 13–17].

In this report, we present 98 patients, reporting the results of PAAG injection. This report is based on observations of these patients who had previously undergone cosmetic soft tissue augmentation using PAAG. These patients were unsatisfied by the outcome or presented with a complication of PAAG.

Materials and Methods

From February 1997 to June 2008, 98 of the cases presenting to the private office of the senior authors for complications of PAAG as a soft tissue filler were included in the study. The inclusion criteria required injection of PAAG mainly for cosmetic purposes, dissatisfaction with the result of soft tissue augmentation or presentation of a complication related to gel injection, consent given for tissue biopsy, and acquisition of a culture. Gel-related complications were verified as asymmetry, nodularity or a lumpy mass, migration of the implant, inflammation, ulceration or abscess formation, and hypersensitivity reactions.

The exclusion criteria specified inflammatory soft tissue diseases, skin disorders involving the injection site, immune system disorders, pregnancy, substance abuse, diabetes mellitus, and previous administration of other types of soft tissue fillers. The patients were asked to bring the product catalog or receipt with them for precise definition of the PAAG brand used in previous injections. However, we contacted the physicians originally in charge of injecting the product and asked them to review their files and confirm the brand of PAAG used for every patient.

For all the patients, lab values (complete blood count with differential, plasma levels of immunoglobulin, liver function tests, and urinalysis) were obtained. The gel then was removed by using a small skin incision at the site and milking to empty the place of the gel, after which vigorous irrigation was applied to evacuate the gel. Tissue sampling then was obtained in cases of the breast augmentation procedure. Tissue biopsy was not performed if the site of gel administration was on the face or exposed areas of the body. In cases of inflammatory signs such as redness, tenderness, and warmth, samples were sent for culture as well.

Histologic specimens were fixed in buffered formalin, embedded in paraffin, cut into 5-μm sections, and stained with hematoxylin-eosin. One surgical pathologist blinded to the clinical data performed the assessment. The patients were followed up for at least 6 months after evacuation of the gel, and proper cosmetic surgery such as use of autologous fat injection, dermo-fat grafting, augmentation mammaplasty, or mastopexy (in cases of breast reshaping) was performed if requested.

Results

The study enrolled 98 patients (86 women and 12 men) who met the inclusion criteria. The patients ranged in age from 18 to 67 years (mean, 36 years). Of the 98 patients, 87 were injected with Interfall, 9 with Aquamid, and 2 with Esteform. The sites of injection in downward prevalence were facial regions (nasolabial fold, frown line, lips, periorbital region, and cheeks), breasts, buttocks, and legs (Table 1). The time from injection to the presenting of complaints ranged from 6 months to 4 years (mean, 19 ± 8 months). The exception was one patient in whom an anaphylactoid reaction was observed 1 week after gel injection.

Table 1 Site of polyacrylamide hydrogel injection and its frequency
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Our findings included inflammation (Fig. 1), infection, asymmetry, irregularity of the injection site, gel migration (Fig. 2), pain in cold weather and feeling of expansion in a warm environment, and finally skin necrosis and hyperpigmentation (Fig. 3). Table 2 demonstrates the frequency of symptoms in the patients. Abnormal lab values consisted of increased white blood cell count; eosinophilia; positive specimen culture; increased C-reactive protein (CRP), serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT); hyperglycemia and glucosuria; and abnormal values of immunoglobulin E (IgE). Table 3 represents the distribution of abnormal laboratory values among the patients. Histologic evaluation showed granuloma formation (n = 17), fat necrosis (n = 9), and fibrosis (n = 17) in specimens (Figs. 4, 5, 6).

Fig. 1
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Inflammation of the injection site 27 months after polyacrylamide hydrogel (PAAG) injection

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Fig. 2
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Downward migration of polyacrylamide hydrogel (PAAG) 2 years after Aquamid injection to the frown line. It caused pseudohyperthelorism to the patient

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Fig. 3
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Hyperpigmentation of the injection site 21 months after polyacrylamide hydrogel (PAAG) injection

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Table 2 Frequency of presenting symptoms in patients
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Table 3 Abnormal lab values and their frequencies in patients
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Fig. 4
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Fat necrosis and diffuse macrophage infestation in breast tissue

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Fig. 5
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Breast tissue containing small droplets of gel surrounded by fibrosis

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Fig. 6
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Gel droplet, multinuclear giant cells, and thick fibrosis prominent in the tissue biopsy

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For all 16 patients who had injections in their breasts, biopsies were taken from the site of injection. All had granuloma and inflammation. In cases of inflammation at the injection site, the specimens showed positive tissue culture in 11 cases. The test results were positive for coagulase-negative Staphylococcus in eight cases, Staphylococcus aureus in two cases, and Escherichia coli in one case.

The patients were followed up for at least 6 months after gel removal. The findings showed that gel-related signs such as inflammation, pain, and feeling of expansion resolved completely. However, hyperpigmentation of skin, necrosis, and fibrosis remained unchanged.

For eight patients, gel removal by squeezing and irrigation of normal saline was not sufficient, and the gel could not be removed completely. Three patients, after seemingly complete removal of the gel, experienced reaccumulation of the gel in 2–5 months, which necessitated further operations to extract the material.

Representative Cases

Case 1

A 26-year-old woman presented with inflammation and edema of her lips. She had been injected with 5 ml of Estiform gel to her lips for lip augmentation in the private office of a general practitioner 11 days before presenting to our center. She experienced severe edema of the lips and difficulty breathing 1 week after injection (Figs. 7 and 8). The edema was progressive, involving her face and neck. She was admitted to the intensive care unit (ICU), intubated and administered intravenous dexamethasone and broad-spectrum antibiotics (azthreonam, vancomycin, and clindamycin).

Fig. 7
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Anaphylactoid reaction in the patient 1 week after polyacrylamide hydrogel (PAAG) injection into her lips (frontal view)

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Fig. 8
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Anaphylactoid reaction in the patient 1 week after polyacrylamide hydrogel (PAAG) injection into her lips (lateral view)

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The next day, the patient became stable. She was extubated and received 60 mg of prednisolone daily. After 2 days, an ear, nose, and throat (ENT) specialist tried to evacuate the gel using two vertical incisions in the upper and lower lips, but the procedure was unsuccessful. The culture of lip secretion was positive for coagulase-negative Staphilococcus, and lab results showed eosinophilia, elevated levels of SGOT, SGPT, IgE, CRP, fibrinogen, and blood glucose (185 mg/dl). Urinalysis also showed positive results for glucose, although the patient had no history of elevated blood glucose or glucosuria. The patient’s blood levels of IgG and IgM were normal.

The patient stayed 3 days in ICU and 40 days in internal medicine wards. The inflammatory symptoms resolved, but in 2 months, she experienced a moon face, microstomia, and a fibrotic scar around her lips that caused her difficulty eating, drinking, and talking (Figs. 9 and 10).

Fig. 9
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The same patient 6 months after gel removal. High-dose corticosteroid therapy has caused the patient’s moon face

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Fig. 10
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Fibrosis around the patient’s lips has caused her microstomia and limitations in eating, talking, and smiling

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Case 2

A 42-year-old woman presented to our clinic reporting lumpy masses and ptosis of her breasts. Her breasts had been injected with PAAG (200 ml each) by a general surgeon 4 years before she presented. She had been satisfied with the appearance of her breasts at first, but they began to migrate downward later. A prominent ptosis and dependency was observable. She also complained of pain in her breasts in the cold and a feeling of expansion in a warm environment. Obvious stiffness and nodularity around her nipples were prominent at her physical examination.

A 2-cm horizontal incision in the submammary area was made in each breast, and the gel was evacuated by milking, with the remainder irrigated. The gel cavity was left open, and after 1 month, a superior pedicle vertical mastopexy was performed in which some additional stiff masses were excised and sent for pathology (Figs. 11 and 12). Microscopic evaluation demonstrated giant cells engulfing foreign body particles supported by wide zones of fibrosis. Fat necrosis and dense fibrosis was eminent in the specimens obtained from both breasts (Figs. 13 and 14).

Fig. 11
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Breast ptosis and dependency 4 years after polyacrylamide hydrogel (PAAG) injection (left), Breasts after removal of PAAG (middle). The same patient 2 months after superior pedicle vertical mastopexy (right)

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Fig. 12
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The same patient (lateral view)

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Fig. 13
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Giant cells and fibrosis are prominent around polyacrylamide hydrogel

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Fig. 14
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Fat necrosis and macrophages are visible in the specimen of breast tissue

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Case 3

A 31-year-old woman came to our office reporting pain in her cheeks. She had undergone injection of gel into her cheeks (10 ml each) and lips by a general surgeon. After 18 months, she began to feel extreme pain, a burning sense in the cold, and a feeling of expansion in her cheeks in a warm environment. Facial expressions such as laughing, smiling, and chewing caused her pain and discomfort as well. She was content about her lips at first. However, by 8 months, her lips had an asymmetric look (Fig. 15).

Fig. 15
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A 31-year-old woman reporting pain and burning sensation in her cheeks and abnormal appearance during facial expressions

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In the first stage of treatment, gel was emptied by two small incisions in her nasolabial folds and milking (Fig. 16). The extracted substance was homogenous and yellowish in color, not clear and transparent. The tissue culture results for bacteria were negative for this patient. After 3 months, we injected autologous fat into her cheeks. Figures 17 and 18 show the result of fat injection 6 months after the operation.

Fig. 16
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Evacuation of polyacrylamide hydrogel (PAAG) from the patient’s cheek. The extracted substance is not clear and transparent

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Fig. 17
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View of the patient at the time of presentation (left). The same patient after evacuation of polyacrylamide hydrogel (PAAG) (middle). View of the patient 3 months after autologous fat injection (right). The patient’s symptoms (pain and burning sensation) were resolved completely after gel extraction. The patient’s lip asymmetry is prominent

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Fig. 18
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Same patient (lateral view)

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Case 4

A 59-year-old woman presented to our clinic reporting dimpling in her right suborbital region that had caused her downward retraction of the inferior eyelid and scleral show. Interfall had been injected into her cheeks 13 months before her first visit to our clinic. At 7 months after the injection, she experienced edema, inflammation, and pain in her right cheek.

Despite the administration of antibiotics (cloxacillin and metronidazol), an abscess emerged in 2 weeks, which resolved spontaneously. Puss secretion continued for months, and after resolution of the abscess, a scar tissue formed. At our visit, there was a dimple in her right suborbital region and retraction of her lower eyelid (Fig. 19).

Fig. 19
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Suborbital scar and dimpling after spontaneous emptying of abscess

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With the patient under stand-by anesthesia, a small incision was made lateral to the lesion. The skin was elevated from the cheek bone, and a pocket was made for placement of a dermal fat graft. At the same time, other small incisions (2–3 mm) were made to empty the place of the gel that had caused ballottement at palpation. The gel was milked out, and the place was irrigated with a copious amount of normal saline using a small cannula. The evacuated gel had a yellowish appearance with white granules. A dermal fat graft then was excised from the patient’s lower abdomen and advanced into the pocket (Fig. 20).

Fig. 20
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View of the patient before (left) and after (right) dermal fat graft

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The tissue culture tested negative for bacteria and fungus. After 5 months, remnants of the gel had reaccumulated. We tried to empty the place of gel using a mosquito clamp and small incisions from which yellow jellylike material with white granules was extracted. A delicate 5–0 nylon suture was used just for approximation. The patient had the same problem 3 months later. The same procedure was performed for the patient, but at this writing, she has the same complaint.

Discussion

In this report, we present some complications of PAAG. It is estimated that 10,000 different soft tissue filler applications consisting of hyaluronic acid, PAAG, collagen, artecol, and hydroxyl apatite are performed annually in Iran. Therefore, office visits by patients for their side effects are quite common for plastic surgeons.

The growing market for soft tissue fillers has led to their wide application for facial contouring, breast and buttock augmentation, and other cosmetic procedures. Considerable advertisement of PAAG in recent years and mounting requests for cosmetic procedures in developing countries have made PAAG a popular substance for both patients and doctors.

It has been 11 years since the introduction of PAAG as a biosynthetic soft tissue filler in Iran. It is provided with three different trademarks (Aquamid, Interfall, and Esteform), and several workshops have been held to persuade general practitioners, general surgeons, oral and maxillofacial surgeons, ENT specialists, and plastic surgeons to use PAAG in aesthetic surgeries. The last workshop was held in Kish Island of the Persian Gulf in 2007. There PAAG was strongly recommended as a nontoxic, nonpyrogenic, and biocompatible material that has shown no findings of infection, inflammation, gel migration, or foreign body reaction.

Because recent studies have shown some complications with PAAG injection [8, 13–18], Iranian plastic surgeons usually refrain from using it and prefer biologic materials such as autologous fat when possible. However, great efforts to publicize polyacrylamide products and the ease of its application even by general practitioners and general surgeons on one hand and its affordability for patients seeking aesthetic surgery on the other hand are the reasons why we observe many patients undergoing augmentation procedures using synthetic soft tissue fillers. It is not rare for these patients in the clinical setting to report its adverse effects and complications.

The authors are very conservative and uncertain in applying PAAG. Because we observed some patients reporting adverse effects of PAAG from the first years of its application in Iran, we have held back from its injection, not risking our patients’ health and appearance by the possible serious adverse effects of this gel although this possibility might be very low and even negligible. We usually prefer autologous fat or hyaluronic acid injection because of the safer profiles and more predictable outcomes.

Most of the previous studies concerning the long-term effects of PAAG on humans and animal models seemed to be promising in terms of safety and an aesthetic view and did not demonstrate serious and unpredictable complications [4, 5, 9–11, 19]. Von Buelow and Pallua [12] reported no severe side effects during a 2-year follow-up period for 101 patients and observed only local reactions in some patients, which were transient and resolved spontaneously. They did not detect any granuloma formation during the first 2 years after treatment with Aquamid. This finding was not concordant with our study because we observed gel migration, granuloma formation, fat necrosis, and fibrosis in our patients.

Christensen et al. [7] in a study investigating the long-term effects of PAAG on human breast tissue declared that neither thick fibrosis, calcification, nor necrosis were present in any of their biopsy specimens. This also was contrary to our findings because we observed thick fibrosis and fat necrosis in our biopsy specimens. However, none of the biopsy specimens in our study had any calcification.

One advantage of PAAG over other soft tissue fillers was considered to be the good tissue cohesive properties, preventing its migration from the site of injection [5]. However, we observed eight cases in which gel migration from the original injection site was the main unsatisfactory element, even in one patient who had been injected with PAAG in her frown line. Downward gel migration had caused pseudohyperthelorism (Fig. 2).

A total of 31 patients reported asymmetry that was not present in the first months of gel injection. This could not have been attributable to the injection technique because the asymmetry was not present in the first months after the cosmetic procedure and seemed to be caused by water exchange between PAAG and surrounding tissue.

Skin necrosis and hyperpigmentation can be very upsetting for patients seeking cosmetic procedures, especially in the exposed areas of their bodies (Fig. 3). This side effect, although not common, can negatively affect patients’ quality of life, and its possibility must be taken into consideration during consultation with the patient before gel injection.

Most of our patients were not aware of the possible adverse effects of PAAG injection in cosmetic procedures, and they had not been informed by their physicians. Many patients stated that if they had been aware of the possibility of their result, they would never have undergone such an unpleasant experience in the first place.

In 2004, De Bree et al. [15] reported a case of severe granulomatous response to injection of PAAG into the facial tissue. We also detected inflammatory reactions in the face and breast regions of 51 of our patients (Fig. 1). Granuloma formation was a common histopathologic feature. De Bree et al. [15] stated that lower adverse effects reported for tissue augmentation by PAAG compared with silicone could be due to a much more frequent administration of silicone as a soft tissue filler. We share their view that clinical experience and histopathologic reports of PAAG safety are not enough. As soft tissue augmentation by PAAG has increased, we observe more local side effects and patient dissatisfaction.

Other products and methods also are used for soft tissue filling in Iran such as hyaluronic acid, fat injection, silicone gel, and the like. It really is hard to estimate the exact frequency of their usage because a wide spectrum of physicians inject them, and it is so hard, if not impossible, to gather this information. Plastic surgeons usually use hyaluronic acid and fat injection more often than silicone gel and PAAG.

Among the soft tissue fillers, hyaluronic acid products are quite popular in Iran among plastic and reconstructive surgeons. It is biocompatible, and no serious adverse reactions have been reported since the start of its usage in Iran. It is more expensive than PAAG but has a safer profile and fewer side effects.

Conclusion

Polyacrylamide hydrogel in its different forms may be superior to other soft tissue fillers in terms of safety and biocompatibility. However, adverse effects from its injection can be quite notable and contrary to the expectations of the patients seeking cosmetic procedures. Plastic surgeons should be cautious in applying synthetic soft tissue fillers, and the possibility of their complications and adverse effects must be taken into consideration and discussed in detail with patients.