Product

Aquamid^® is a non-absorbable soft volume filler for aesthetic and reconstructive purposes. The polyacrylamide hydrogel (PAAG) Aquamid^® is one of the new macromolecules that are used as implants and tissue fillers in reconstruction and aesthetic dermatology. Aquamid^® hydrogel is a 2.5% cross-linked PAAG made from acrylamide and N,N′-methylene-bis-acrylamide, ammonium persulphate/tetramethyl ethylenediamine (AMPS / TEMED) redox initiator system, and 97.5% purified water. It is not biodegradable and offers a long-lasting effect. Each batch is analyzed for consistency and compliance with product specification, including narrow tolerances of elasticity modulus, pH and impurities, and degradation products from the polymerization reaction. Aquamid^® is developed, produced, and commercialized by Contura International A/S, Søborg, Denmark. It was approved and CE marketed in Europe in 2001 for facial augmentation and minor body contouring and is available in more than 40 countries worldwide in Europe, Asia, the Middle East, and Latin America.

Aquamid^® has been evaluated in clinical trials by Von Buelow and colleagues, Christensen et al, Narins et al, and Wolter & Pallua, involving more than 5000 patients including a comparative trial in the USA. Data from these trials have been used to support a PMA application to the US Food and Drug Administration (FDA). Aquamid^® is not yet approved for sale in the USA, but is expected to get FDA approval by the end of this year.

Studies by Bello and colleagues and by De Cassias Novaes & Berg have shown that this PAAG does not migrate within the tissue after subcutaneous injection because of its large molecular size and high cohesive properties. Christensen found that cells grew well in the Aquamid^® gel, which allows vessel ingrowth from adjacent tissue. It is kept in place by means of a fibrous capsule (endoprosthesis) that develops after being injected in the subcutaneous tissue. These capsules are surrounded by fibroblasts and macrophages (Fig. 11.1). Another study by Zarini and colleagues emphasized the importance of the microstructure and porosity of hydrogels in relation to their functions and interactions with surrounding medium and tissue. Hydrogels could behave as an accessible foreign body that creates the appearance of infections that are untreatable. PAAG can exchange both physiological and non-physiological constituents very efficiently with the surrounding medium. In the context of hydrogels as tissue fillers, Brahm et al considered the ability of water and solutes (including an antibiotic) to cross between the hydrogel and the surrounding tissue to be attractive.

Figure 11.1 Microphoto of Aquamid^® injected into the chin 4 years previously. The gel (in blue) is surrounded by muscle cells (MC in red), fat cells (FC in white) and connective tissue (CT in pale red). Aquamid^® is anchored by a fine network of host connective tissue strands (see arrows).

Courtesy of Dr Lise Christensen.

The hydrogel is homogeneous, containing no microparticles or microspheres, and its filling effect is immediate. It relies exclusively on adding volume from the gel itself, unlike tissue fillers that are particle based and depend on foreign-body reaction to achieve the desired effect.

Patient selection

Patients have to have clear insight into their treatment goals and the permanent nature of Aquamid^®. It should not be injected into patients with dental caries and chronic bacterial sinusitis. The safety of PAAG has not been studied in pregnant women. Common aesthetic indications for Aquamid^® are nasolabial folds, cheek contouring, jawline contouring, nose enhancement, and marionette lines, as well as for lip augmentation, and for volumizing temples, cheeks, and chin. Aquamid^® is also used to correct signs of facial lipoatrophy or fat wasting in HIV-positive patients, as in the trial by Von Buelow.

Technique / treatment

As with all permanent fillers the appropriate injection technique and the judicious use of the filler in the proper location and in the right plane of tissue are fundamental for success. Injections of PAAG should be conducted using aseptic technique. The injecting physician should wear sterile gloves, and the face of the patient has to be carefully cleaned with an antiseptic treatment. PAAG is injected subcutaneously with a 27-gauge needle in a retrograde, fan-like manner by injecting the gel while withdrawing the needle (Fig. 11.2). It should not be injected in large boluses in single sessions, but rather should be administered with a multi-line injection technique of small droplets. A series of small deposits facilitates tissue integration and vascularization of the implanted hydrogel, minimizing the risk of migration and other late-onset complications such as biofilm-assisted infection. PAAG has to be injected strictly subcutaneously; care should be taken when retracing the needle not to inject into the dermis and not to overcorrect. A light massage of the tissue after injection will help to obtain even distribution of the gel (Figs 11.3 and 11.4). If necessary touch-up injections may be spaced apart by several weeks. Although PAAG should not be thought of as a reversible tissue filler, it may be possible to remove the implant through a small incision under local anesthesia without damaging surrounding tissue. Complete or partial removal is possible because PAAG remains soft after injection.

Figure 11.2 Polyacrylamide hydrogel is injected subcutaneously with a 27-gauge needle in a retrograde, fan-like manner by injecting the gel while withdrawing the needle

Figure 11.3 Treatment with 3 mL of Aquamid^® for both nasolabial folds: (A) before treatment; (B) 2.5 years after treatment.

Courtesy of Dr Martin Janssen.

Figure 11.4 A light massage of the tissue after injection (in the direction of the arrows) will help to obtain even distribution of the gel.

Efficacy

In a double-blinded, randomized, multicenter, non-inferiority trial study by Narins et al with a 12-month follow-up with 312 patients, PAAG proved to be non-inferior to stabilized hyaluronic acid (NASHA™). It was as effective as NASHA™ in the aesthetic enhancement of nasolabial folds at 6 months, and effectiveness persisted throughout the 12-month follow-up. Treatment-related adverse events (AEs) occurred with equal incidence; most were mild to moderate, transient, and related to injection procedure. One serious adverse event (infection) was thought to be related to treatment with PAAG; it resolved within 5 days after appropriate treatment.

Complications

Aquamid^® appears to be well tolerated. In the above study by Narins et al, safety results were based on the intention-to-treat analysis set, comprising all 315 subjects who received one of the two randomly assigned treatments.

A high proportion of subjects in each treatment arm experienced at least one AE during the 12 months of follow-up, with similar proportions in each arm (88.1% of the PAAG group, 85.7% of the control group). The incidence of treatment-related AEs through the 12-month follow-up was the same in each treatment group (85.7%), with the majority (48.5%) considered mild and transient, and resolving within 7 days. The most common treatment-related AEs were typical of those seen with injection of soft tissue fillers and included for the PAAG and control groups, respectively: bruising (73% versus 76%), edema (63% versus 78%), redness (51% versus 57%), and tenderness (44% versus 52%). Fewer than 4% of subjects experienced an AE with onset after the optimal treatment visit (14 days after the final injection). None were severe or serious and included edema, induration, nodule formation, redness, pain, itching, uneven distribution, or small subcutaneous lump. One serious AE, infection in a subject in the PAAG group, was deemed to be related to treatment, representing an incidence of 0.5% of subjects. Cefuroxime, indometacin, and clobetasol were prescribed for this subject. The bacterial culture was positive for Corynebacterium spp. and Staphylococcus aureus.

Because PAAG contains no animal protein, there is a low risk of allergic reactions. Although a few case reports (by Alijotas-Reig et al, Liu & Cheung, and Abenavoli et al) raise the question of whether complications occur over the long term with PAAG, there are a number of unresolved questions pertaining to these reports. These questions include whether undetected bacterial infection with biofilm formation was present, the source and sterility of the PAAG used (manufacturing standards are not consistent among all manufacturers of PAAG), and whether the substance used actually was PAAG. All filler procedures, including those using PAAG, have a risk of introducing bacteria during injection and any signs or symptoms suggesting inflammation should be considered as an infection and treated immediately with antibiotics. The PNA-FISH study, reported by Bjarnsholt et al, supports this practice. This study demonstrated that infection with bacteria in microcolonies, and not delayed hypersensitivity, causes culture-negative, late, adverse reactions to PAAG, suggesting the presence of a biofilm. Corticosteroids and large doses of non-steroidal anti-inflammatories are not recommended because they aggravate the condition by masking symptoms, making it resistant to further treatment and lowering the immune response. This study also demonstrated how equally important it is to follow proper sterile technique during injection. Although recognizing that AE reporting may not reflect the true incidence of AEs, the manufacturer’s data on reported events with 2.5% PAAG Aquamid^® suggest a low rate of complications, with a spontaneously reported AE rate of less than 1 per 1000 syringes (unpublished data, Contura Inc.). As of July 2009, more than 360 000 syringes of 2.5% PAAG had been sold worldwide. The primary safety end point was the incidence of AEs with mild and transient effects that are typically related to the injection.

Discussion

Aquamid^® (PAAG) belongs to a group of macromolecules that are widely used as injectable fillers in aesthetic and reconstructive surgery.

While several studies (by De Cassias Novaes & Berg, Christensen, and Zarini et al) have addressed the histological reactions of tissues to injected PAAG, there is a sparcity of data on the physical–chemical interaction between PAAG and other interstitial solutes and on the exchange of water and solutes between the PAAG macromolecule and its surroundings. Regarding the application of Aquamid^® as a tissue filler, Brahm et al found the efflux characteristics to be favorable in the context of a tissue filler that has an open structure to water and solutes. The ease of exchange of water and solutes, including an antibiotic, between the hydrogels and the surrounding tissue appears very attractive, since the hydrogel might not behave as an inaccessible foreign body that creates an unreachable pocket for infections. The fact that benzylpenicillin had access to PAAG is indeed an advantage from a pathophysiological point of view, since PAAG as an open extracellular matrix can house pathogenic microorganisms that can be affected by it and most likely by other high-molecular-weight antibiotics.

The results of the study demonstrate that 2.5% PAAG is as effective as NASHA™ for correction of nasolabial folds. Given that 2.5% PAAG is not biodegradable, persistence of the effect throughout the 12 months of evaluation is not unexpected, and it is anticipated that longer term follow-up would demonstrate a continued long-lasting effect. Pallua & Wolter demonstrated a duration of effect beyond 12 months. This 2.5% PAAG offers promise as a long-lasting soft tissue filler. It is well tolerated and it could be demonstrated that Aquamid^® is as effective as NASHA™ in correction of nasolabial folds.