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Dermal Fillers: Focus on Hyaluronic Acid

Authors: Norra MacReady  Faculty and Disclosures


Hyaluronic Acid Fillers

At the American Society for Aesthetic Plastic Surgery (ASAPS) 2008 meeting, the characteristics and indications of the hyaluronic acid (HA) fillers currently on the market were discussed in a panel discussion entitled "Hyaluronic Acid: Does Size Matter?"[1] This question introduces one of the variables -- particle size -- that contributes to the different qualities and clinical effects of the various HA fillers. Other variables include gel hardness, HA concentration, and degree of cross-linking.

Z. Paul Lorenc, MD, Clinical Professor of Plastic Surgery at New York University School of Medicine, and Lorenc Aesthetic Plastic Surgery, New York, NY, began the session by asking another question "Why are we here?" He answered this question by noting that HA injections are the second most frequently performed aesthetic procedure in the United States. "It's a very important part of my practice, and it will become an even more important part of all our practices."

HA is a glycosaminoglycan, a naturally occurring, hydrophilic linear polysaccharide that is a major component of the extracellular matrix in epithelial, connective, and neural tissues. In the skin, HA maintains dermal volume and viscoelasticity. Dr. Lorenc noted that HA products may be derived from animal or bacterial sources; animal-based HAs have a longer chain length and a molecular weight of 4-6 megadaltons, whereas bacterially derived HAs are shorter and have a molecular weight of 1-3 megadaltons. The HA fillers most widely used in clinical practice today are nonanimal HAs.

Nonanimal HAs are produced by a streptococcal fermentation process and stabilized by cross-linking. Unmodified HA has a half-life of only 24-48 hours in tissue, making it unsuitable for use as a dermal filler. However, synthetically cross-linking the HA improves stability, longevity, and elastoviscous properties.[2] There is debate about the ideal degree of cross-linking and whether cross-linking affects HA biocompatibility and longevity. Dr. Lorenc stated that a higher degree of cross-linking produces more resistance to degradation (although there is a limit on how much cross-linking can be used), as does larger particle size.

Currently available nonanimal HAs include Restylane and Perlane (Medicis; Scottsdale, Arizona) and Juvéderm Ultra and Juvéderm Ultra Plus (Allergan, Irvine, California). These fillers are approved by the US Food and Drug Administration (FDA) for the temporary correction of moderate-to-severe facial wrinkles and folds (such as nasolabial folds). Both the Restylane family of products and the Juvéderm family of products use butanediol diglycidyl ether (BDDE) as the cross-linking agent for the HA, but there are differences.

Restylane and Perlane are minimally cross-linked gels with a HA concentration of 20 mg/mL. These products are based on HA particle dimension, which is established during a sizing process during the division of the gel. Restylane has a particle size of 250 microns and is most appropriate for mid-to-deep dermal injections; Perlane has a particle size of 1000 microns and is used for deep dermal/superficial subcutis injections.

The Juvéderm fillers are homogeneous, nonparticulate HAs with a higher degree of cross-linking and a HA concentration of 24 mg/mL. Juvéderm Ultra is recommended for mid-to-upper dermal injections, and Juvéderm UltraPlus is used for mid-to-deep dermal injections.

Gel hardness (G'), or rheological (flow) properties, is another differentiating factor in HA fillers. The higher the G' the stiffer the product and the more difficult it will be to inject.

There is now some evidence suggesting that HA fillers may stimulate de novo collagen synthesis in the skin,[3] enhancing its properties as a filler. Dr. Lorenc described a study from the laboratory of John Voorhees, MD, in which 11 patients received 3 intradermal injections of a HA filler (Restylane) into 1 photodamaged forearm and saline into the other forearm. Punch biopsy samples were obtained at 4 and 14 weeks after injection, and collagen synthesis was assessed using immunohistochemical analysis, polymerase chain reaction, and electron microscopy. There was significantly more type 1 collagen formation at the HA injection sites. Study authors posited that mechanical stretching of fibroblasts by the HA induced collagen production. This, suggested Dr. Lorenc, could explain why patients often report improvements in their appearance up to 12 months after receiving HA fillers.

Dr. Lorenc concluded by noting that there are no head-to-head comparisons between Restylane products and Juvéderm products, and that injector technique is more important than the differences between the 2 families of products. "So, in the end, size does matter. But how size is delivered matters more."

Clifford P. Clark III, MD, Assistant Clinical Professor of Plastic Surgery at the University of South Florida, and a cosmetic surgeon in Winter Park and Orlando, Florida, began his presentation by saying, "We've come a long way since cross-linked collagen. We used to be comfortable with just treating the occasional nasolabial fold. Now we can talk about refilling and reshaping the face."

He pointed out that any procedure should start with a global assessment of the patient's face, particularly with respect to photoaging, volume changes, and the effects of gravity. He warned that plastic surgeons must keep their patients' expectations realistic through a comprehensive discussion of a product's efficacy and risks. He stated that he tries to "emphasize the beauty of a multifaceted approach," so that nonsurgical patients can be transitioned to surgical patients when appropriate.

Dr. Clark divided the factors affecting the clinical performance of dermal fillers into 2 categories: injector-related and patient-related. He reiterated Dr. Lorenc's statement that injector-related factors essentially boil down to technique and choice of filler. On the patient's side, oxidative or inflammatory status, metabolism, the health of the skin, and inherent movement patterns all affect the outcome. For example, he described a heavy smoker as "a walking electron" who generates a lot of free radicals, which hasten the aging process.

Like Dr. Lorenc, Dr. Clark thinks that degree of cross-linking can extend longevity; however, he questioned the view that longevity correlates with particle size, based on comparisons between Hylaform and Hylaform Plus, which are animal-based HAs with different particles sizes but comparable longevity. He noted, however, that "there are many talented injectors who feel that particle size helps with correction for deeper injections."

Of note, product firmness, as reflected in the G', appears to play a role in patient satisfaction. Dr. Clark described a study in which immediate efficacy, product longevity, and patient satisfaction were compared among 205 randomized patients who underwent treatment with calcium hydroxylapatite (CaHA; Radiesse; BioForm, San Mateo, California), Juvéderm 24, Juvéderm 24HV, or Perlane for correction of nasolabial folds.[4]The CaHA was associated with greater immediate efficacy, longer duration, and higher patient satisfaction than any of the HA-based products. Essentially, Dr. Clark said, "the patients preferred a firmer product in the nasolabial crease, despite there being only a modest difference observed by clinical evaluators." Dr. Clark noted, "I don't think that would work everywhere, but in the nasolabial crease, the patients preferred something harder."

In the end, Dr. Clark concluded, clinical outcomes are determined by a variety of factors, the most important of which is the patient's past experience with the filler.

In a discussion of complications associated with HA fillers, Mark Rubin, MD, of the Lasky Skin Center in Beverly Hills, California, distinguished between true adverse outcomes and events that patients may perceive as adverse outcomes but are actually normal reactions that resolve over time. Examples of the former include:

  • Allergic reactions;

  • Granulomas;

  • Vascular occlusion or compromise;

  • Tyndall effect (bluish tint resulting from injections that are too superficial);

  • Overcorrection or persistent lumpiness;

  • Infection; and

  • Sterile abscesses.

The exact incidence of complications is unclear because FDA clinical trials are usually designed to continue for only 6 months, and patients may not complain about complications that occur after they have been treated, Dr. Gold noted. He noted that a great advantage of HA products is that they are reversible with hyaluronidase or simply by "nicking and squeezing."

Examples of normal, transitory reactions include:

  • Needle marks;

  • Bruising;

  • Erythema or edema;

  • Acneiform eruptions; and

  • Transient lumpiness.

Perhaps the biggest drawback associated with HA fillers is the pain associated with injecting them. Dr. Rubin noted that HA products containing lidocaine are now available in Europe and should soon be available in the United States.

Managing the Nasolabial Fold

In a session on nasolabial folds, Victoria Vitale-Lewis, MD,[5] Chief of Plastic Surgery at Holmes Regional Hospital in Melbourne, Florida, explained that she divides patients into 3 categories, depending on the primary etiology underlying the folds: "saggers," whose defect results mostly from cheek ptosis; "sinkers," in whom the folds derive mainly from volume deflation; and "smirkers," in whom muscle hyperactivity is the main cause of the problem. Smirkers can be distinguished by downturned oral commissures.

When treating "saggers," Dr. Vitale-Lewis injects HA fillers using the techniques of fanning and linear threading. If the folds are deep, she uses a layering approach. "Sinkers" receive a calcium hydroxylapatite (CaHA; Radiesse) or poly-L-lactic acid (PLLA; Sculptra; Dermik; Bridgewater, New Jersey) filler. She administers PLLA in 2-4 treatments at 6-week intervals and prefers it to fat grafts because the results are more predictable and can persist for 24 months after the last injection. When working with PLLA, she recommends reconstituting it at least 2 hours prior to the procedure or, preferably, the night before, if possible. "Smirkers" receive 2-4 units of botulinum toxin in the fold of the depressor anguli oris to augment treatment of the nasolabial fold.

Lipoinjection, also called lipoinfiltration, also shows promise in the treatment of nasolabial folds. Daniel Del Vecchio, MD, Consulting Plastic Surgeon at Massachusetts General Hospital in Boston, Massachusetts, and colleagues attempted intraoperative fat harvesting, processing, and administration in 16 patients undergoing abdominoplasty. Preparing the fat was a 3-step process that took approximately 23 minutes and involved harvesting, mincing, and morselizing, he explained. The fat was loaded into 3-cc syringes, and an average of 1.5 cc was injected into each nasolabial fold. Postoperative swelling lasted 2-3 days. Over a follow-up period of 9-14 months, patients achieved good cosmetic results. Complications occurred in only 2 patients, who complained of palpable graft material accumulating at the injection site. All in all, said Dr. Del Vecchio, intraoperative mechanical processing is possible, "but it's a real operation; it's not just a dermatological procedure."

Managing the Tear Trough

The technique of "injecting fullness" into the face dates to 1911, when doctors attempted the procedure using paraffin compounds, said Sydney R. Coleman, MD, of Tribeca Plastic Surgery, New York, NY.[6] Today, lipoinfiltration is gaining popularity due to its salutary effects on skin texture, pigmentation, and pore size, as well its volumizing effects, Dr. Coleman noted in a panel on managing the tear troughs. He warned, however, that "most people look better with some tear trough, especially men."

Once a patient has recovered from the initial effects of the procedure, Dr. Coleman noted, the results can persist and, in some cases, even continue to improve for as long as 10 years. Indeed, recovery is probably the hardest part of lipoinfiltration. Dr. Coleman urged physicians to tell patients that they will experience 3-4 weeks of significant edema, and he suggested showing them postprocedure photographs so that they know what to expect. Other potential problems include:

  • Excessive fullness: the most common complication, due to injection of too much fat (Dr. Coleman advised erring on the side of injecting too little rather than too much);

  • "Tea-staining": slight hyperpigmentation thought to result from prolonged low-grade inflammation, which eventually resolves;

  • Visible or palpable accumulation of fat; and

  • Inadequate correction.

For patients who want to avoid the prolonged down time associated with conventional lipoinjection of the tear troughs, Catherine Bergeret-Galley, MD, of Paris, France, reported on a procedure that she uses with good results: injection of botulinum toxin into the frontalis corrugator and orbicularis muscles, followed by malar enhancement with a dense, reticulated HA product. Good candidates for this procedure have lower lids that are not too puffy and skin that is not too thin. Realistic expectations are important, as the patient must understand that the dark circles associated with the tear trough deformity may not completely resolve.

This activity is supported by an independent educational grant from Medicis.



  1. Hyaluronic Acid: Does Size Matter? [Panel discussion]. Program and abstracts of the American Society for Aesthetic Plastic Surgery (ASAPS) 2008 Annual Meeting; May 1-6, 2008; San Diego, California.
  2. Falcone SJ, Berg RA. Crosslinked hyaluronic acid dermal fillers: A comparison of rheological properties. J Biomed Mater Res. 2008 Jan 15 [Epub ahead of print].
  3. Wang F, Garza LA, Kang S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol. 2007;143:155-163.
  4. Moers-Carpi M, Vogt S, Santos BM, Planas J, Vallve SR, Howell DJ. A multicenter, randomized trial comparing calcium hydroxylapatite to two hyaluronic acids for treatment of nasolabial folds. Dermatol Surg. 2007;33(Suppl 2):S144-S151.
  5. Effective Management of the Nasal Labial Fold. [Session]. Program and abstracts of the American Society for Aesthetic Plastic Surgery (ASAPS) 2008 Annual Meeting; May 1-6, 2008; San Diego, California.
  6. Lower Lids and Troughs: Problems and Solutions. Program and abstracts of the American Society for Aesthetic Plastic Surgery (ASAPS) 2008 Annual Meeting; May 1-6, 2008; San Diego, California.
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