There are several different classes of synthetic dermal fillers and volume enhancers including semipermanent and permanent products available in the United States. Based on clinical and scientific evidence, this article reviews the chemical and polymeric properties, clinical data, patient selection, indications for use, injection technique, and adverse event profiles of permanent synthetic injectables currently used in clinical practice in the United States: medical-grade liquid injectable silicone and polymethyl methacrylate. Understanding the unique characteristics of these two products reinforces the advantages and disadvantages of each, including under what circumstances they should be used and why they perform the way they do.
Key points
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Bellafill (previously known as Artefill) has been marketed and sold in the United States as a permanent dermal filler for the correction of nasolabial folds since 2007 and received FDA approval for acne scarring in December 2014.
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Bellafill is currently the only “on-label” dermal filler approved by the FDA for the treatment of moderate to severe, atrophic, distensible facial acne scars on the cheeks of patients over the age of 21.
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The number of subjects affected by granuloma in the 5-year Bellafill postmarketing study was small (1.7%), with most events being mild to moderate in severity.
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Liquid injectable silicone was the first highly popularized injectable filler and is one of the oldest and longest lasting.
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Medical-grade silicone oil used off label for soft tissue augmentation with the correct indications and with the microdroplet technique is safe and economic permanent dermal filler.
Introduction
With the wide acceptance of temporary fillers, such as hyaluronic acid (HA), it is easy to see why permanent fillers with longer-lasting effects are quickly gaining popularity. According to the American Society for Plastic Surgery Procedural Statistics, there were 2.2 million soft tissue filler procedures performed in 2013, representing an increase of 13% over prior year. It is not uncommon for patients who experience superior results with temporary fillers to request more permanent enhancements. Their tolerance for the inconvenience and repeat cost of short-term, temporary fillers is waning as newer-generation fillers with longer durations are coming on the market (Joseph J, Eaton L, Cohen S. Current concepts in the use of Bellafill. Submitted for publication).
Before the modern era of injectable collagen and HA as dermal fillers, several unapproved materials were used. The first permanent facial filler in the twentieth century was paraffin oil. This was followed by a variety of other synthetic fillers, such as mineral oil, linseed oil, beeswax, and lanolin. Medical-grade silicone was approved in 1959 by the US Food and Drug Administration (FDA). Liquid injectable silicone (LIS) oil has been used as permanent soft tissue filler in aesthetics for more than half a century under the auspices of “off-label use of an approved medical device.”
There are currently more than 200 dermal fillers and volume enhancers available internationally. In the United States, the Center for Devices and Radiologic Health division of the FDA regulates injectable dermal fillers as medical devices. To receive a premarketing approval in the United States, a medical device manufacturer must demonstrate safety and effectiveness supported by human clinical studies for specific indications, such as “moderate to severe wrinkles and folds.” Approval typically requires clinical evidence supported by a US, multicenter, randomized pivotal study using the approved standard of care, which historically was collagen, as a comparator. With more new fillers coming on the US market, head-to-head clinical trials between products of the same or similar type are now the gold standard. Only first-in-class fillers tend to gain approval with a single-arm study, or by using a no-treatment control as a comparator.
Currently there is no universally accepted classification system for injectable fillers; however, the source of the filler may be categorized as natural/animal, synthetic, or natural synthetic. Fillers are further classified by the duration of effect, such as temporary, semipermanent, or permanent. Permanent fillers are basically nonresorbable. This article addresses two products that are currently being used as permanent soft tissue fillers in the United States: polymethyl methacrylate (PMMA) (eg, Bellafill) and LIS oil used in an off-label capacity.
Introduction
With the wide acceptance of temporary fillers, such as hyaluronic acid (HA), it is easy to see why permanent fillers with longer-lasting effects are quickly gaining popularity. According to the American Society for Plastic Surgery Procedural Statistics, there were 2.2 million soft tissue filler procedures performed in 2013, representing an increase of 13% over prior year. It is not uncommon for patients who experience superior results with temporary fillers to request more permanent enhancements. Their tolerance for the inconvenience and repeat cost of short-term, temporary fillers is waning as newer-generation fillers with longer durations are coming on the market (Joseph J, Eaton L, Cohen S. Current concepts in the use of Bellafill. Submitted for publication).
Before the modern era of injectable collagen and HA as dermal fillers, several unapproved materials were used. The first permanent facial filler in the twentieth century was paraffin oil. This was followed by a variety of other synthetic fillers, such as mineral oil, linseed oil, beeswax, and lanolin. Medical-grade silicone was approved in 1959 by the US Food and Drug Administration (FDA). Liquid injectable silicone (LIS) oil has been used as permanent soft tissue filler in aesthetics for more than half a century under the auspices of “off-label use of an approved medical device.”
There are currently more than 200 dermal fillers and volume enhancers available internationally. In the United States, the Center for Devices and Radiologic Health division of the FDA regulates injectable dermal fillers as medical devices. To receive a premarketing approval in the United States, a medical device manufacturer must demonstrate safety and effectiveness supported by human clinical studies for specific indications, such as “moderate to severe wrinkles and folds.” Approval typically requires clinical evidence supported by a US, multicenter, randomized pivotal study using the approved standard of care, which historically was collagen, as a comparator. With more new fillers coming on the US market, head-to-head clinical trials between products of the same or similar type are now the gold standard. Only first-in-class fillers tend to gain approval with a single-arm study, or by using a no-treatment control as a comparator.
Currently there is no universally accepted classification system for injectable fillers; however, the source of the filler may be categorized as natural/animal, synthetic, or natural synthetic. Fillers are further classified by the duration of effect, such as temporary, semipermanent, or permanent. Permanent fillers are basically nonresorbable. This article addresses two products that are currently being used as permanent soft tissue fillers in the United States: polymethyl methacrylate (PMMA) (eg, Bellafill) and LIS oil used in an off-label capacity.
Liquid injectable silicone
Overview
LIS was the first highly popularized injectable filler and is one of the oldest and longest lasting. LIS is not FDA approved as dermal filler; however, highly purified liquid silicone oil is frequently used “off-label” as a medical device for soft tissue augmentation, such as facial volumizing of lips and cheeks, or as filler for correction of facial wrinkles and folds, such as glabellar lines and nasolabial folds (NLFs). LIS is highly purified long-chain polydimethylsiloxane trimethylsiloxy terminated silicone oil, which is a sterile, generally inert, nonpyrogenic, clear, colorless oil with a viscosity of 1000 centistokes. Silicone oil is well accepted because of its natural feel and ease of injection, and is well tolerated in small volumes. The mechanism of action of silicone oil is the stimulation of a fibrotic reaction within the dermis, which is followed by low-grade inflammation and subsequent capsule formation.
Legal Status of Liquid Injectable Silicone
FDA guidance on “off-label” use of marketed drug and devices allows for physicians to use legally available products for an indication that is not in the approved labeling, providing that the physician uses good medical practice in the best interest of the patient, is well informed about the product, bases its use on firm scientific rationale and on sound medical evidence, and maintains records of the product’s use and effects.
Product Information
Two forms of LIS are FDA approved as medical devices in the United State, both for use in ophthalmology as retinal stabilizing agents. Silikon 1000 (Alcon, Ft. Worth, TX) is available in 10-mL glass vials filled with 8.5 mL of sterile silicone oil, and ADATO Sil-OI-5000 silicone oil (Bausch + Lomb, Rochester, NY) is available in prefilled syringes. Silicone oil is found in abundance from manufacturers in Mexico and South America; however, these formulations may contain impurities that can results in undesirable complications. Therefore, their use should be strictly avoided.
Patient Selection
Any facial defect can be examined for filling with silicone, including thin lips, nasal defects, smoker’s lines, glabellar frown lines, NLFs, poorly defined cheekbones or chins, or postsurgical deformities. Broad-based facial scars from trauma or surgery ( Figs. 1 and 2 ), and acne scars that disappear with manual stretching, are good candidates for treatment with silicone. Patients who are pregnant, are nursing, or who have active skin infections or uncontrolled systemic diseases are not candidates.
Silicone Injection: Microdroplet Technique
The ideal injection technique of silicone oil as a facial filler, after the treatment area has been cleaned and prepared, consists of microdroplet application with a 27-gauge by 0.5-inch needle, or with a 25- or 27-gauge microcannula into the dermal-subcutaneous junction. After entering the skin at a 30° angle, fluid silicone is injected in a retrograde fashion at 2- to 4-mm intervals, starting outside of the perimeter of the depressed area. For larger areas, multiple passes with a fanning injection technique may be required. Serial puncture technique of 0.05- to 0.1-mL aliquots of LIS is also a commonly used way to administrator the microdroplets of LIS in the area to be treated. Multiple treatment sessions are usually required to obtain the desired outcome. The microdroplet injection technique requires spacing the injections by at least a month or longer to allow adequate fibroplasia to occur. The injected microdroplets of silicone become surrounded by a capsule of collagenous fibrous tissue, which holds them in place and minimizes migration. In addition, this gradual fibroplasia ensures the injected area has the same texture as the adjacent tissue and that the product is not palpable.
The Case for Liquid Silicone: Clinical Data Supporting its Use for Facial Soft Tissue Augmentation
An abundance of published literature, dating back almost 40 years, provides clinical evidence that purified medical-grade silicone oil, when used judiciously by experienced clinicians for facial soft tissue augmentation, can provide safe and effective outcomes. In 1986 Webster and colleagues reported on 20 years of experience using LIS in postrhinoplasty patients. Three hundred forty-seven patients were treated with a total of 1937 treatments. The product was used conservatively with cautious injection of small amounts of silicone using the microdroplet technique. This study demonstrated that using very small doses of LIS is a safe and effective adjunct to cosmetic rhinoplastic procedures and can be used for correction of nasal defects that may not be amenable to revisional surgery.
Also, in 1986 Webster and colleagues reported on a 20-year experience using the microdroplet technique for liquid silicone injection performed for camouflaging furrows and groves, augmenting facial eminences, and elevating certain depressed scars. The report spanned 235 patients, including 2811 treatments. This study supported other work indicating induction of collagen deposition around the microdroplets, thus providing augmentation from volumes of collagen and silicone.
Hevia reported on his 6-year experience in treating patients with 1000-centistoke polydimethylsiloxane in his private practice. This retrospective chart review included 916 patients who received 5246 treatments in 3307 visits, with an average of 3.5 visits per patients and 1.6 treatments per visit. Treatment areas included facial rhytides, acne scars, lips, infraorbital, nasolabial, and general contours. Adverse events were limited to overcorrection in 11 patients (1%). This study concluded that PDSM-1000 was found to be effective and safe in the cosmetic practice setting.
Duffy reported on his 22-year experience involving the treatment of more than 3000 patients using LIS and concluded that pure silicone may be superior to any currently available agent in properly selected patients for permanent correction of certain types of defects. Jones and colleagues reported data on 77 patients suffering from human immunodeficiency virus–associated lipoatrophy who were treated with LIS. In this study, supple and even facial contours were routinely restored, all patients tolerated the treatments well, and no adverse events were noted.
In 2010, Moscona and Fodor published the results of a 179 patient retrospective study of LIS for lip augmentation. The microdroplet technique was used in all cases, and not more than 1 mL per lip per session was injected. Long-term results (3–7 years), satisfaction level, and complications were evaluated. Eighty-five percent of the patients reported excellent or good results. Most (76%) patients considered their lips to be as soft as they were before treatment. No complications were recorded for 91.1% of the patients. Complications encountered by the rest were minor and temporary, such as ecchymosis and hematoma in 6.2%, and invisible but small palpable nodules in 2.2%. This study concluded that LIS is safe for a period of 3 to 7 years and gives a high level of patient satisfaction with minimal complications.
A 10-year experience across 206 cases using LIS for soft tissue augmentation was conducted by Jacinto in the Philippines. Most (82%) patients were female and between the ages of 21 and 30 years. Fifty-five percent were treated for acne scars, 42% nasolabial grooves, 13.5% marionette lines, 12.6% glabellar lines, 9.8% postvaricella scars, 9.3% inframalar depressions, 1.8% posttraumatic scars, 1.4% lipodystrophy, 1% lip augmentation, 0.9% sleep lines, and 0.4% contour defects. Seventy-two percent had excellent results, 18% had good results, 2% had fair results, and only 0.5% had poor results. This study concluded that silicone oil injected with the correct indications and with the microdroplet injection technique is a safe, economical, and permanent dermal and subcutaneous filler.
A simple yet permanent method of tissue augmentation using an emulsification of LIS and HA was reported in 2012 by Fulton and Caperton (N = 95) in which they mixed 0.5 mL of 1000 centistoke LIS with 1 mL of cross-linked HA, such as Restylane or Juvederm, into an emulsion between two 3-mL Luer-lock syringes connected with a Luer-lock to Luer-lock adapter. The emulsion was then injected through either a 27-gauge needle or through a 25- or 27-gauge microcannula into the mid-dermis, subcutaneous tissue, or periosteum. They found the emulsion provided immediate improvement in depressions, folds, and facial contours. It was most beneficial for distensible acne valleys; NLFs; glabellar frown lines; augmentation of the vermillion border of the lips; and projection of the nose, cheekbones, and chin. Exterior nasal deviations and soft tissue defects were also improved. Complications were minimal and included temporary bruising, erythema, and mild edema. Small, temporary nodules were easily leveled with massage and no cases developed silicone granuloma. This study found that treatment remained stable during the 2-year follow-up period.
Histologic evidence
Zappi and colleagues performed 35 skin biopsies, which were examined by light microscopy on 25 patients who had been injected with liquid silicone for soft tissue augmentation procedures between 1 and 23 years prior. The microscopic study revealed in 100% of the cases the continued presence, in significant amounts, of the silicone previously injected into the target areas, where it failed to elicit any significant adverse reactions. This study concluded that silicone, because of its high performance and its inertness, reflected by the lack of any adverse reactions to its presence in the target site, should be regarded as valuable filler, at least for the correction of small depressed facial scars.
Complications of Liquid Injectable Silicone
Complications of LIS range from minor to serious. Minor complications include erythema, ecchymosis, and edema that occur at the injection site, which are not specific to LIS and are seen with other fillers.
Injectable silicone, especially of questionable or adulterated sources, has led to some undesirable local and systemic effects. Although considered biologically inert, this material has been implicated in a variety of adverse reactions, including reports of chronic cellulitis, inflammatory nodules, lesions, migration, ulceration, and silicone granuloma formation. Often these complications are the result of the use of industrial grade silicone, which contains many contaminants, injected by unlicensed or unskilled practitioners.
All dermal fillers have the potential to cause complications. Unintended reactions such as granulomas, infections, and vascular occlusion, can follow treatment with LIS. Injecting physicians must be aware of these potential complications because early medical care and treatment may help minimize the consequences for the patient and the physician.
Silicone Discussion
LIS has many individual characteristics that physicians would classify as “ideal” for a soft tissue augmentation agent. It is odorless, colorless, nonvolatile, noncarcinogenic, thermally stable to allow heat sterilization, chemically stable when stored at room temperature for long periods of time, and does not have to be reconstituted before use.
Over the years, the use of LIS for soft tissue augmentation has been associated with a great deal of controversy and negative publicity. Although historical complications have occurred, likely resulting from the presence of adulterants and impurities, modern purified silicone products approved by the FDA for injection into the human body may be used with minimal complications when strict protocol is followed. Although its use remains controversial, LIS is an important and effective dermal filler for long-term correction of scarring and facial contour defects.
Although the quality of the product has significantly improved, in terms of purity, several severe adverse events have been published, and the product remains off-label in the United States. The treatment time is limited, the patient discomfort and morbidity are minimal, and the results are long lasting ; however, physicians must be advised that the misuse of this agent or other materials masquerading as medical-grade LIS have created a pervasive climate of distrust and a veritable minefield of negative medicolegal possibilities.
Medical-grade silicone oil used off label for soft tissue augmentation, with the correct indications and with the microdroplet injection technique, is a safe and economical permanent dermal filler. Rare permanent erythematous papules and transient ecchymosis appear on deep dermal injections. Unfortunately, no large-scale and randomized FDA clinical trials have been conducted seeking FDA approval for an aesthetic indication for LIS; therefore the jury is still out on its confirmed safety and effectiveness for soft tissue augmentation. Despite this fact, LIS has still been used successfully in facial aesthetics for more than half a century.
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