Injectable soft tissue fillers: Permanent agents

INTRODUCTION — Soft tissue fillers are used alone or in combination with other aesthetic procedures to correct wrinkles and to restore tissue volume lost due to aging, lipoatrophy, or other causes. In contrast to resorbable fillers such as hyaluronic acid, fillers that contain polymethylmethacrylate microspheres, silicone, or hydrogel polymers persist indefinitely in tissue. Cautious and conservative use of permanent fillers is essential, as improper injection techniques can lead to long-lasting adverse effects.

Use of permanent filling agents has fallen significantly. Concern for permanent adverse effects and the availability of many effective, temporary (semipermanent) fillers, which have a more favorable side effect profile, favors use of temporary agents. Vascular occlusion, which can result in blindness, can occur with both permanent and temporary agents. (See "Injectable soft tissue fillers: Temporary agents".)

The efficacy, use, and adverse effects of permanent soft tissue filling agents will be reviewed here. Information on resorbable soft tissue fillers and an overview of the clinical use and complications of soft tissue fillers are available elsewhere. (See "Injectable soft tissue fillers: Temporary agents" and "Injectable soft tissue fillers: Overview of clinical use".)

PRECAUTIONS — Many patients can achieve cosmetically pleasing results with temporary fillers, and the decision to utilize a permanent filling agent should be considered carefully. In the event that a hyaluronic acid gel (a commonly used temporary filling agent) is placed incorrectly in tissue, the adverse cosmetic result can be rapidly corrected through the administration of hyaluronidase or can be left to spontaneously resolve over the course of several months as the filler is degraded. In contrast, unfavorable cosmetic results following misplacement of permanent fillers may require surgical intervention and may be difficult or impossible reverse. (See "Injectable soft tissue fillers: Temporary agents", section on 'Reversal'.)

Additionally, use of a filling agent with a limited duration of effect provides the clinician with the flexibility to respond to changes in patient preferences and allows the clinician to adjust the placement of fillers in concordance with the cutaneous and structural changes that occur with age over time. Thus, patients who desire treatment with permanent filling agents must be screened carefully. Patients who are unsure of their desired outcomes, who have a history of unsubstantiated poor satisfaction with cosmetic treatments, or who are new to the use of soft tissue fillers are poor candidates for treatment with permanent agents.

As with semipermanent filling agents, blindness can occur if embolization of a permanent filler substance inhibits perfusion of the central retinal branch of the ophthalmic artery. Most reported cases of blindness following use of a permanent filler have involved autologous fat injections; however, cases of blindness following injection of polymethylmethacrylate microspheres and liquid silicone also have been reported [1,2]. (See "Injectable soft tissue fillers: Overview of clinical use", section on 'Early adverse effects' and "Central and branch retinal artery occlusion".)

POLYMETHYLMETHACRYLATE MICROSPHERES — ArteFill, which is now known as Bellafill in North America, is a nonbiodegradable injectable filling agent composed of 30 to 50 micrometer polymethylmethacrylate (PMMA) microspheres suspended in a water-based gel containing 3.5% bovine collagen and 0.3% lidocaine. Previous formulations of PMMA microspheres were marketed under the names Arteplast and Artecoll. Modifications in microsphere size and product purification methods have improved the biocompatibility of Bellafill compared with its precursors [3].

Bellafill is the only injectable permanent filling agent approved by the US Food and Drug Administration (FDA), and this approval is limited to its use for nasolabial folds. However, the PMMA filler has been used for a variety of other indications, including additional facial wrinkles, contour defects on the face and neck, and acne scars [4,5].

Mechanism of action — After implantation, the bovine collagen component of Bellafill dissipates over the course of one to three months, leaving behind the nonbiodegradable PMMA microspheres [6]. The microspheres stimulate a local inflammatory reaction that is followed by the deposition of granulation tissue during the first few weeks after implantation [3]. The connective tissue subsequently matures, and by three months after injection, PMMA microspheres are surrounded by newly formed collagen. The presence of new collagen accounts for the observed volume-filling effect.

Efficacy — The efficacy of PMMA microspheres for facial wrinkles was evaluated in a randomized trial of 251 patients treated with either a PMMA filler (Artecoll) or a collagen filler (Zyderm II or Zyplast) [6]. A total of 1334 glabellar frown lines, nasolabial folds, radial upper lip lines, and marionette lines were treated in up to two treatment sessions over the course of one month. Six months after treatment, photographic assessment by masked observers revealed that PMMA was superior to collagen fillers for the treatment of nasolabial folds. Although the masked observers did not detect a statistically significant difference in improvement for the other treated sites at this time point, an extended phase of the study for patients treated with PMMA found statistically significant improvement in wrinkle severity scores compared with baseline values for all four sites at 12 months. In addition, long-term follow-up studies of recipients of PMMA fillers indicate that beneficial effects can persist for at least four to five years [7,8].

Use — Similar to other soft tissue fillers that contain bovine collagen, patients must be skin-tested for hypersensitivity reactions to bovine collagen prior to injection. Skin tests are performed with intradermal injection of 0.1 mL of collagen on the ventral forearm four weeks prior to treatment. Patients with positive skin tests should not be treated. PMMA injections are also contraindicated for patients with known allergies to any of the product ingredients or a history of keloid or hypertrophic scar formation.

Individuals with well-defined lines and furrows and minimal excess skin are good candidates for treatment with PMMA [5]. Injections are not recommended for areas of thin skin, such as the lower eyelid and neck, or for patients with generally thin, loose skin, as the implant may remain palpable or visible [9]. In addition, PMMA should not be used in the lips due to an increased risk for lumpiness or beading after injection.

Bellafill is supplied in prefilled syringes, and a 26-gauge needle is typically used for injection. The product should be implanted in the deep reticular dermis and overcorrection of defects should be avoided. A series of conservative injections is often required to achieve optimal results.

Touch-up injections can be performed one to three months after the initial treatment. Because new collagen synthesis contributes to the effect, optimal results occur after approximately 3 to 12 months. Additional improvement more than one year after treatment may also occur [7].

Adverse effects — Potential complications of PMMA include nodules due to superficial placement, persistent redness or telangiectasias, hypertrophic scarring, or the delayed appearance of granulomas. Granulomas occurred in approximately 2.5 percent of patients treated with Arteplast and 0.02 percent of patients treated with Artecoll [4,7,10]. The risk for granuloma formation after treatment with Bellafill appears to be lower than for Artecoll [5].

The utilization of proper injection technique may reduce the risk for adverse effects [5]. When they occur, granulomas can be treated with intralesional corticosteroid injection. Nodules and hypertrophic scarring also can respond to intralesional corticosteroids [5,11].

HYDROGEL POLYMERS — Hydrogel polymer fillers are synthetic, nonbiodegradable, hydrophilic gels with a high degree of elasticity.

Polyacrylamide hydrogel — Available throughout Europe, Australia, Asia, and Mexico, Aquamid and Aquamid Reconstruction are nonbiodegradable filling agents composed of 2.5 percent cross-linked polyacrylamide and 97.5 percent water [12]. Aquamid Reconstruction is slightly more viscous than Aquamid.

Mechanism of action — Polyacrylamide hydrogel augments soft tissue exclusively through a direct, volume-filling effect. The hydrogel becomes an integrated part of the patient's soft tissue.

Efficacy — Polyacrylamide hydrogel is effective for soft tissue filling [13-17]. In a 12-month randomized trial of 315 patients treated for nasolabial folds, the efficacy of Aquamid was similar to a hyaluronic acid filler (Restylane) [18]. Side effects were mostly mild and transient and similar for both treatment groups. Of note, one serious treatment-related infection occurred among the patients treated with Aquamid. The infection resolved after antibiotic therapy and surgical removal of the product.

Polyacrylamide hydrogel was also effective for facial soft tissue augmentation in an uncontrolled study of 251 patients with various facial contour or soft tissue defects. After 12 months, 93 percent of the 228 patients who were available for follow-up exhibited good or very good responses to treatment [14]. The benefits of treatment were long-lasting; similar rates of response were observed in a subset of patients five years after their last treatment [19].

Use — Aquamid and Aquamid Reconstruction are used for the treatment of deep wrinkles and folds and for the correction of facial contours. The products are supplied in prefilled syringes as Aquamid and Aquamid Reconstruction. The more viscous Aquamid Reconstruction is best suited for injections where a large volume of product is required, such as in the treatment of lipoatrophy. Aquamid is injected with a 27-gauge needle, and a 25- or 27-gauge needle is typically utilized for injection of Aquamid Reconstruction.

Both products should be placed into the subcutaneous fat and overcorrection should be avoided (figure 1). Polyacrylamide hydrogels should not be used intradermally, and, therefore, are not appropriate for the correction of fine wrinkles.

Adverse effects — Polyacrylamide hydrogel appears to be well tolerated; side effects are generally temporary and transient, including swelling, pain, redness, hematoma, or pruritus [14,15]. Other potential side effects include nodule formation, local induration, skin discoloration, and infections [19,20]. Delayed granulomatous reactions, ulceration, bone erosion, and migration of polyacrylamide hydrogel in tissue have been reported in a few patients [21-25].

Polyalkylimide hydrogel — Bio-Alcamid is another nonbiodegradable hydrogel. It consists of 96 percent water and 4 percent synthetic reticulate polymer (polyalkylimide). Bio-Alcamid is not available for use in the United States.

Mechanism of action — Once implanted, polyalkylimide hydrogel becomes encapsulated by a very thin rim of collagen, isolating it from the host tissues. Similar to polyacrylamide hydrogel, the product's efficacy results from a direct volume-filling effect.

Efficacy and use — Polyalkylimide hydrogel has been studied most extensively for HIV-associated lipoatrophy and has been effective for this indication in a small randomized trial and case series [26-32]. The product has also been used for other indications, including lip augmentation and the cosmetic improvement soft-tissue and bony contour defects [28,33,34]. Like polyacrylamide, injections should be placed into the subcutaneous fat (figure 1).

Adverse effects — Common adverse effects of injection include mild and transient swelling, pain, bruising, and erythema [32]. There have also been reports of infections developing months to years after implantation, delayed inflammatory reactions, and migration of the product in tissue [12,35-42]. Granulomas have occurred in at least two patients treated with this agent for lip augmentation [41].

LIQUID INJECTABLE SILICONE — The use of liquid injectable silicone (purified polydimethylsiloxane) for soft-tissue augmentation is controversial due to concern over the potential for long-term complications. Liquid injectable silicone should be utilized only by experienced and expert injectors in carefully selected patients. In the United States, liquid silicone is FDA approved only for intraocular use.

Mechanism of action — The efficacy of liquid injectable silicone as a soft tissue filler results from a combination of a direct volume-filling effect of the injected material and the formation of new collagen around individual silicone microdroplets in tissue [43,44].

Efficacy and safety — No randomized trials have evaluated the use of liquid injectable silicone for cosmetic soft tissue augmentation. In a retrospective study of 916 patients treated by a single practitioner with liquid injectable silicone (1000-centistoke purified polydimethylsiloxane) for rhytides, acne scars, lip augmentation, or facial contour defects, treatment appeared to be effective and safe [45]. Adverse effects included signs of overcorrection in 11 patients (1 percent) and hyperpigmentation in one patient. No granulomatous or other persistent inflammatory reactions were noted. A pilot study in which 77 patients were injected with silicone to correct HIV-associated lipoatrophy also found that treatment was well tolerated [46]. Adverse events were limited to mild and transient pain, edema, erythema, and ecchymoses.

The possibility of long-term benefit from silicone when used as a facial soft tissue filler was evident in a study in which little or no time-related change in the response of facial HIV-associated lipoatrophy to liquid injectable silicone was observed in all of three patients clinically assessed at both 18 months and 9 years after treatment [47]. In addition, a questionnaire-based study in which 179 patients treated with liquid injectable silicone for lip augmentation were successfully contacted after three to seven years found that 85 percent of patients rated their results as good or excellent [48]. Complications were limited to burning or local hematoma immediately after injection (6 percent) and small nodules attributed to improper placement of silicone (2 percent).

Although the risk for serious adverse effects appears to be less than 1 percent when purified, medical grade silicone is used with proper injection techniques [44-46,48-54], reports of granulomas, disfiguring nodules, lymphedema, and migration of liquid silicone after injection have led to lasting concern over the use of this agent [51,55-64]. Many complications associated with silicone injection have been the result of improper use, large volume injections, or injection of industrial-grade or adulterated products [44,65-67].

Granulomas may occur weeks to decades after injection and can be severely disfiguring and debilitating [51]. Treatments have included intralesional corticosteroids, oral minocycline or doxycycline, imiquimod, etanercept, and oral tacrolimus [44,68-71].

Use — Only pure, medical grade silicone should be used for soft tissue augmentation. In the United States, there are two commercially available products: Silikon 1000, and its more viscous counterpart, AdatoSil 5000. Due to its less viscous nature, Silikon 1000 is more suitable for cosmetic soft tissue injection [43].

The microdroplet serial puncture technique, defined as the injection of 0.01 mL or less at 2 to 10 mm intervals subdermally with a small diameter (eg, 27- to 30-gauge) needle, should be employed during treatment [44,72]. In most cases, no more than 0.5 to 1 mL of silicone should be injected per treatment session, and additional treatments should be separated by no less than one month [44]. Undercorrection is the goal of treatment, as further improvement occurs as new collagen forms around silicone microdroplets. Optimal collagen formation is attained by approximately 12 weeks [44].

AUTOLOGOUS FAT — Autologous fat transfer has been used for the correction of a variety of contour defects involving the face or body [73-79]. The main advantage of autologous fat in comparison to other soft tissue fillers is the lack of risk for hypersensitivity or foreign body reactions.

Objective data on the longevity of transplanted fat are limited, and the retention of fat has been estimated to range from 20 to 80 percent [80-83]. A variety of factors, including the harvesting technique, type of fat implanted, treatment site, injection technique, and experience of the injector can influence the efficacy of treatment [84-89]. The advent of new harvesting and processing techniques, such as the addition of platelet-rich plasma or adipose-derived stem cells to transplanted fat, may lead to improved viability [84-88,90]. Additional studies are necessary to explore the in vivo efficacy of these interventions.

Although the risk for hypersensitivity reactions is negligible, fat transfer procedures can be complicated by morbidity in the donor site, prolonged edema, infections, contour irregularities, and necrosis or calcification of the injected fat [91]. Fat emboli leading to stroke and vision loss have also been reported in association with this autologous fat transfer [1,2,92-102].

SUMMARY AND RECOMMENDATIONS

●Injectable filling agents are useful for the replacement volume lost from soft tissue due to a variety of factors. Permanent soft tissue fillers persist indefinitely in tissues. The potential adverse effects of permanent filling agents must be considered carefully prior to use. (See 'Introduction' above and 'Precautions' above.)

●Bellafill, a product that contains polymethylmethacrylate microspheres and bovine collagen, is injected into the deep reticular dermis and fills soft tissue through the stimulation of new collagen formation. Due to the bovine collagen component, patients must be skin-tested prior to use. Treatment of the lips and areas of thin skin should be avoided. (See 'Polymethylmethacrylate microspheres' above.)

●Hydrogel polymers, including polyacrylamide and polyalkylimide hydrogels, augment soft tissue through a direct volume filling effect. Injections are placed into the subcutaneous fat. (See 'Hydrogel polymers' above.)

●Liquid injectable silicone exerts its effects through acting as a direct volume filler and a stimulant for new collagen formation. Only pure, medical grade silicone should be used for injection, and a microdroplet serial puncture technique should be used. When improper formulations or injection techniques are utilized, silicone can induce severe adverse effects. Liquid injectable silicone should be used only by expert and experienced injectors. (See 'Liquid injectable silicone' above.)

●Autologous fat transfer provides soft tissue augmentation without the risk for allergic reactions. The degree persistence of fat in the treated site is variable and is dependent on multiple factors, such as clinician technique and treatment location. Fat embolus is a potential serious complication of this procedure. (See 'Autologous fat' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Alastair Carruthers, FRCPC, who contributed to an earlier version of this topic review.