1. Copyright restrictions may apply Contemporary Review of Injectable Facial Fillers Kontis TC. Contemporary review of injectable facial fillers. JAMA Facial Plast Surg. Published online November 26, 2012. doi:10.1001/jamafacial.2013.337.

2. Copyright restrictions may apply Introduction The use of injectable fillers for the treatment of facial aging has become a multibillion dollar industry. Hyaluronic acid, calcium hydroxylapatite, and poly(methyl methacrylate) have been vigorously studied with respect to safety and efficacy in well- designed randomized controlled trials (RCTs). Poly-L-lactic acid has also shown safety and efficacy, but there are limited RCTs.

3. Copyright restrictions may apply Purpose The article reviews the evidence-based studies that have been published for the currently available dermal fillers.

4. Copyright restrictions may apply Relevance to Clinical Practice Increased acceptance of the use of cosmetic injectable fillers has encouraged many physicians and paraprofessionals to offer filler injections in their practices. It is important for the practitioner or technician to understand the data pertaining to the safety and efficacy of these materials.

5. Copyright restrictions may apply Description of Evidence Articles were obtained from standard PubMed searches using the keywords for each of the filler types discussed. Articles selected included reviews, consensus statements, and clinical trials. For the review, more weight was placed on blinded clinical RCTs.

6. Copyright restrictions may apply Description of Evidence Injectable Fillers Listed by Dates of FDA Approval

7. Copyright restrictions may apply Controversies and Consensus: Hyaluronic Acid An ideal filling agent because it is biodegradable, biocompatible, and nonimmunogenic. Initial clinical trials were double-blind, split-face RCTs of nasolabial fold treatment and had to prove at least equivalence to collagen as the control. All studies showed clear superiority over collagen with minimal adverse events. By 2008, collagen was noted to be clearly inferior to the hyaluronic acid fillers; in subsequent studies, Restylane became the comparator. The addition of lidocaine to hyaluronic acid products was shown to increase patient comfort in clinical trials.

8. Copyright restrictions may apply Ideal qualities for injection: longevity, low adverse events profile, nonantigenic, nonirritating, nontoxic, and biocompatible. Unlike hyaluronic acid fillers, it stimulates neocollagenesis with the synthetic bone microspheres acting as scaffolding for the new collagen fibrils. In multiple RCTs as well as a consensus statement, it was concluded that calcium hydroxylapatite was efficacious and safe for treatment of volume loss in the lower face. Not available with lidocaine, but FDA approved for mixing with lidocaine prior to injection. Controversies and Consensus: Calcium Hydroxylapatite

9. Copyright restrictions may apply Approved in 2004 for lipoatrophy in patients with human immunodeficiency virus and in 2009 for aesthetic volume replacement. Synthetic polymer similar to absorbable suture material that acts as a collagen stimulator. Early studies reported frequent formation of subcutaneous nodules; however, increasing product dilution, resuspension at least 2 hours before injection, and injection into the subdermal or preperiosteal planes has diminished nodule formation. There are no RCTs using poly-L-lactic acid because there is no similar product to use as a control. Controversies and Consensus: Poly-L-lactic Acid

10. Copyright restrictions may apply Only FDA-approved permanent filler to treat the nasolabial folds. Polymer of microspheres suspended in bovine-based collagen with lidocaine. Skin testing is required. Incidence of granuloma formation improved with newer formulations. A 5-year safety and efficacy study showed continued and improved correction between the first and fifth years after injection. Not recommended for use in the lips owing to a high rate of nodule formation. Controversies and Consensus: Poly(methyl methacrylate)

11. Copyright restrictions may apply Tissue harvested by punch biopsy and cultured to produce a fibroblast line. Autologous tissue, biocompatible, and low incidence of hypersensitivity reactions. Approved in 2011 for correction of moderate to severe nasolabial folds. Still in clinical trials to determine longevity of correction. An RCT compared product with placebo (transport medium without living cells); however, future controlled studies (using hyaluronic acid or similar fillers) are needed to determine efficacy and safety. Controversies and Consensus: Autologous Fibroblasts

12. Copyright restrictions may apply Comment Implications for patients and health care providers: –Clinicians now have multiple injectable fillers from which to choose. High-level data show that the currently available dermal fillers are safe and efficacious. –Patients should confirm that their injections are being carried out by qualified and properly trained individuals.

13. Copyright restrictions may apply Comment There is an abundance of data on the safety and efficacy of the hyaluronic acid, calcium hydroxylapatite, and poly(methyl methacrylate) fillers. There are no blinded RCTs of poly-L-lactic acid because there is no suitable control. All studies on poly-L-lactic acid have been clinical trials. Comparisons of autologous fibroblasts vs hyaluronic acid fillers need to be performed in split-faced, double-blinded RCTs.

14. Copyright restrictions may apply Conclusions The safety and efficacy of dermal fillers on the market today are clearly delineated by the current literature. The development of facial filling agents is an actively evolving process. Currently available filling agents have been refined to maximize results and minimize complications. As the world of facial filling products continues to expand, it is evident that there are multiple opportunities for further research in these areas.

15. Copyright restrictions may apply Contact Information If you have questions, please contact the corresponding author: –Theda C. Kontis, MD, Facial Plastic Surgicenter, Johns Hopkins Medical Institutions, 1838 Greene Tree Rd, Ste 370, Baltimore, MD 21208 (tckontis@aol.com). Conflict of Interest Disclosures Dr Kontis has served on the speaker’s bureau for Allergan, Medicis, and Valeant.