Safety of Dermal Fillers

Facial wrinkles are the most visible morphological change of the aging process.¹ Therefore, several rejuvenation methods have been developed to cure these unloved signs of the times, such as botulinum toxin, laser treatments as well as topical active ingredients.^2-4 Recently, dermal fillers have become a popular means of addressing contour defects and soft-tissue augmentation.^5-7 Current statistics from the American Society for Aesthetic Plastic Surgery indicate that in 2011, more than 1.2 million people were treated with hyaluronic acid injections in the United States. Following chemodenervation with botulinum toxin, skin rejuvenation with hyaluronic acid is on the second position of the Top 5 Nonsurgical Procedures of 2011 in the United States.⁸ Although this minimally invasive treatment is considered to be safe, adverse events (AEs) occur.⁹ Between 2003 and 2008 the US Food and Drug Administration received 930 post-marked reports of adverse event, 823 were deemed severe, and 638 required medical treatment and follow-up. Referring to the systematic review from Sturm LP et al.,⁵ the main reported severe AEs are allergic reactions, granuloma and lump formation, abscess formation, and infections. This review is to assess the safety of injectable dermal fillers for the management of lines and rhytids on the aging face.

“Injectable facial implants, also known as wrinkle fillers, dermal fillers or facial soft tissue fillers, are medical device implants approved for medical use by the Food and Drug Administration (FDA) to fill in facial wrinkles in order to create a smoother appearance.”¹⁰ Throughout the world, approximately 150 different types of dermal fillers are available. Corresponding guidelines of US Food and Drug Administration injectable dermal fillers can be classified into two main categories, namely temporary (absorbable) fillers, and permanent (non-absorbable) fillers. Innovative cell therapies form the third category (Table 1).

Hyaluronic Acid (HA)
Hyaluronic acid is the most important polysaccharide in human extracellular matrix, which acts as a scaffold for collagen and elastin. Its high water storage capacity augments and hydrates the skin.^6,11 When used as an injectable filler agent, hyaluronic acid consists of repeating polymer chains of the polysaccharide with interval cross-links of agents that bind the polymer together. By varying the type of cross-linking material and the amount, the characteristics of the gel can vary in the degree of hardness, amount of lift, duration of survival, and resistance to degradation by heat or enzymes.¹¹ Further distinction between the different available products can be made between the source, animal or non-animal, and the galenics, mono- or biphasic.^6,12 Since its FDA approval in 2003, hyaluronic acid has become the “gold standard” of injectable fillers.¹² To this day, four hyaluronic acid fillers have been approved for cosmetic use: Restylane^®, Juvederm^®, Perlane^®, and Belotero^®.¹³

Calcium Hydroxylapatite (CaHA)
In 2006, CaHA, known as Radiesse^®, was approved by the FDA for the augmentation of moderate to severe facial lines and folds as well as for facial soft-tissue loss from HIV-related lipoatrophy.¹⁴ This injectable filler substance consists of 30% concentration of 25 μm to 45 μm CaHA spherical particles suspended in sodium carboxymethyl-cellulose (CMC) gel.¹¹ As the CaHa particles are made of calcium and phosphate ions identical to the mineral portion of bone, it is characterized by an outstanding biocompatibility with the human organism.¹⁵ Soft tissue augmentation with CaHA filler leads to long-term deposition of new collagen.¹⁶

Poly-L-lactic Acid (PLLA)
Poly-L-lactic acid, tradename Sculptra^®, was FDA approved in August 2004 for the correction of facial atrophy, secondary to HIV, and therapy for AIDS. In 2009, PLLA was approved for the