image of silk fabric and dry skin

J. S. Dover, MD, FRCPC1-3, A. Carruthers, MD, FRCPC4, J. Carruthers, MD, FRCSC5, M. Alam, MD6
1SkinCare Physicians of Chestnut Hill, Chestnut Hill, MA, USA
2Department of Medicine (Dermatology), Dartmouth Medical School, Hanover, NH, USA
3Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA
4Division of Dermatology, University of British Columbia, Vancouver, BC, Canada.
5Department of Ophthalmology, University of British Columbia, Vancouver, BC, Canada.
6Section of Cutaneous and Aesthetic Surgery, Department of Dermatology, Northwestern University, Chicago, IL, USA


There is no ideal filler, nor will there be a single product that can satisfy all requirements. However, RESTYLANE®, a non-animal, stabilized hyaluronic acid (NASHA, Medicis), is a very versatile augmenting agent. It has been in clinical use for 8 years and experience has shown it to be close to the ideal filler in many respects. This review will outline the background to the use of RESTYLANE®, and will focus on the clinical use of this material.

Key Words: filler, hyaluronic acid, NASHA

The pace of development of filler substances in the last few years has been phenomenal. Consider that for more than 20 years there was only one US FDA approved cutaneous filler device, bovine collagen (Zyderm®/Zyplast®, Inamed Aesthetics). Bovine collagen has several distinct disadvantages. Two skin tests are necessary, producing a minimum 4- to 6-week treatment delay between the initial consultation and the first treatment. Results are short lived, and the thickest collagen, Zyplast®, lasts only 2-4 months. Beading is relatively common because the product becomes firm and nonmalleable soon after injection.

In February 2003, human collagen (Cosmoderm?/Cosmoplast?, Inamed Aesthetics) was approved by the US FDA. In December 2003, the US FDA approved RESTYLANE®, a cross linked nonanimal source hyaluronic acid. Two other forms of cross-linked hyaluronic acid, Hylaform® and Hylaform® Plus (Inamed Aesthetics) were approved by the US FDA in the summer and fall of 2004, respectively. RESTYLANE® is made by Streptococci and Hylaform® is derived from chickens’ combs. They also differ in the amount and degree of cross-linking, which affects, among other things, duration of effect. Many more fillers are under development, and some are pending US FDA approval.

Considering the complexity of the areas/conditions being treated, as well as the aims and desires of the individual being treated, there is no ideal filler. Futhermore, no single product will be able to satisfy all requirements. However, a product would be useful in the majority of clinical situations with the following properties:

  • non-permanent but long-lasting
  • have minimal side-effects
  • not require allergy testing
  • be easy to use/inject
  • be cost-effective both to the physician and patient.

RESTYLANE®, a non-animal, stabilized hyaluronic acid (NASHA) is not ideal, but is far closer to this set of criteria than previous fillers.

RESTYLANE® has been available in Europe since 1996, and in Canada since 1998. It is used in more than 60 countries to correct a variety of wrinkles, lines, and contour defects and to enhance the lips. It was approved in the US in December 2003, for use in mid-to-deep dermal implantation for the correction of moderate-to-severe facial wrinkles and folds, such as the nasolabial folds.

Benefits of RESTYLANE® include:

  • having a very low allergic potential so that skin tests are unnecessary
  • having a very natural look and feel
  • lasting significantly longer than any of the collagens
  • being moldable and very easy to work with.

Disadvantages include temporary redness and swelling at the injection site, which is most clinically significant when the lips are injected and most often resolves within 3-4 days. Allergic reactions are rare. Most of those reported occurred prior to 2000 when the level of contaminants in the product were dramatically reduced.1

The best data on RESTYLANE® comes from a study of 138 subjects that led to US FDA approval.2 This was a bilateral paired comparison study of the efficacy and safety of RESTYLANE® vs. Zyplast® use in the nasolabial folds. The products were injected at baseline, followed by touch-ups as necessary to achieve “optimal cosmetic improvement”. Judging subjects’ folds using a 5-point scale (none, mild, moderate, severe, extreme), both products achieved a 1.5 point improvement. At 6 months, the RESTYLANE® injected side still had a 1 point improvement, whereas the Zyplast® injected side had a 1/3 point improvement. At 6 months after injection RESTYLANE® was considered to be superior in 62% of patients vs. 8% of patients for Zyplast®.

There were more adverse events in the Zyplast®-treated side, but these were mainly minor lumpiness or material showing through the skin. Whereas on the RESTYLANE®-treated side there was more swelling and tenderness (see Table 1).

Adverse Effects RESTYLANE (%) Collagen (%)

Table 1: Adverse events in the Restylane®/Zyplast® study2

Other Forms of NASHA

The cross-linked structure of hyaluronic acid forms a gel with limitless molecular weight. This is then passed through screens with varying pore sizes to form the injectables with differing particle sizes. This difference between particle size and molecular weight is an important concept in the field of hyaluronic acid-based materials. Resulting from this, each form of cross-linked hyaluronic acid can be packaged as a number of different injectables. For example, NASHA is packaged as RESTYLANE® Fine Lines (or RESTYLANE® Touch), RESTYLANE® Perlane®, and RESTYLANE® SubQ. Each of these products will be applicable in an appropriate clinical setting. Large studies done with hyaluronic acid show no difference in duration.2,3

Clinical Use

RESTYLANE® is used on the face in a variety of places and for a variety of indications, so for the sake of clarity we shall discuss the uses in different categories, recognizing that, at times, this distinction can be artificial. RESTYLANE® is a very flexible product that can be used for most of the NASHA indications but we shall indicate where we use the different forms of NASHA by preference. Care is always taken to ensure that the product is not injected into a vessel especially when injecting the periocular area.

Fine Lines

Good examples of areas where fine lines are treated would be the glabella, the cheeks, and the perioral area. In these areas we inject RESTYLANE® in the mid-dermis or higher using a serial puncture technique. One should always feel the resistance of the dermis as one is injecting. The glabella and the perioral areas are usually treated in conjunction with BOTOX® (botulinum toxin-A, Allergan) therapy. It is not unusual to have to use RESTYLANE® only once in the glabella if good BOTOX® therapy is maintained afterward. With regard to the fine perioral lines, it is of vital importance NOT to simply inject the lines since this will lift the surrounding skin, reversing the youthful “ski-jump” projection of the lips. We prefer to enhance the vermilion border and perhaps the lips themselves and to only inject the fine radial rhytids very gently. RESTYLANE® Touch is designed for this kind of fine work.

Nasolabial Folds

We frequently use a threading technique along the nasolabial fold, concentrating on the upper Y-shaped area below the nares and lateral to the ala. Deepening of this area is related to age-induced loss of fat so correction will produce a more youthful appearance. Because there is less movement in this area close to the nose, correction persists well. The further down the nasolabial fold one is correcting, toward the smile lines beside the oral commissure, the shorter the duration of the correction. In addition, the smile lines are produced by the expression of a positive emotion and so correction of this area may be less of a priority. Discussion of this differential treatment of the nasolabial folds with the subject prior to treatment is very important. Injection is in the mid-to-deep dermis. Where it is available, RESTYLANE® Perlane is often used for nasolabial fold correction.


The lips are one of the most important areas for the use of RESTYLANE® and deserve separate discussion. The aim of lip injection is, in younger individuals, to enhance the size and shape of the lips. In older individuals the aim is more one of correction: to get the lips back to where they were rather than to increase their size. For many patients, the aim is a combination of the two. Injecting lips is more likely to produce adverse events than any other area. In particular, short-term swelling is common and bruising is also seen frequently if good technique is not used. In order to limit this effect, the application of ice or ice packs for 5-20 minutes after injection is favored by some.

Though there is nothing in the literature to support its use at this time, some experienced clinicians provide patients with prednisone 30mg to be taken the morning of the procedure and again the next morning; or 30mg to be taken at bedtime on the day of injection if their lips are swollen, and 30mg to take the following morning if their lips are swollen. Using this technique, minimizes swelling which allows the treated individual to continue with their business and social life rather than having to hide for a day or two. Lip injection is quite uncomfortable. Many use infraorbital and mental nerve blocks to limit discomfort while others prefer distraction techniques such as vibration analgesia.

To limit bruising the needle should be inserted gently through the lip mucosa close to the vermilion and gentle pressure exerted on the plunger. The needle tip can then be advanced using RESTYLANE® to dissect ahead of the tip, and moving blood vessels out of the way (the “push-ahead” technique). It should be possible to reduce the bruising rate to well below 10% using this technique as well as to avoid the use of NSAIDs, etc.

We use a threading technique on the lips. The needle tip is inserted either just mucosal to the vermilion for vermilion enhancement, or 2-3mm on the mucosa for lip enhancement. Gentle pressure on the plunger should produce flow of the RESTYLANE® across the lip in the chosen plane ahead of the needle tip. It is essential to continue the injection into the area of the commissure, and above and below the commissure. RESTYLANE® is our NASHA of choice for lip enhancement.


Because of the persistence of NASHA, especially in non-mobile areas, correction of volume loss or enhancement of volume is an increasingly important indication for the use of RESTYLANE®, as well as Perlane® and RESTYLANE®SubQ. Some of the areas where it is used are:

  • the temporal eyebrow area to produce a lateral eyebrow lift
  • the nasojugal fold to soften the hollows under the eyes (inject just above the periosteum)
  • the zygomatic area to enhance the cheekbone
  • the infraorbital hollowing to correct age-related fat loss
  • the sides of the chin to correct fat loss and to soften the jowls
  • the tip of the chin to augment the mentum.

RESTYLANE® is injected deep into these areas with no attempt at dermal injection. We will frequently use a 30 gauge 1″ needle, or an even longer needle in order to fan the material deep in the subcutis and then massage aggressively in order to avoid lumpiness. Bruising is a risk when injecting at this level because of the larger vessels so using the “push ahead” technique described under Lips described above will be helpful.


NASHA fillers are very effective. RESTYLANE® lasts twice as long as collagen, no allergy testing is required, and it has an excellent safety profile. Results, however, are highly technique-dependent. The treating physicians must select the subjects and the type of wrinkle or crease carefully, with experience they can become highly skilled in the use of this filler.


  1. Andre P. Evaluation of the safety of a non-animal stabilized hyaluronic acid (NASHA – Q Medical, Sweden) in European countries: a retrospective study from 1997 to 2001. J Eur Acad Dermatol Venereol 18(4):422-5 (2004 Jul).
  2. Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg 29(6):588-95 (2003 Jun).
  3. Carruthers J, Carruthers A. A prospective, randomized, parallel group study analyzing the effect of BTX-A (Botox) and nonanimal sourced hyaluronic acid (NASHA, Restylane) in combination compared with NASHA (Restylane) alone in severe glabellar rhytids in adult female subjects: treatment of severe glabellar rhytids with a hyaluronic acid derivative compared with the derivative and BTX-A. Dermatol Surg 29(8):802-9 (2003 Aug).