While the dermal filler market has surely blossomed in the past decade, the search for and use of filler agents goes back to the 1890s, when human fat was first used as a dermal filler. By the early 1900s, paraffin was used as dermal filler to correct the absence of a testicle in a patient who was castrated for tuberculous epididymitis. While met with enthusiasm at first, the filler had disastrous results over the first 20 years of the 20th century. Silicone emerged in the 1940s, but it too was quickly associated with adverse events. The first collagens came to market in the US about three decades ago, with bovine collagen that required skin testing being approved first, followed by human collagen. They lasted a mere two to three months however, and thus the search for the perfect filler was still on.

In 1996, the first hyaluronic acid (HA) filler was approved in Europe, paving the way for a range of subsequent HA fillers. Hyaluronic acid is a carbohydrate polymer found ubiquitous in all living organisms. Though not permanent, HA was safe and lasted much longer than collagen. This century has seen the emergence of calcium hydroxyapatite (CaHA) based fillers, HA-plus-lidocaine fillers, and polycaprolactone fillers, the latter currently outside the United States only.

Demand for fillers is high and continues to grow. The market for HA fillers—at $40 million in 2000—grew to $300 million by 2005.

Understanding HA Fillers

With the growth of the hyaluronic acid filler market, dermatologists have become more aware of specific features of the various formulations that influence their placement and performance. Understanding these features will help clinicians better understand how new and emerging fillers fit into the treatment portfolio.

One of these factors is cross-linking. Naturally occurring hyaluronic acid is highly soluble, so cross-linking (also called stabilization) is used to form a water-insoluble polymer hydrogel network that is more resistant to degradation. The degree of cross-linking varies across formulations.

Relatively new to the market, non-particulate, or monophasic, gel fillers are single cross-linked with an ether bond in a two-stage process. First, long HA chains are bound with BDDE (1,4-Butanediol diglycidyl ether). Then, BDDE is used to bond short chains to the newly formed network. This network is a homogeneous mass of short- and longchain HAs, but it is generally weaker than the network of particulate HA. In monophasic gel fillers, the concentration of HA and/or the cross-link density are the primary determinants of durability. Note, however, that the nature of monophasic gels may make them less susceptible to antioxidant degradation than other HA formulations.

For particulate HA fillers, durability depends on density of cross-linking, concentration of HA, and the size of the HA particles. Like gels, most particulate fillers use BDDE for cross-link bonding, although divinyl sulphone (DVS) is sometimes used.

Smaller particles are appropriate for more superficial placement, while the depth of possible placement increases in relation to the particle size. Since smaller particles have a larger surface area, they are more rapidly degraded once placed in the skin and will require more frequent treatments, relative to larger particle fillers.

Another important feature of HA fillers is their elastic modulus, expressed as G'. This is essentially a measure of the gel's ability to withstand changes from external mechanical forces. Coupled with the measure of cohesivity, which reflects resistance to mechanical breakdown, G' can be an indicator of a gel's lifting effect. Lift capability increases as G' and cohesivity increase.

HA Fillers

Restylane Vitale and Restylane Vitale Light (Galderma/Qmed) are extensions of the Restylane line currently not available in the US. Restylane Vitale is intended for placement in the mid- to deep-dermis of patients with mature, thick, photodamaged skin. Like its counterparts, Restylane and Perlane, it has an HA concentration of 20mg/mL. Due to its hydrating effect, the filler improves elasticity and smoothness of the skin with a profound and long-lasting effect, due to the fact that the HA is cross-linked.

In contrast, Restylane Vitale Light has an HA concentration of 12mg/mL and is intended for placement in the mid-dermis. It restores a more fresh and natural tone and is intended for younger, thinner, more delicate skin with less photodamage.

Both Restylane Vitale and Restylane Vitale Light can be injected using an injector pen (Fig. 2) that facilitates deposition of uniform aliquots of 200 units of 10 microliters. The pen design may enhance comfort and control for the injector, given that treatment requires the precise placement of multiple, reproducible dosages of gel.

Also available outside the US from Galderma/Q-med is Macrolane for body contouring. This HA-based gel is developed specifically for use to define the pectoral muscles of men, enhance the buttocks of men and women, and even to shape the calves or reduce the appearance of large surgical scars. Treatments take 60-90 minutes. The product is no longer being promoted for use as a breast enhancement agent as it may interfere with mammogram readings.

Among the Juvederm (Allergan) products, Juvederm Voluma is currently marketed outside the US, including in Canada. It is a facial contouring or volumizing agent intended for deep dermal placement and not a wrinkle filler. In company-reported trials, results lasted up to 18 months. No migration has been reported with the agent. The product is highly cohesive and has a significant lifting effect when injected.

The agent in third place (after Allergan and Q-med/Galderma) in the worldwide HA filler market is not available in the US. The Teosyal PureSense (Teoxane Laboratories) range with lidocaine includes agents for indications from deep to superficial. Initial FDA studies have been completed.

One of the newest fillers on the US market, Belotero Balance (22.5mg HA/ mL, Merz Aesthetics) is part of a range of products developed by Anteis SA and marketed outside the US. Belotero Soft (20mg HA/mL) and Intense (25.5mg HA/ mL) round out the line.

Non-HA Fillers

Calcium hydroxyapetite (CaHA 30%) in a gel carrier (Radiesse, Merz Aesthetics) is available in the US, and according to 2007 data from the American Society for Aesthetic Plastic Surgery, the filler is the fastest growing category. The agent is intended for long-term volumization, with histological evidence showing that over time the CaHA microspheres stimulate new collagen growth. This new collagen persists even as the body naturally degrades and eliminates the CaHA. In one study involving 1,000 patients, more than 80 percent reported durability of effect of 12 months or more. Radiesse has a higher G' than most HA fillers.

The product is preferably mixed with lidocaine. This decreases the pain of injection in addition to changing the extrusion force of the agent, allowing the material to flow easily.

Polycaprolactone (PCL; Ellanse, AQTIS Medical) filler is not available on the US market, although PCL is FDA approved in a suture and as a drug delivery system. Like CaHA, PCL (30 percent) in a carrier gel functions as a filler to provide immediate volumization. The PCL particles stimulate neocollagenesis, building a tissue scaffold that persists even after the PCL is naturally reabsorbed. Multiple formulations are available with different durability, intended to last from one to four years. The company refers to this as “tunable longevity.” According to data cited by the marketer, up to half of patients who have tried a filler eventually discontinue because they become dissatisfied with the short duration of effect. With its longevity up to four years, Ellanse is targeting those patients.

An Expanding Field

The global filler market continues to expand, and US physicians truly are at the tip of the iceberg. Variations of HA filler lines expand the options for filling and volumizing aimed at shallow wrinkles and overall “refreshing” of the skin to deeper wrinkles and contouring. New developments and novel fillers are also providing new opportunities not only to fill wrinkles but to contour the face and other body sites. This remains an exciting time for injectable therapies.

Dr. Galadari has no conflict of interest in this material. He has received honoraria from Allergan, Merz, Teoxane, Q-med, and Aqtis and clinical trial support from Aqtis.

Hassan I. Galadari, MD, FAAD is Assistant Professor of Dermatology, Residency Program Director, at the College of Medicine and Health Sciences at United Arab Emirates University. He is also a Consultant Dermatologist at Tawam Hospital/ Johns Hopkins Medicine.