Soft Tissue Augmentation in Dermatology – 2009 Update

Hyaluronic acid fillers

In order to understand HA fillers, some basic terms and characteristics that make HA fillers unique, are needed. HA or hyaluronan is a glycosaminoglycan, which consists of repeating non-sulphated disaccharide units of glucuronic acid and N-acetylglucosamine.[4] HA, a naturally occurring substance, is a biopolymer and it exhibits no species or tissue specificity. HA is an essential and abundant component of the extracellular matrix in all animal tissues. HA is highly hydrophilic and therefore attracts water, and helps form large concentrations that can occupy a large volume relative to its mass. It has been found to form gels at even low concentrations. When water is drawn into the HA matrix, it creates a swelling pressure or turgor that enables the HA complex to withstand compressive forces. These characteristics and in particular, the fact that HAs do not exhibit tissue or species specificity, which plays a crucial role in minimizing any potential immunological reactions or other allergic potentials have helped make HA fillers popular among clinicians injecting patients, to improve fine lines and wrinkles and for volume enhancement.

The first HA developed as a dermal filler dates back to 1989, when Balazs et al. described the first injectable HA filler.[5] Although it was not a long-lasting dermal filler, the HA ‘revolution’ had begun.

Factors which are important in characterizing a HA filler

Several differentiators have become important in their development. These include: the source of HA, the concentration of HA being utilized, the particulate size of the HA, the cross-linking of HA and the type of cross-linking agent being used, whether the HA is monophasic or biphasic, and whether an anaesthetic is added to the syringe or not. Some of the original HA fillers used avian rooster combs as the source for their HAs, but more commonly the source is bacteria-based, mainly from the fermentation of the Streptococcus equine bacterium. Most of the newer HA fillers have higher concentrations of HA compared to the older materials. It is felt that those HA fillers with higher concentrations of HA may be longer lasting, therefore, those with concentrations of greater than 20 mg/ml are considered ideal for HA fillers at this time. Cross-linking is important and most utilize ether cross-link bonds to help stabilize the HA. The newer non-particulate HA fillers contain double cross-linking, multiple cross-linking bonds. They may be also in monophasic gels, in an attempt to stabilize the molecule even more. This cross-linking makes the HAs less resistant to degradation, and thus enhancing longevity. As a result of the cross-linking process and non-particulate nature of newer HAs, higher HA concentrations are required to prevent biodegradation from free radicals and other enzymes. This leads to enhanced longevity of the filler. 1, 4-butandiol diglycidylether (BDDA) and 1, 2, 7, 8-diepoxyoctane are the commonly used cross linking agents. Larger HA particles tend to last longer as fillers, and are usually designed for deeper filler injections.

Both monophasic and biphasic fillers have their advantages; monophasic HA fillers are more cohesive, may last longer and may not migrate as much following its injection. However, biphasic HA fillers are more easily customized, to obtain the appropriate particle size to suit the indication and the anatomic area being treated.[2]

Numerous HA fillers are available in Europe and elsewhere around the world. In the US, due to a more stringent FDA approval process, there are fewer products available; although recently, many more are undergoing clinical evaluation through FDA-approved protocols. The remainder of this manuscript is going to focus on the fillers available in the US, reviewing their clinical studies and FDA approvals.

Analysis of results of different fillers

a) Restylane family: The first of the ‘new’ fillers in the US was Restylane. Restylane received its FDA approval in the US in December 2003, although it received its EU clearance much earlier, in 1996. It has been injected in well over ten million treatment sessions worldwide and is considered the standard against which all other and all new HAs are measured. It is manufactured by Q-Med AB (Uppsala, Sweden) and is marketed in the US and Canada by Medicis Pharmaceutical Corporation (Scottsdale, AZ USA). Restylane is a non-animal stabilized HA, commonly referred to as NASHA, produced from the fermentation of equine streptococci. It is cross-linked with BDDA, with a 1% degree of cross-linking. Restylane has an HA concentration of 20 mg/ml and its gel particulate size is 400 μm. It has a particulate size of 100,000 gel particles per milliliter and is the first of the Restylane family of products available from Q-Med and Medicis. Restylane's FDA approval is for mid-dermal applications, such as, deep wrinkle correction, lip augmentation, nasolabial fold correction and for glabellar creases. It received its initial FDA approval for six months duration of correction. Restylane has also been successfully used in the treatment of tear trough deformities

Perlane, the second product released in the Restylane family, contains 8000 gel particles per milliliter and is indicated for deeper injections and deeper clinical defects. In other parts of the world, this product is known as Restylane Perlane.[6]

Other products in the Restylane family include Restylane Touch™, Restylane Lipp™, Restylane SubQ™ and Restylane Vital™. A newer product, known as Macrolane™, has been introduced into Europe, mainly designed for volume enhancement. Further information on these products can be obtained from Restylane website.[7]

The two pivotal European clinical trials that led to the approval of Restylane in Europe will be discussed in detail here. These trials, by Duranti et al.[8] and Olenius[9] showed the safety and efficacy of Restylane in the correction of the nasolabial folds. In the first trial by Duranti et al., 78% of the patients who enrolled found that they were able to maintain moderate-to-marked clinical improvement for eight months following the injection. In the second study, by Olenius, there was correction of 82%, noted at 12 weeks and 69% at 26 weeks. Adverse events (AEs) noted in these two clinical trials were predominantly injection-related AEs, consisting of treatment-site erythema, hyperpigmentation at the treatment site and pain from the injection itself, reported in 13% of the patients in these trials. As experience grew with the product, injection techniques were refined, a later study of a large series of patients, Friedman et al.,[10] found that the injection related AE rate was, in fact, occurring in only 0.15% of the patients receiving Restylane injections.

Shortly after these reports, several cases of what was described as delayed implant hypersensitivity, were reported in European literature.[11–13] Through these evaluations, it was determined that there was a 0.4 to 3.7% risk of this occurring following Restylane implantation. As a result of this delayed implant hypersensitivity occurring in more patients than was acceptable, a more purified Restylane product was manufactured by Q-Med, and this more purified product, NASHA, is what is currently available today. Clinical evaluations with the new purified Restylane and with clinicians mastering their injection technique, AEs were reduced to 0.06% and hypersensitivity reactions were reduced to 0.02%, and threrfore considered acceptable for continued use. This helped in the acceptance of this new NASHA product on a broader basis. These factors, and the fact that HAs in general requiring no skin testing prior to injection as stated earlier, led to the commencement of the pivotal US clinical trials for Restylane.

The US clinical trials for Restylane compared Restylane in one nasolabial fold with Zyplast collagen, the standard collagen injectable material available at that time, being injected into the other nasolabial fold. In this clinical trial by Narins et al.,[14] 138 individuals were included for evaluation. The majority of the patients enrolled were females (93%) and Caucasians (89%). The protocol design consisted of injection in each nasolabial fold with each product for optimal correction. The patients were asked to return at two weeks for any touch-up injections if needed. Optimal correction was the goal of the injection process and patients were allowed two sessions if needed, to achieve their optimal correction. The study results showed that optimal correction was achieved in 1.4 sessions for both the products being injected. The volume needed for Restylane, for volume correction, showed a mean of 1.0 ml (range 0.3 to 2.8 ml), while the amount of Zyplast used showed a mean of 1.6 ml (range of 0.1 to 5.0 ml). The Wrinkle Severity Rating Scale (WSRS) score for Restylane was superior at all time points, as compared to the Zyplast side. This was true at two months, four months, and six months following the optimal correction of the nasolabial folds. At the six-month evaluation Restylane was rated superior in 56.9% of the patients compared to Zyplast in 9.5% of the patients. The Global Aesthetic Improvement Scale (GAIS) was also superior for Restylane at all time points, with a 62% rating for Restylane superior at six months, as compared to 8% rating for Zyplast superior.

Adverse events were evaluated at each follow-up visit during the course of the study. Mild-to-moderate injection site reactions occurred in a similar and non-statistical fashion with both the products (93.5% Restylane, 90.6% Zyplast). These were short-lasting in all cases, usually resolving within seven days. Of all treatment-related AEs during the evaluation, 26.4% were reported for Restylane and 39.1% for Zyplast. Delayed-onset reactions were noted in 8.7%; all resolved within two to three months without intervention. There were no reports of hypersensitivity reactions reported during the trial.

Further evaluations have been performed with Restylane over the past several years in the US.[15–17]The evaluations have continued to show the safety and efficacy of this product in each and every study. Two of the US clinical evaluations are very important and warrant in depth discussion. The first, by Odunze et al.,[18] evaluated 60 patients who received Restylane injections, one-third of whom were of darker skin types, (Fitzpatrick skin types IV - VI). They noted no untoward AEs in the darker skin color group, providing evidence that Restylane can be safely injected into patients of all skin types. The second study, by Narins et al.,[19] also studied Restylane, but looked at repeat injections and longevity associated with repeat injections in seventy-five patients in a multicenter evaluation. The patients were randomized to receive retreatment of one of their nasolabial folds at 4.5 months and the contralateral fold at nine months after correction of both folds at the initial visit. Results were presented and analyzed at 18 months. The WSRS improved significantly (p < 0.001) from baseline, with mean improvement noted from 1.1 to 1.7 grades. Ninety-seven percent of all the patients responded to this retreatment program, and the efficacy of the retreatment schedules did not differ significantly. The AEs reported were all local and consisted of swelling and bruising at the treatment site, which occurred in 33%, and were not rated as serious in this study. Thus, Restylane was shown to maintain correction for 18 months following a repeat injection at 4.5 months. This study led to a second submission to the FDA, known as a supplemental PDA, for its label, giving a new indication for Restylane longevity up to 18 months with a repeat injection at 4.5 months.

Following the approval of Restylane, Perlane received its FDA approval for deeper dermal defects, especially for those have deep nasolabial folds and for other lines and wrinkles that require a larger particle size HA filler. Lastly, clinical studies are at the concluding stage at this time, on a new Restylane product with lidocaine incorporated into the syringe itself. More information on this product should be available soon. Clinical examples of Restylane are shown in Figures 1 and 2.

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Figure 1

Before treatment (a) and after treatment with Restylane (1.0 cc) to nasolabial folds (b)

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Figure 2

Before treatment (a) and post treatment with Restylane (1.0 cc) to the nasolabial folds and marionettes lines (b)

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b) Juvederm family: The next group of HA is known collectively as Juvederm. Juvederm is manufactured by Lea Derm, a subsidiary of the Corneal Group (Paris, France). It was brought to the US by Inamed and was purchased several years ago by Allergan, Inc. Allergan, the makers of Botox™, are the current distribution source worldwide for Juvederm. There are two current formulations of Juvederm available in the US – Juvederm Ultra and Juvederm Ultra Plus. Six different formulations of Juvederm have been developed by Corneal, with differing concentrations of HA in each formulation, ranging from 18 mg/ml to 30 mg/ml. Both the available US products contain 24 mg/ml of HA, respectively, with Juvederm Ultra Plus containing 24 mg/ml of HA in high viscosity. Both the US Juvederm formulations were FDA approved in June 2006 – Juvederm Ultra for deep wrinkles and defects and Juvederm Ultra Plus for deeper furrows, such as, the nasolabial folds. The Juvederm family is produced from the bacterial fermentation of equine streptococci. The HA is cross-linked with a patented single-phase BDDE-phosphate buffered from 6.5 – 7.3 pH. With a higher concentration of HA and more cross-linking than other HA fillers, it has been suggested that the Juvederm family of products may persist longer than other HA fillers, and also have a smoother injection flow.[20]

Baumann L et al.,[21], in an important clinical trial, compared three Juvederm products, with Zyplast collagen, in the treatment of nasolabial folds. Four hundred and twenty-three patients completed the clinical trial of a 24-week evaluation. Over 300 patients received an additional treatment, at the conclusion of the clinical trial in order to further examine the long-term efficacies of these products. Results from this multicenter clinical evaluation showed that both, the Juvederm family, and the Zyplast collagen, showed significant improvements at all points during the course of the 24 week clinical trial. The three products of the Juvederm family studied showed a significantly greater efficacy than the bovine collagen product; the efficacy increased with time and was greatest at 24 weeks after the last treatment. Utilizing a four-point scale, an improvement of at least one point was seen in more than 80% of the Juvederm-treated patients compared to a 0.5 improvement, on an average, in the Zyplast-treated patients. At the end of 24 weeks of injection, long-term results showed that there was 57% improvement at eight months, 37% at 10 months, and 18% at 12 months.

Adverse events were similar for both the Juvederm side and the Zyplast side that were treated, and were similar for all of the Juvederm products studied. Mild-to-moderate treatment site reactions were seen in a majority of patients, all of which resolved within seven days. No long-term adverse reactions were noted. Patient preference data suggested a 78% preference for Juvederm 30, 88% for Juvederm 24HV, and 84% for Juvederm 30HV. From this clinical study, Juvederm 24HV and Juvederm 30HV were chosen for the US market, both of which contained 24 mg/ml of HA, with Juvederm Ultra having 9% cross-linking, while Juvederm Ultra Plus had 11% cross-linking. Because of the long term follow-up during this multi-center clinical trial, the investigators were able to show longevity at one year following optimal correction, and therefore, were able to receive FDA clearance for up to one year.[22]

Most clinicians who utilize Juvederm have noted that it does inject easily through the syringe and that results are commonly observed for 6 to 12 months. Local injection site reactions are rare and there has been some discussion that the injection of Juvederm results in a more natural appearance than the other HA fillers, although no clinical studies with regard to this debate have been performed. Clinical examples of Juvederm are seen in Figures 3 and 4. A newer form of Juvederm, with lidocaine incorporated into the syringe itself, is now available in Europe, and pending FDA approval in the US at present.

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Figure 3

Before treatment (a) and immediately post treatment with Juvederm (1.0 cc) to the nasolabial folds and tear trough (b)

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Figure 4

Before treatment (a) and immediately post treatment with Juvederm (1.0 cc) to the nasolabial folds and marionettes lines (b)

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c) Hydrelle: The next HA filler that received FDA approval was originally known as Elevess and is currently known as Hydrelle. Hydrelle is marketed through Coapt Systems (Palo Alto, CA, USA) and is manufactured by Anika Therapeutics (Bedford, MA, USA). Hydrelle contains the highest concentration of HA of all products, in the market at this time, 28 mg/ml, and it also contains 0.3% lidocaine, the first of the US products receiving FDA clearance for an HA with lidocaine. It is cross-linked with p-phenylene bisethyl carbodiimide or biscarbodiimide or BCDI, which is a novel HA cross-linker. Its source of HA is from equine streptococci. The US clinical pivotal study for Hydrelle (Elevess) studied 191 individuals who received Elevess in one nasolabial fold and CosmoPlast in the other nasolabial fold. Patients had significant improvement in the Elevess side at both four and six months following optimal correction. AEs were similar in both groups and not significant. They consisted mainly of treatment site reactions and resolved in the majority of cases within seven days.[23] Patients who still had improvement at the six-month time frame were eligible to enter a nine- (n = 90) and 12 month (n = 84) extension follow-up clinical trial. The patients maintained their improvement at these time frames as well; with the Elevess side showing more improvement than the CosmoPlast side.[24]

In clinical practice, this material is easy to inject with a 27 gauge needle; however, the 30 gauge needle supplied with the syringe makes the injection process a little more difficult than most of the other HA fillers. The addition of lidocaine is a benefit and most patients note a decrease in pain, almost immediately after the first injection into the skin.

d) Prevelle: The next HA filler that received FDA approval is known as Prevelle™ Silk. This product is the next generation of an earlier HA filler, known as Captique™, which is not available anymore. Captique was manufactured by the Genzyme Corporation (Cambridge, MA, USA) and was originally marketed by Inamed and then Allergan, and was later sold to the Mentor Corporation (Santa Barbara, CA, USA), who now markets the newer formulation of Captique, known as Prevelle Silk. more recently, Mentor HAS BEEN purchased by Johnson (Skillman, NJ USA). The product contains 4.5 – 6.0 mg/ml of HA, is 20% cross-linked with divinyl sulphone and has a gel particle size of 500 μm. On account of the low concentration of HA in the product, the clinical results were of short duration, in the three to six month time period.

Prevelle Silk combines Captique with 0.3% lidocaine and the pivotal trials for this product, conducted by Monheit et al.,[25] showed that Prevelle Silk had a significant difference in pain associated with the injection process and postprocedure pain. The majority of patients receiving Prevelle Silk do not have significant post-treatment erythema or post-treatment swelling. Patient preference was also significantly more in favor of the Prevelle Silk over Captique. Prevelle Silk is generally preferred for patients needing instant correction with very little potential for adverse effects. Genzyme and Mentor have more fillers on the horizon, which will be part of the Prevelle family. The first of these products should be available towards the end of 2009 or early 2010.