Take a look at the current crop of temporary, permanent, and semipermanent soft-tissue injectable fillers

Until the ultimate injectable filler is discovered, a plastic surgeon’s best bet is to carefully select the substance and technique that best matches the target anatomy. Here, we explore a brief history of injectable fillers and review what research and practice have uncovered thus far.

Soft-tissue augmentation has become an integral part of a dermasurgery practice. Soft-tissue fillers date back more than a century, when tissue augmentation was first attempted with autologous fat.1 Since then, different substances have been used to fill soft-tissue defects. Injectable paraffin was used in the early 1900s, followed by liquid silicone 50 years later. Both substances risked causing irreversible dermal and subcutaneous granulomatous reactions. One of the greatest advances in soft-tissue augmentation was the development of injectable bovine collagen, which received FDA approval in 1981 as the first xeno­genic soft-tissue filler.2

Today, the search for the ideal filler has resulted in a growing list of biologic implants, including autologous, semisynthetic, allograft, and synthetic materials. These soft-tissue fillers can be organized into temporary, permanent, and semipermanent categories. Semipermanent fillers are categorized as those that last 2–5 years.


Temporary Fillers

Filler Characteristics
Filler Gauge Needle Injection Site Technique Zyderm®/Zyplast® 30 Superficial dermis/mid-dermis Serial puncture CosmoDerm®/CosmoPlast® 30 Superficial dermis/mid-dermis Serial puncture Restylane® 30 Mid-dermis Serial puncture threading Sculptra® 26 Subcutis Criss-cross threading Radiesse® 26 Subdermal Fanning with molding Artefill® 27 Subdermal Threading

Injectable Bovine Collagen

The introduction of bovine collagen revolutionized the filler industry in the United States. Its use became widespread beginning in the 1980s. Bovine collagen comes in three forms that vary in concentration and density. These represent the “gold standards” of injectable fillers, against which all the newer materials are measured. These implants are sterile, purified bovine dermal collagen (mostly type I) in a phosphate-buffered saline with 0.3% lidocaine. The densest bovine collagen implant differs in that it contains glutaraldehyde cross-linked collagen, which makes the product less prone to collagenase degradation, as well as less immunogenic.3 The two less-dense bovine collagen fillers contain lidocaine, which reduces pain on injection. Because bovine collagen may produce an allergic reaction, skin testing is required. The test site is observed after 1 month for erythema, induration, or tenderness. About 3% of individuals develop a positive response, and 1%–2% of further patients develop an allergic reaction despite a negative skin test. Therefore, a second test on the contralateral arm is recommended 2–4 weeks later.2 

The two less-dense implants are injected into the superficial papillary dermis with a 30-gauge needle using a serial puncture technique almost parallel to the skin surface, such that a yellow blanching is observed when the material flows into the superficial dermis. The denser implant is injected into the mid or deep reticular dermis at more of an angle to the defect and is placed deeper without blanching or overcorrection.4

Indications for thin bovine collagen include horizontal forehead lines, glabellar lines, crow’s feet, nasolabial lines, fine lip lines, marionette lines, and acne scars. Superficial rhytides respond best with a duration of about 3 months and slightly longer with the thin implant of higher concentration. The denser bovine collagen works best for deep nasolabial folds, marionette grooves, deep acne scars, and lip augmentation. Its results typically last longer, with reported durations of 3–6 months.5 Because of the rare possibility of vascular compromise and tissue necrosis, it is contraindicated in the glabella.3 

Adverse reactions to injectable bovine collagen include nonhypersensitive reactions such as bruising, superficial beading, herpes reactivation, and bacterial infections. Hypersensitive reactions are typically associated with antibovine collagen antibodies that do not cross-react with human collagen but do result in redness and swelling at the treatment site. Rarely, systemic symptoms may occur. A second form of delayed hypersensitivity may occur as sterile abscesses or cysts at the treatment site. These can be treated with incision and drainage, and/or intralesional steroids. However, they can persist for more than 2 years.2

Autologous Collagen

Autologous collagen is an injectable dermal filler derived from cultured auto­logous fibroblasts. An autologous graft is obtained from a 3-mm punch biopsy from postauricular skin. The sample is shipped to the manufacturer, placed in a culture medium, grown, and sent for processing. A test dose of cultured fibroblasts is returned to the physician in 6 weeks for treatment at 8 weeks after the original biopsy. It is believed that the fibroblasts will stimulate the patient’s own collagen formation over the ensuing several months after implantation. One study found that 92% of patients were satisfied with the results 1 year after treatment, but longer-term studies have not yet been performed.6 It has been used in scars, wrinkles, and stretch marks, and some claim results lasting as long as 2  years. Several years ago, it was withdrawn from FDA consideration, but it has been reintroduced and has just completed Phase III clinical trials in the United States.7 

Allogeneic Collagen

One form of allogeneic collagen is a suspension of injectable collagen matrix derived from human donor cadaveric tissue that has undergone extensive screening for bacteria and viruses. It has been reported to last longer than bovine collagen—up to 6 months—and is useful in people allergic to bovine collagen. There have been no reported allergic reactions to this product; however, it is no longer available for use.3

A second form is an acellular dermal graft harvested from cadavers or tissue banks so that only a dermal matrix (collagen, elastin, and glycosaminoglycans) remains. A micronized injectable form of this has recently been developed. A study comparing this form and thick bovine collagen for lip rejuvenation found no significant differences in results at 3 and 6 months; but at 12 months, better results were seen with this micronized cadaveric collagen.5

There are also two recombinant human collagen fillers obtained from cultured newborn foreskin fibroblasts. Like bovine collagen, these syringes are mixed with lidocaine to minimize pain on injection. Because they are derived from human material, they do not require skin testing for hypersensitivity reactions. These products appear to be no more durable than their bovine counterparts.5 Human recombinant fillers are in common use today; in fact, their use has replaced much of the original bovine collagen filling agents used in the 20th century.

Autologous Fat Injection

After tumescent infiltration of local anesthesia, autologous fat can be harvested either by syringe or aspirator. Common donor sites are the thighs, buttocks, and abdomen. Fat is then separated from serum, often via centrifuge. Recipient sites that respond well to separated fat injection include the dorsal hand, depressed temples or cheeks with subcutaneous atrophy, and deep nasolabial folds. Injection placement of fat can be either in a subcutaneous or fascial plane. Swelling and bruising are common.2 In published reports, duration of correction varies from a few months to 2 years.1 

Hyaluronic Acid Derivatives

Hyaluronic acid is a naturally occurring, ubiquitous polysaccharide that is identical in all species. Its high affinity for water provides for hydration and skin turgor. Currently, there are four FDA-approved hyaluronic acid derivatives. These fillers last longer than bovine or cultured human collagen, typically around 6 months. One FDA-approved filler is a cross-linked hyaluronic acid derived from rooster comb. It is a medium-density product recommended for fine- to medium-depth wrinkles and lip augmentation. Adverse reactions occur in fewer than 2% of patients and include erythema, ecchymosis, and acne. It has been found comparable to thick bovine collagen in duration.1 Recently, a version with a larger particle size has been approved for moderate to severe wrinkles and folds. Studies have found it comparable to its medium-density counterpart in correcting nasolabial folds at 12 weeks.8 

The two other FDA-approved hyalu­ronic acid agents are nonanimal-stabilized hyaluronic acid (NASHA) fillers produced by the fermentation of Streptococci bacteria. One of these FDA-approved fillers is part of a family with four different versions, which differ in gel particle size. All four of these contain a higher hyaluronic acid concentration than the animal-derived hyaluronic acid fillers. As the particle size of the filler increases, the depth of injection increases—as does the size of the soft-tissue defect that can be corrected. The smallest particle-size filler of this family is injected into the upper dermis for very superficial and fine wrinkles, and the largest is placed in the subcutaneous plane for deep-volume correction (such as shallow cheek defects). Currently, only the second-densest NASHA filler of this family is FDA approved. A randomized, double-blind study comparing the efficacy and tolerability of this NASHA filler versus thick bovine collagen in the correction of nasolabial folds found that this now FDA-approved NASHA filler outlasted the bovine collagen (at least 6 months after treatment) but was more painful.9 Because of its biocompatibility, hypersensitivity reactions to the NASHA implants are extremely rare, and, when they do occur, the most likely etiology is an impurity of bacterial fermentation.10

There is another nonanimal-stabilized hyaluronic acid filler family that is not yet FDA approved but has been used successfully in Europe and Canada. It is supplied in three densities ranging from light to high. Its medium-density product has a similar user profile to the approved NASHA fillers. The highest-density form is best used for deeper defects, such as subcutaneous fat atrophy. It is a more viscous gel, and it has been found to be effective for 12–15 months after treatment.5 


Permanent Fillers

Silicones are synthetic polymers of dimethylsiloxanes, and they are no longer approved as an injectable for cosmetic purposes due to possible serious long-term complications. However, one form recently approved as an ophthalmic device for a retinal tamponade has re-emerged as off-label for soft-tissue augmentation. The silicone is injected intradermally via the microdroplet technique, which results in a gradual improvement corresponding to collagen deposition around the silicone droplets. Lips and nasolabial folds are common locations for silicone placement. Potential adverse events include permanent nodularity and granulomatous dermal reaction. One recent study showed its efficacy in the treatment of HIV facial lipoatrophy.11 

Another permanent filler is a combination suspension of polymethylmethacrylate (PMMA) microspheres in 3.5% bovine collagen solution and 0.3% lidocaine. The collagen is soon degraded after injection, leaving the permanent placement of PMMA, which provides a scaffold for the deposition of new collagen and fibroblasts in the first 3 months. It is injected with a 27-gauge needle deeply into the reticular dermis, just above the junction between the dermis and the subcutaneous tissue. It is best used for deeper and well-defined wrinkles. Patients experience optimal results after just 3 months, and results may be maintained for at least 1 or 2 years in 90% of patients who return for periodic touch-ups. Because of the bovine collagen component, skin testing for hypersensitivity reactions is needed. Adverse reactions include swelling, redness, pain, and granulomatous lumps.12 FDA approval is pending.

Two new permanent fillers used in Europe but not yet FDA approved are NASHA combination fillers. They are comprised of 60% by volume of nonanimal stabilized hyaluronic acid and 40% by volume of acrylic hydrogel particles (hydroxyethylmetacrylate and ethylmetacrylate). While the hyaluronic acid is broken down over a few months, the nonreabsorbable acrylic hydrogel becomes encapsulated by a fibrous connective tissue such that it remains for several years. The thinner version is used for medium to deep wrinkles of the glabella and nasolabial folds, lip outlines, and depressed facial scars. The thicker version is indicated for deep depressions and deformities requiring large volumes. Rarely, local granulomatous reactions can occur.14


Semipermanent Fillers

One semipermanent filler is a synthetic, biocompatible, biodegradable polymer of poly-L-lactic acid that stimulates the production of new collagen through a foreign-body reaction. It works best in treating depressed areas such as hollow eyes and depressed cheeks. The most common adverse reaction is the presence of small, subcutaneous nodules at the treatment site. It is approved in the United States for HIV facial lipoatrophy, and trials are currently under way for other cosmetic uses. After reconstitution with sterile water and lidocaine, it is injected with a 26-gauge needle into the subcutis using a criss-cross threading technique. Studies have shown optimal results at 28 months post-treatment.5

A second semipermanent filler is a suspension of calcium hydroxylapatite microspheres in a carboxymethylcellulose gel. It is approved for the treatment of urinary stress incontinence and vocal cord paralysis, and its use as a soft-tissue filler is currently off-label. It is best given in areas of subcutaneous atrophy and for deep lines of the nasolabial folds. The most common complication was palpable nodules that typically occurred in the lip mucosa; for this reason, it is not indicated for lip augmentation. Recent studies show optimal results 6 months post-treatment, but other reports show persistence for 7 years in other body parts.13 


Conclusion

While the ideal filler has yet to be developed, there are ever-expanding options from which to choose. An optimal filler may actually be best accomplished by combining fillers of varying depths. The art of soft-tissue augmentation will continue to grow exponentially, and this field has a promising horizon.

Suneeta S. Walia, MD, is a dermatology resident, and Lawrence J. Green, MD, is an assistant professor of dermatology, at George Washington University in Washington. They can be reached at swalia@gwu.edu or (202) 741-2618.


References

  1. Bolognia J, Jorizzo J, Rapini R, et al. Soft tissue augmentation. Dermatology. London: Mosby; 2003: 2439-2449.

  2. Klein AW. Skin filling – collagen and other injectables of the skin. Dermatol Clin. 2001;19(3):491-508.

  3. Cheng JT, Perkins S, Hamilton M. Collagen and injectable fillers. Otolaryngol Clin North Am. 2002; 35(1):73-85.

  4. Freedberg I, Eisen A, Wolff K, et al. Substances for soft tissue augmentation. In: Fitzpatrick’s Dermatology in General Medicine. 6th ed, New York: McGraw-Hill; 2003:2560-2564.

  5. Werschler WP, Weinkle S. Longevity of effects of injectable products for soft-tissue augmentation. J Drugs Dermatol. 2005;4(1): 20-27.

  6. Boss WK, Usal H, Fodor PB, Chernoff G. Autologous cultured fibroblasts: a protein repair system. Ann Plast Surg. 2000;44: 536-542.

  7. Elson M. Human-derived materials for soft tissue augmentation – noncombination fillers. Cosmetic Derm. 2005;18(1):71-74.

  8. Pipeline previews. J Drugs Dermatol. 2005;4(1):116.

  9. Narins R, Brandt F, Leyden J, et al. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003;29(6):588-595.

10. Friedman P, Mafong E, Kauvar A, Geronemus R. Safety data of injectable nonanimal stabilized hyaluronic acid gel for soft tissue augmentation. Dermatol Surg. 2002;28(6):491-494.

11. Jones D, Carruthers A, Orentreich D, et al. Highly purified 1000-cSt silicone oil for treatment of human immunodeficiency virus-associated facial lipoatrophy: an open pilot trial. Dermatol Surg. 2004; 30(10): 1279-1286.

12. Lemperle G, Romano J, Busso M. Soft tissue augmentation with Artecoll: 10-year history, indications, techniques, and complications. Dermatol Surg. 2003;29(6):573-587.

13. Sklar J, White S. Radiance FN: a new soft tissue filler. Dermatol Surg. 2004;30(5):764-768.

14. Sidwell RU. Localized granulomatous reaction to a semi-permanent hyaluronic acid and acrylic hydrogel cosmetic filler. Clin Exp Dermatol. 2004;29(6):630-632.