Introduction

Injectable facial fillers have become a cornerstone of aesthetic medicine over the past two decades. Although soft tissue augmentation using industrial-grade silicones can be traced to early last century, widespread adoption of injectable fillers began in the 1980s with the advent of bovine collagen. Since the 1990s, soft tissue augmentation in order to fill lines and volumize or recontour the face has surged to become the second most popular non-surgical aesthetic procedure in North America and a widespread one beyond. Based on the axiom that an aged facial appearance is due in some part to dermal, subcutaneous, and osseous atrophy that naturally occurs over time, injectable facial fillers offer the ability to replace lost volume and restore youthful proportions, providing a foundation for facial rejuvenation. While resurfacing, relaxing, and redraping procedures help round out the facial cosmetic toolbox, aesthetic physicians now recognize the syringe as a mainstay of their armamentarium.

As with certain other non-surgical aesthetic modalities, facial filling is a product-driven procedure. Beyond an adroit injection technique, judicious use of the appropriate product in the proper location is a prerequisite to success. To know the art of injection, one must know the products, and the products vary significantly. In 2010 more than 200 fillers from over 60 manufacturers worldwide were available for tissue augmentation. Although some share characteristics that may predict a similar clinical response or comparable side effect profile, inappropriate substitution with a dissimilar product, particularly by a novice injector or non-core aesthetic provider, invites complications and ultimately patient dissatisfaction and compromises patient safety.

Products (Box 27.1, Table 27.1)

Fillers may be divided broadly into temporary and permanent categories. Temporary fillers are typically biologically derived products that are eventually broken down in vivo after a period of a few months to a few years. This category includes collagens and hyaluronic acids (HAs), the most predominant fillers worldwide. In contrast, permanent fillers comprise mostly synthetic materials that have an in vivo, biodynamic mechanism of action, causing collagen deposition via fibroplasia. For this reason permanent fillers are better at facial volumizing and deep structural augmentation than at ‘line filling’, which is best accomplished with temporary fillers. It is important to note that ‘permanence’ refers to a lack of degradation of the in vivo material over time rather than to a ‘permanent’ cosmetic result. Once placed, permanent fillers do remain in the skin and subcutaneous tissues enduringly without significant product loss. In contrast, permanent aesthetic results are seldom possible owing to continued tissue volume loss and other factors associated with the aging face. Nevertheless, duration of correction is more extensive than with temporary fillers. As such, permanent fillers are less ‘forgiving’. Experience and precise technique are required in order to achieve favorable outcomes.

Table 27.1 Selected permanent fillers by category and composition

HA, hyaluronic acid; PMMA, polymethylmetacrylate.

Polyalkylimide gel

Bio-Alcamid^® (Polymekon, Italy) was first launched in 2000 as an ‘endoprosthesis’ for the treatment of pectus excavatum, postoperative defects, and aesthetic use in the lips, cheeks, and nasolabial folds (Fig. 27.1). It contains a non-degradable, atoxic, non-immunogenic synthetic polyalkylimide cross-linked polymer suspended in water. Although it is approved in Europe, it is not currently approved by the FDA. Bio-Alcamid^® contains a ratio of either 3% or 4% alkylimide polymer to 97% or 96% sterile water. The product is not a particulate one, but rather a gel that is injected as a large bolus. It is meant to be injected subcutaneously rather than into the dermis. It does not require allergy testing and has been histologically shown to induce fibroplasia once implanted.

Figure 27.1 Granuloma of the nasolabial fold 4 years after injection of Bio-Alcamid^®.

Polyacrylamide gels

Polyacrylamide hydrogels contain a non-degradable, atoxic, non-immunogenic synthetic polyacrylamide cross-linked polymer suspended in water. Although polyacrylamide products listed have obtained CE marks (European conformity) for use in Europe, and are also available in Asia, none is currently approved by the FDA for use in the USA.

Aquamid^® (Contura International, Denmark) contains a 2.5% cross-linked polyacrylamide gel in 97.5% sterile water. It has been in use in Europe and worldwide since 2001, primarily for augmentation of nasolabial folds and lips, facial contouring, and for correction of HIV facial lipoatrophy (Fig. 27. 2). It is also a viscoelastic gel without particles. On histology, Aquamid^® appears as a multivacuolated non-birefringent material with a surrounding layer of thin fibrous connective tissue, macrophages, multinucleated giant cells, and lymphocytes.

Figure 27.2 Aquamid^® granuloma.

Amazingel^® (NanFeng Medical Science and Technology Development Co. Ltd, Shijiazhuang, People’s Republic of China) is an ostensibly similar product manufactured in China and available throughout Asia. Although it is readily available for underground purchase through internet distributors, it has not been extensively studied in the Western medical literature apart from other polyacrylamide products, and manufacturer’s product information is not readily available.

Polymethylmethacrylate

Polymethylmethacrylate (PMMA) is a non-resorbable, biocompatible material first synthesized in the early 1900s and used for such varied medical purposes as intraocular implants and bone cements. It was first engineered for soft tissue augmentation in the early 1980s in an attempt to provide a safe implant, with the theory that such a synthetic material might induce long-lasting tissue fibroplasia, in contrast to the temporary volume displacement seen with collagens. Currently available PMMA products are biphasic and suspended in either bovine collagen (Artefill, Suneva Medical, San Diego, CA) or carboxyglutamate (Metacril, private lab, Rio de Janeiro, Brazil).

Arteplast^® was the first-generation commercial PMMA product with 30–42 µm microspheres suspended in a gelatin carrier. It was used in Germany through the early 1990s, but was found to have a high incidence of granuloma formation within the first 18 months of implantation. Such complications were likely due to an inconsistent particle size and the presence of surface impurities found with processing methods.

Artecoll^® (Rofil Medical International, Breda, The Netherlands) (Fig. 27.3) was then introduced in 1992 as a second-generation product with an improved processing and washing method that reduced impurities. Significantly, the carrier was also reformulated, and the PMMA was suspended as a 20% product in 80% bovine collagen with 0.3% lidocaine for improved comfort. Because of the bovine collagen component, Artecoll^® requires allergy testing prior to injection. As such Artecoll^® is considered a biphasic implant, inducing augmentation through displacement with an early collagen component and later through a fibroplastic component caused by PMMA. In 1998, Artecoll^® was approved in Canada, and processing methods were further improved to reduce particle size variability, resulting in fewer incidences of late granuloma formation compared with Arteplast^®. Histology of skin biopsy specimens from areas treated with Artecoll^® show round, sharply circumscribed, translucent, non-birefringent particles, epithelioid histiocytes, multinucleated giant cells, lymphocytes, and occasional eosinophils surrounding the microspheres.

Figure 27.3 Artecoll^®.

Artefill^®, the third-generation iteration of PMMA, was further improved by enhancing the uniformity of the PMMA particle size and by eliminating nanoparticles that had plagued earlier formulations. The collagen matrix was also improved, and Artefill^® was approved by the FDA in 2006 based on safety studies performed earlier in the USA with Artecoll^®. Importantly, Artefill^® is the only permanent filler currently approved in the USA for aesthetic use. Whereas LIS is approved for intraocular implants, and thus may be used off-label for augmentation, Artefill^® may be used on-label for permanent aesthetic augmentation.

Acrylic hydrogel plus hyaluronic acid

Dermalive^® and Dermadeep^® (Dermatech, Paris, France) are biphasic permanent fillers composed of a mixture of 40% hydroxyethylmethacrylate and ethylmethacrylate particles and 60% biodegradable, fluid cross-linked, bacterially derived HA (Fig. 27.4). The acrylic particles are hydrophobic and irregularly shaped in a polygonal fashion. Dermalive^® contains acrylic particles 45–65 µm in diameter, whereas Dermadeep^® contains particles 80–110 µm in diameter. Both products are intended for injection in the deep dermis and subcutaneous regions, with the Dermadeep product indicated for deep subcutaneous injection only. As with most permanent fillers, injections into the superficial and mid-reticular dermis are not recommended. Both products were CE approved and available in Europe in 1998, but were withdrawn several years ago owing to the high incidence of complications. Neither product has ever been FDA approved for use in the USA. Histology of acrylic hydrogels in tissue reveals pseudocystic structures of different sizes and shapes containing polygonal, pink, translucent, non-birefringent foreign bodies with a surrounding granulomatous reaction of epithelioid histiocytes, multinucleated giant cells, some lymphocytes, and occasional eosinophils surround the microstructures.

Figure 27.4 Dermalive^®.

Treatment sites

Although appropriate indications and uses are beyond the scope of this chapter, it is worthwhile to note that permanent fillers have been extensively used throughout the face and body, and complications in each area have been reported. Documented facial complications have occurred in the eyelids, eyebrows, glabella, temples, cheeks, nose, nasolabial folds, labiomental folds, lips, and pre-jowl sulci. Traumatic surgical scars and atrophic acne scars have also been treated with permanent fillers, and have also been noted to have complications. Non-facial complications have been reported in the chest, breasts, penis, and buttocks as well, particularly when large amounts are injected in single sessions.

Complications

Most permanent fillers are found outside North America: throughout Europe, Asia, and Latin America. They are less common in Canada and uncommon in the USA, primarily because of the stringent approval requirements mandated by the FDA. Those submitted for approval to the FDA must undergo a rigorous clinical trials process prior to approval. The upside of such a process with respect to patient safety is that many complications are identified prior to widespread use. Such is the case for Artefill^®, the only permanent filler currently approved for aesthetic use in the USA. Outside of the USA, however, standards are less rigorous, when they exist at all. Europe requires all products used in the EU to have a CE certificate. However, such a certificate only ensures the technically correct manufacturing of the preparation and is not a guarantee of biological safety. Since clinical trials are not held before product approval, identification of filler complications must be done retrospectively and gathered through anecdotal series. This system allows the widespread use of most permanent filler products prior to the assurance of safety, and therefore the largest numbers of reports of permanent filler complications originate in Europe.

All cosmetic fillers, whether temporary or permanent, may induce adverse reactions (Table 27.2). Practically, it is useful to divide complications into early (0–14 days), late (14 days to 1 year), and delayed (beyond 1 year) reactions. Early reactions include erythema, pain, edema, bruising, and bleeding. Such reactions are inherently due to the invasive nature of the injection itself, are usually mild to moderate, and are typically self-limited to the first 14 days. They may be exacerbated, however, by poor technique.

Table 27.2 Filler complications

HSV, herpes simplex virus. Gray shading signifies reactions that take on extra significance due to permanent nature of filler.

Other early and late complications that may occur with both temporary and permanent fillers are due directly to injector variables. Inexperience and poor technique increase the risk of such complications. These include discoloration, vascular occlusion, embolism, cutaneous necrosis, undercorrection, overcorrection, asymmetry, contour irregularity, textural irregularity, and migration. Such complications, when seen with short-term resorbable and even long-term resorbable fillers, will eventually resolve as the product is resorbed. However, this group of undesirable effects is further complicated with the use of a permanent filler, as the augmenting agent will then no longer dissipate, but rather remain in vivo and serve as a continued stimulant.

The most vexing complications, however, occur because of as-yet poorly understood phenomena that result from host tissue interactions with the injected product in addition to bacterial interference. That is, they may be related either to the product itself or to the biological interaction of the product and host response to a foreign body, or foreign antigen in residence on the foreign body. Inflammation, infection, biofilm formation, foreign-body granulomas, and late-onset granulomas may all occur with both temporary and permanent fillers, but they occur disproportionately with permanent ones. These complications may occur in the early, late, or delayed phases, but tend to be skewed toward the late and delayed periods with permanent products. With permanent fillers increasing dramatically over the past decade, both in number of fillers and in number of patients treated, delayed adverse events are now more commonly seen. Furthermore, they are increasingly recognized as the most challenging aspects of permanent tissue augmentation owing to their tenacity and resistance to treatment. The characteristic of duration that makes a permanent product seemingly advantageous with respect to good results is also the one that engenders the least desirable group of complications. Not all complications are created equally, however, and the following adverse reactions are exacerbated, or take on extra significance, owing to the permanent nature of the filling product.

Overcorrection is an injector-dependent iatrogenic complication that is particularly troublesome with permanent fillers, and may occur with any of the permanent fillers (see Table 27.1). Overcorrection may be due to both too much product placed in a particular area as well as an underestimation of the degree of fibroplasia that will occur over time. With bovine collagens in the 1980s and 1990s, slight overcorrection was intentional at the time of treatment, and in fact was good practice, as a significant degree of the immediate correction achieved in the office would dissipate over the next few days. Gross volume displacement was the mechanism for achieving results with collagen alone, and further augmentation by fibroplasia was not expected. However, such a strategy does translate well into the realm of permanent fillers, as these depend heavily on augmentation by fibroplasia over time in addition to immediate gross volume displacement. To apply the overcorrection strategy of collagens to the permanent fillers is to invite disaster, as products that work by inducing collagenous deposition will continue to effect augmentation over several weeks to months afterwards. That is, tissue will be augmented beyond the immediate gross displacement due to product volume. For this reason, most permanent fillers should be placed in smaller amounts over multiple sessions spaced several weeks to even months apart in order to allow adequate time for tissue augmentation to occur between sessions. Otherwise, the physician runs the risk of injecting more product ahead of the oncoming augmentation curve – a set-up for overcorrection.

Asymmetry may occur with all permanent fillers by a similar mechanism (delayed fibroplastic augmentation), and care should be taken to ensure that relatively equal amounts of product are symmetrically placed. Such a strategy is elementary, but may sometimes prove challenging when working with permanent filler products that do not show an immediate volume correction. Cognizance of how much product is being placed as one proceeds through the injection is important, and the amount injected in each site or region should be recorded by a nurse scribe in real time rather than after the injection session is complete. Allowing adequate time between injection sessions in important as well in order to avoid placing too much product in a particular area.

Contour irregularities and textural irregularities may also occur with all of the permanent fillers and are due either to placement of the filler product too superficially (textural irregularity) or to placement of too much product too superficially (contour irregularities). As a rule, permanent fillers are best for deep placement, and should rarely be placed any more superficial than the deep reticular dermis. Most should be placed in the subcutaneous layer or deeper. Moreover, the particulate nature of some permanent fillers such as PMMA and the acrylic hydrogels does not allow for the smooth, soft, and pliable texture desirable for superficial placement. LIS, on the other hand, is a soft and pliable product, but may still lead to textural and contour irregularities when placed superficially. Fibroplastic fillers are essentially best used as deep fillers rather than superficial ones to avoid these complications. Caution should also be taken when injecting permanent fillers into areas with overlying thin skin. The lips are a notoriously unforgiving site for textural and contour irregularities owing to their anatomical characteristics – a thin cutaneous and mucosal layer overlying a region particularly sensitive to volume changes. All but the most experienced of injectors should avoid permanent fillers in the lips.

Migration of product along tissue planes to sites distant from injection has been the historical bane of LIS and is a concern with all permanent fillers when large volumes are injected. Injection of large boluses of silicone in a single site or single session has been well documented to increase the risk of product tracking along tissue planes to distant body sites. Indeed, historically adulterants have been intentionally added to silicone oils in an effort to prevent LIS migration, causing further complications owing to a host response to the adulterants. With LIS, using the microdroplet serial puncture technique prevents migration from occurring. The total surface area and resulting surface tension of a given volume of LIS are greatly increased when divided into multiple microdroplets. The increased surface tension holds the microdroplet in place. As fibrosis occurs in the ensuing weeks following LIS microdroplet deposition, a collagenous capsule is created around the microdroplet. The collagenous capsule results in further containment of the microdroplet and prevents migration to other tissue sites. LIS injected in large boluses demonstrates the physical properties of an oil and may track along the planes of least resistance, whereas microdroplets of LIS remain in place long enough for slow collagenous anchoring to occur. Moreover, the increased surface area of multiple microdroplets results in an increased total volume of collagen deposition and a subsequent improved clinical response. These principles may be extended to other permanent fillers as well to help avoid migration.

Complications in the final group are due to the host response to a foreign body, or product and host tissue interactions. Inflammation, foreign-body granulomas (Figs 27.5, 27.6), and late-onset granulomas (Fig. 27.7) may be due to the host immune response independent of infection, in which case the filler serves as the foreign body. However, they may also be due to bacterial biofilm formation, in which case both the filler and biofilm colony, or possibly bacteria that have been reactivated to a planktonic state, serve as a foreign-body nidus for pathological inflammation. Such complications have been seen, but poorly understood, for as long as permanent fillers have been utilized. Only in the last decade have theories regarding the etiology of such complications begun to coalesce and, although biofilms are now viewed as the likely culprit, more research is needed to fully elucidate all mechanisms involved.

Figure 27.5 Silicone granuloma (foreign-body granuloma).

Figure 27.6 Lower lip granuloma 6 months after injection of Aquamid^®.

Figure 27.7 Delayed-onset granuloma 2.5 years after injection with Dermalive^®.

While an exhaustive discussion of bacterial biofilms is beyond this chapter, this phenomenon is increasingly recognized as a possible etiology of permanent filler complications, including inflammation, recurrent infection, and granulomas. Bacterial biofilms are durable subclinical infections on the surface of a foreign body or prosthesis. They are living colonies that adhere to the foreign-body surface, in this case a microdroplet or bolus of permanent filler, and are self-encapsulated by a protective matrix to help avoid a host response. This protective capsule also helps the biofilm avoid penetration and destruction by antibiotics. Bacteria in biofilms may remain quiescent for months or years, then reactivate to a free planktonic state to cause inflammatory and infectious sequelae. Importantly, biofilm colonization may remain subclinical, as bacteria in the biofilm state are resistant to culture, likely explaining the ‘sterile’ abscesses seen at times with permanent fillers. The irregularities of particulate fillers (PMMA and acrylic hydrogels) may support biofilms, but they may also be found on the smooth surfaces of LIS microdroplets and any other permanent substrate. Indeed, biofilms may occur on temporary fillers as well, although they are less significant owing to the lack of substrate permanence. Bacteria that cause biofilms are likely introduced during injection through the skin or mucosa, and, while the normal flora encountered during injection can never be completely eliminated, some authors have begun to advocate adopting a sterile approach when injecting permanent fillers, in contrast to the clean approach used for many temporary fillers, with the idea that the chance for introduction of bacteria and subsequent biofilm formation may be reduced. Biofilms may play a more important causative role in hydrophilic gels in contrast to hydrophobic fillers. Christensen and colleagues found that, in polymer non-biodegradable gels, the major cause in the development of foreign-body granuloma was likely biofilm formation, which they found in all specimens of patients treated with Aquamid^®. Such a distinction has strategic implications for treatment, as biofilm causation on hydrophilic products may respond very well to antibiotic treatment. In contrast, hydrophobic fillers with microspheres may not be associated with biofilms, and may respond better to steroid treatment. One author (L.G.W.) has collected data on 52 patients with foreign-body granulomas after Artecoll^® or Dermalive^®. Neither biofilms nor bacteria could be detected in any patient with electron microscopy.

Inflammation manifesting as tissue erythema and swelling has been reported as a complication during both the late and delayed periods. It has been reported with both LIS and PMMA products, but appears particularly prevalent with the polyalkylimide gels, polyacrylamide gels, and acrylic hydrogels. The Injectable Filler Safety (IFS) Study published in Europe in 2007, the largest collection of documented complications to date, documented several types of adverse events found with both biodegradable and non-biodegradable products, but particularly implicated permanent fillers as associated with delayed and late inflammatory complications.

Foreign-body granulomas and late-onset granulomas are the most challenging complications to treat, and are the archetypal permanent filler complications. Both are manifestations of the host’s natural immunologic response to a foreign body. Indeed, injecting a foreign body into the host, even a biocompatible, non-toxic, inert one as the permanent fillers are, naturally elicits a granulomatous foreign-body response, characterized by the appearance of macrophages and foreign-body giant cells that arrive to both phagocytose the foreign material and deposit a fibroplastic collagenous response in an effort to ‘wall-off’ or neutralize it. This is, after all, the main mechanism of action for fibroplastic tissue augmentation. Ideally, the foreign-body granulomatous reaction creates a controlled fibrous microscar around the surface of the implanted filler, and augmentation proceeds in a controlled, limited, and predictable manner. However, if the fibroplastic response does not cease, either because of an ongoing interaction with the foreign product itself or because of the synergistic presence of bacteria, possibly present in a bacterial biofilm, the fibroplastic response will manifest as a foreign-body granulomatous complication. Late-onset granulomas result from the same phenomena, but typically occur at least 1 year after injection. These may be explained by continued host–filler interactions, as there is evidence that the ‘permanent’ microparticles and gels can be further modified by the host immune response even years after injection. Alterations to the surface of Dermalive^® particles have been documented by electron microscopy (EM) at 2 years, suggesting the product is altered in some fashion over time. This may be due to incomplete polymerization, where low-molecular-weight oligomers are left in the copolymer after final processing, or ongoing hydrolization. Most late-onset granulomas are likely explained, however, by the fact that bacteria that were introduced during injection had the opportunity to establish a biofilm around the injected product, and the biofilm has been reactivated or triggered to cause a host response, either by distant inflammation or infection or by further mechanical insult (Box 27.2). One aspect of the IFS Study evaluated the time elapsed until the appearance of adverse reactions after the injection of permanent fillers. Results showed that the mean time until the appearance of granulomatous reactions with polyacrylamide gels was 7.0 ± 10.6 months, with acrylic hydrogels was 12.3 ± 13.7 months, and with PMMA was 25.5 ± 37.1 months, demonstrating that late-onset granulomas are a significant potential complication with each of these products.

Evaluation methods

Histopathology, scanning EM, high-frequency ultrasound, bacterial culture, polymerase chain reaction (PCR), and fluorescent in situ hybridization (FISH) have all been used to evaluate granulomatous and infectious complications due to permanent fillers. Two questions naturally arise when a granulomatous complication ensues: (1) What product was placed? (2) Is the area infected?

The first question is best addressed through histopathology rather than history. Histopathological study of the lesions is the ‘gold standard’ technique to identify the responsible filler. With modern products, the particles of each filler have specific microscopic characteristics that allow identification (Fig. 27.8). EM may be used if histopathological studies prove inconclusive or further research is warranted (Fig. 27.9). Recently, high-frequency ultrasound has also been reported to identify and quantify the presence of filler in vivo, as well as to detect inflammation, granulomas, and the presence of different fillers in the same area. Nevertheless, evaluation of the exact offending agent may prove difficult when a patient presents with a history of injection with an ‘unknown’ product, or an illicitly injected one. A history of ‘silicone’ injections most often eludes detection. Although silicone may be detected on histopathology, the clinician has no method of testing whether or not adulterants were also present in the injected material. Non-purified and unknown products are often lumped under ‘silicone’ injections by patient history, and these should be distinguished from modern purified products meant for human soft tissue augmentation and appropriately injected.

Figure 27.8 Histology of Dermalive^® particles 4 years after injection, showing incomplete polymerization.

Figure 27.9 Electron microscopic photograph of an Artecoll^® microsphere surrounded by a multinucleated giant cell.

Courtesy Dr Josef Schroeder, Central EM-Unit, Department of Pathology, University Hospital Regensburg, Germany.

Detection of infection may be accomplished through routine bacterial cultures of tissue samples or exudate, but granulomas will often be negative on culture. This should not allay the concern for latent bacterial infection, as biofilms may be present and unculturable. In such cases, PCR may also be used to detect bacterial presence, but has also reportedly been negative in the setting of a suspected infection. FISH analysis may also help detect bacterial presence in the setting of a negative Gram stain and bacterial culture.

Treatment

Treatment of transient, self-limited filler complications due to injection, including erythema, bleeding, bruising, edema, pain, and herpes simplex virus activation, has been well documented in the literature. However, treatment of permanent filler complications in the second and third categories (see Table 27.2) presents a greater challenge. Several treatment methods have been reported in the literature, including topical products, systemic medications, minimally invasive procedures and modalities, and surgical excision. Treatment options are dependent upon the specific product and patient reaction, and should be individualized. One tenet is to avoid surgical excisions that will result in scarring until all other treatment options have been exhausted.

Treatment of complications in the second category, those due to procedural technique, becomes more challenging when the product placed is permanent, as there is generally no reversing agent as is seen with hyaluronidase for HA products. Discoloration may be treated with the appropriate laser for the target chromophore if one exists. Often, however, discoloration is due to a Tyndall effect and no target chromophore exists. Destruction with a carbon dioxide laser has been reported to be effective. Vascular occlusion, embolism, and cutaneous necrosis should be managed aggressively immediately upon recognition with vasodilating agents such as nitroglycerin paste. If the filler contains an HA component (Dermalive^®, Dermadeep^®), hyaluronidase may help dissolve a portion of the product. Undercorrection is simply treated in subsequent sessions. However, overcorrection, asymmetry, contour irregularities, and texture irregularities require the permanent filler to be reduced or removed in some fashion. Needle aspiration, liposuction, extrusion after incision with an angled blade or Nokor needle, and surgical removal have all been reported as effective with permanent fillers. Alternatively, an injected steroid may cause tissue atrophy and help counter slight irregularities, as is done with hypertrophic scarring. However, one must take caution not to create a ‘doughnut’ effect, with residual central prominence and surrounding atrophy. Migration is better avoided than treated, but surgical removal and liposuction are strategies for gross debulking of filler products in this situation.

Treatment of complications in the third category, which includes inflammation, infection, extrusion, and granuloma formation, are best geared toward the host immune response and infectious agents, or ultimately by product reduction and removal (Box 27.3). Treatment is difficult, and no one single method has reliably proven effective. Immunomodulators strike at the biological mechanisms underlying the granulomatous response. Topical immunomodulating treatments such as imiquimod have been reported effective for granulomas, likely through dampening of the local host immune response. Injected immunomodulating medications such as corticosteroids and 5-fluorouracil (5-FU) can also be effective for localized inflammation and granulomas (Fig. 27.10A,B). Oral steroids work by systemic, non-specific immunomodulation and may be required for severe reactions over short to medium durations. Systemic biological medications such as etanercept and infliximab have also been successful in altering the systemic immune response and decreasing granuloma activation and formation.

Figure 27.10 (A) Dermalive^® granuloma; (B) with improvement after treatment with intralesional 5-fluorouracil and steroids.

If product reduction or removal is necessary, minimally invasive techniques should be attempted first when practical, including needle aspiration, extrusion after incision, and liposuction. Ultimately, laser destruction or surgical removal may be necessary, but these modalities should be reserved for cases that are particularly problematic or that have not responded to more conservative therapies. Cassuto et al have described a minimally invasive, minimally scarring technique for laser-assisted evacuation of infectious lesions after hydrogels using a lithium triborate laser at 532 nm as well as a method for intralesional treatment of granulomas caused by gels containing microparticles with an 808 nm diode laser to facilitate product evacuation (Fig. 27.11A,B).

Figure 27.11 (A) Late-onset granulomas; (B) with improvement after treatment with the method described by Cassuto et al.

Combinations of the above treatments may also be successful. In one author’s experience (L.G.W.), a combination of oral steroids and intralesional 5-FU has been successful for late-onset granulomas after hydrophobic fillers (Dermalive^®, Artecoll^®).

Particularly with respect to late-onset granulomas, oral and / or intralesional antibiotic therapy should be attempted prior to, or at least alongside, other treatment modalities, as biofilms are likely the etiologic agent. Some authors feel that initial treatment with any agent other than antibiotics may allow the biofilm colony to thrive, possibly setting up an opportunity for long-term and recurrent granulomatous sequelae. Ultimately, a multimodal treatment approach may be necessary. A suggested therapeutic ladder for late-onset granulomas includes treatment with antibiotics first and foremost, possibly along with an immunomodulating agent such as a steroid. Failing that, escalating immunomodulating medications should then be used, followed by minimally invasive and ultimately surgically invasive treatments until a response is achieved.

Conclusion

All fillers are not created equal, and the aesthetic practitioner who wishes to treat the varied manifestations of facial aging and effectively guide patients to the desired outcome must know which ones will help accomplish patient goals and which ones will not. Myriad ‘permanent’ products are available, and most fall into particulate and non-particulate categories. All may cause the full spectrum of filler complications. Permanent fillers share the same complications seen with temporary fillers, plus additional ones made more significant by their non-resorbable nature. The most difficult complications, foreign-body and late-onset granulomas, are increasingly recognized with permanent fillers and may be attributed to product–host interaction as well as to bacterial biofilm formation, a difficult etiology to treat. A suggested therapeutic ladder includes antibiotic therapy, laser treatment with optic microfiber (as described by Cassuto et al), immunomodulation, and possibly eventual surgical removal. Permanent fillers abound, and will only increase over the next decade, as soft tissue augmentation has become the basis of an ever-expanding worldwide cosmetic industry. Even patients who do not have ready access to permanent fillers (such as in the USA) may easily find them abroad, or illicitly for consumption. The modern aesthetic physician must recognize the products, the complications, and the treatment strategies, although there is more work to be done to elucidate underlying causes and best approaches for success.