Hyaluronic Acid Fillers
Gary D. Monheit, M.D.
Associate Professor
Department of Dermatology
University of Alabama at Birmingham
Birmingham, Alabama

The use of temporary yet non-invasive techniques for wrinkle and volume correction has begun an industry of soft tissue and skin fillers. Beginning with collagen in the early 1980’s, techniques for correction of nasolabial folds, forehead and glabella wrinkles and lip augmentation were developed. The quest for other temporary yet biocompatible agents without the necessary skin tests for allergy has begun the development of hyaluronic acid fillers. The hyalurons have specific advantages over collagen and recently a plethora of new products has emerged on the market. This article will discuss the properties of hyaluronic acid filler products, their differences and their uses as soft tissue fillers.

Hyaluronic acid is a naturally occurring linear polysaccharide found in the extracellular matrix of connective tissue, synovial fluid and other tissues. There is no antigenic specificity for species or tissues and thus has no potential for allergic or immunogenic reaction in humans. In humans, it serves as the ground substance of dermis, fascia and most fluid mediums because of its viscoelastic properties. It is found in all vertebrate animals and as a “biofilm” around bacteria. It has high concentrations in soft connective tissue extracellular matrix, vitrous of eye, hyaline cartilage, synovial joint fluid, disc nucleus, umbilical cord and skin dermis. It has specific physical and biochemical properties in normal tissue. As a physical background, it functions as space filling, lubrication, shock absorption and protein exclusion. Its biochemical properties include modulation of inflammatory cells, interaction with the proteoglycans of the extracellular matrix and as a helper in free radical scavenging. (Figure 1)

Hyaluronic acid was first isolated 70 years ago and the name hyalos (Greek – glassy) along with uro (uric acid) was used for the space filling and viscoelastic properties. Natural hyaluronic acid has a half life in tissue for only one to two days undergoing aqueous dilution and enzyme degradation in the liver to carbon dioxide and water. For use as a dermal filler, a longer tissue residue time is needed.

Cross-linking native hyaluronic acid forms stable larger molecules with similar biocompatibility and viscoelastic filling properties yet longer residue time in tissues. The bonding creates a larger macromolecule transforming the hylan fluid to a more cohesive gel which is hygroscopic, thus swelling with absorption of water. Particulate cross-linking thus creates water insoluble gels that will remain stable in tissue as they are slowly resorbed over months.1 (Figure 2) The physical properties of these bonded molecules give hylan fillers their unique qualities. They include:

1) Gel hardness or rheological (flow) properties as measured by energy stored as the gel is deferred by passage through a syringe and then restored to an expanded viscoelastic state.
2) Particle size within the gel
3) HA concentration of particles and gel in each milliliter
4) Swelling – the gel’s ability to resist dilution, thus a factor in the filler longevity
5) Soluble versus insoluble HA – particulated versus fluid components.

Each of these factors are a determinant in the properties of each of the individual HA’s and how they produce clinical effects for soft tissue augmentation.2 (Figure 3)

Medically useful hyaluronic acid was first isolated and purified in 1962 and licensed by the FDA to Pharmacea as Healon® for ophthalmic use. In the 1980’s, cross-linking was perfected to support the stability and viscoelastic properties as a “hyaluronan”. Biomatrix developed hylaform (hylan B) as the first hyaluronic acid skin filler which was released in Europe 1996.2

At present, there are four hyaluronic acid skin fillers FDA approved in the United States: Hylaform, Hylaform Plus, Captique and Restylane. Hylaform and Hylaform Plus are derived from the body of rooster combs which is purified and cross-linked with divinyl sulfone. It has been available worldwide since 1998 and recently in the United States in 2004.3

Clinical phase III studies were completed in the United States – 2002 – demonstrating non-inferiority to collagen for correction of nasolabial folds up to four months in a double blind randomized study carried out in eight sites with over 300 patients. There were very few adverse events with no evidence of immunogenic or allergic reactions with very little inflammatory response. Since then, the filler has favorable results for the treatment of facial wrinkles, folds and grooves, acne scars and used as a volume lip filler.4
Restylane is a bacterial derived, cross-linked hyaluronic acid gel produced from cultures of streptococcus equi. Though hylaform is avian derived and Restylane from a bacterial source, there is no significant allergy or immunogenicity found in either product. Initial European studies of this Sweedish product revealed excellent correction of the nasolabial folds with sustained correction in over 60% of patients over six months. (Olenius)5 An Italian study in which injections were at multiple sites including glabellar lines, nasolabial folds, marionette lines, lips and depressed acne scars resulted in good patient satisfaction with moderate improvement at eight months.6

The major U.S. study by Narins et al. was a randomized double-blind split face study with Restylane and Zyplast for efficacy and safety. At six months, Restylane was found to be superior to Zyplast in 60% of patients, and less Restylane was needed to reach full correction than Zyplast.7

Side effects noted for Restylane in all three studies included erythema, induration, edema and bruising. The induration and swelling were most problematic during the first few days but could last up to a week. Inflammatory reactions of the lips have been symptomatic enough to require a short course of systemic corticosteroids.5,6,7

There have been a number of reports, documenting allergic hypersensitivity reactions to both Restylane and Hylaform (Michaels, Lowe, Alster). Friedman presented a retrospective review of Restylane reactions in 2000 including patients worldwide. The larger series revealed one out of 1400 developed a documented hypersensitivity reaction with localized induration and swelling at the treatment site. Special attention was given to reactions of necrosis in the glabella area which has been reported in the past from Zyplast. This is thought to be due to embolization of particulate material in the subdermal plexus of vessels. None developed systemic allergic responses. Comparing this report to prior adverse event reporting, it was found there was less hypersensitivity reactions in 2000 which was thought to be due to the reformulation of Restylane in 1999 with less protein.

Though the above reviewed hyaluronic acid fillers are available in the United States, many more HA fillers are on the market in Europe. (Table I) These are of variable concentration, gel viscosity, particulate size and some with adjunctive agents. Very few have rigorous clinical testing though they have CE approval. Without FDA approval, there is significant risk for a clinician to import and use these products. Some, though are now undergoing clinical investigation in the United States for FDA approval. Juvederm is a hyaluronic acid filler developed by Corneal Industries (Paris, France) with CE approval since 2000. It presently is undergoing clinical investigation in the United States by Inamed and marketed in Europe under the name Hydrafil. Juvederm differs from the other FDA approved HA products as it is a homogeneous gel rather than particulate-based, giving it less exposure for inflammation and degradation. It is available in three forms: Juvederm-18 for superficial wrinkles; Juvederm-24 used in the mid and upper dermis; and Juvederm-30 which is longer lasting for medium and deeper dermal injections.8 Phase III clinical trials are presently underway in the United States. This and other new HA products are referred to as monophasic as the gel phase predominates rather than particles. The clinical advantages of longevity and less inflammation is yet to be established.

Patient treatment with hyaluronic acid fillers.
In evaluating a patient for an HA filler, one must conduct a full evaluation of what the patient desires and whether the product can fulfill their wishes. One must evaluate the depth of the fold or wrinkle, the area to be treated (eyelid skin versus nasolabial) prior treatments, allergies, pain tolerance, down time, tolerance and financial impact with those variables the clinician then must objectively evaluate the wrinkle, fold or groove to be treated as to depth, how much filler needed, asymmetry and skin type.

Choosing the correct filler is important for natural results. Restylane or Hylaform will give natural and biocompatible results filling nasolabial folds or lip volume filling but will not produce good results for treatment of fine lines in eyelids or vertical fine lines on lips. Zyderm or Cosmoderm is our available filler for the upper dermis. Deeper grooves or folds can be treated with the larger particle hyaluronic acid, Hylaform Plus, but can also be treated with Restylane or Captique. (Table II) (Table III)

After a full pretreatment consultation and the decision for the appropriate hyaluronic acid filler is made, the patient’s face is cleaned with disinfectant and pretreatment photographs are taken. It is important for the patient to be seated in an upright position to visualize the gravitational effect of the wrinkles and folds. It is preferred that the patient’s head is supported with a headrest.

Hyaluronic acid preparations do not contain lidocaine thus separate anesthesia is necessary. The choices include: topical anesthetics, field block, and peripheral nerve block. These may be accompanied by anxiolytics if needed and “talkesthesia”. (Table IV)

Topical anesthesia can provide adequate anesthesia for many patients, especially with limited treatment on the nasolabial folds or marionette lines. Lip augmentation or coverage of multiple areas in the perioral region invariably requires lidocaine injection for infraorbital and mental nerve blocks. The proper use of an infraorbital nerve block will give good anesthesia for the upper lip supplemented by a lower lip mental block and the extended mucosal miniblock for the lateral commissure and surrounding perioral skin. (illustration) Using this technique, full anesthesia of the perioral area can be obtained.9 (Figure 4)

Hylans are generally injected through a 30 gauge needle though the larger particle materials may require a 27 gauge needle. For hylans, more pressure is required through the plunger of the 1 cc. syringe than injecting collagen because of the intrinsic rheological properties of the gel as it is deformed through the needle. It then expands within the tissue giving a greater volume swell than seen with collagen. The needle bevel can be either up or down but the physician must direct the filler into the mid to deep dermis. This can be monitored by the back pressure felt on the plunger. Injecting into the subcutaneous tissue will release the filler too quickly through the needle and the needle should be pulled back until appropriate positioning is established.

Injection techniques include linear threading, serial puncture and fanning. (Figure 5) While serial puncture is most commonly used for collagen injections, retrograde linear threading is most appropriate for hyaluronic acid injections, especially in nasolabial folds and lip filling. The needle is placed in mid to deep dermis at 30 to 60 degree angle and then advanced horizontally below the wrinkle or groove. The filler is released as the needle is withdrawn, monitoring its placement within mid dermis. Placed too high, a blanch or “peau d’orange” will occur and too deep the filler will be in the subcutaneous tissue. This technique is repeated until the volume defect is fully corrected. One should ensure full correction is achieved yet overcorrection is not produced. This technique is commonly used for glabellar furrows, forehead wrinkles, nasolabial folds and lip augmentation.10

Fanning technique is a variation of linear threading in which the needle is redirected in a triangular or a circular volume defect until it is corrected. It is commonly used for filling the labial triangle at the superior aspect of the nasolabial fold, the lower lip and marionette, deeper lip filling and brow augmentation. Serial puncture, though used less for hylans – is helpful for the deep filling of tear troughs, touching up lips and nasolabial folds. Injecting too superficially can produce nodules and sausage-like deformity on the skin surface with depot induration that may last for weeks. (Figure 6)

After injection, the clinician can use massage to smooth irregularities or nodules and move material to the most aesthetic position. An icepack is used after injections to relieve discomfort and reduce swelling. HA fillers are hygroscopic and may increase correction 10-15% after injection unlike collagen which loses volume. (Figure 7)

Areas most amenable to hyaluronic acid fillers include nasolabial folds, marionette lines, lip augmentation, brow augmentation and forehead and glabellar folds not amenable to botulinum toxin.

The following approaches are used in specific areas:

1) Nasolabial Folds – Folds are variable from deep furrows to superficial wrinkles, dependent on whether the folds are induced by strong facial muscles and those induced by SMAS ptosis. Each requires different injection techniques and variable viscosity of filler. (Figure 8, 9)
a. Deep furrows
i. Restylane or Hylaform Plus
ii. Linear threading and fanning the superior triangle
b. Superficial wrinkles
i. Restylane, Hylaform or Captique
ii. Linear threading and serial puncture
c. Technical pearls
i. Stretch and compress skin to visualize the fold
ii. Inject medial to fold to avoid further cheek ptosis
iii. Avoid multiple punctures to reduce the incidence of bruising
2) Lips – Hyaluronic acid filler treatments are performed for lip augmentation in younger patients and lip reshaping for the older patient who has a loss of volume, while collagen can be used at the vermilion and for the correction of the radial grooves. The lower lips should be filled evenly with upper lips as the central lower lip normally protrudes slightly beyond the upper lip. (Figure 10)

Lip injections are painful and a full perioral nerve block should be performed as described previously. Lips are filled in three distinctive planes:
1) The vermilion
2) The wet-dry junction of the red lip
3) The dental arcade giving superior lip volume through the mucosa

Hyaluronic acid is especially useful as a lip filler because of its hygroscopic property and the natural viscoelastic feel and appearance. Fine vertical lines may not be correctable with presently approved HA and need a more superficial filler such as Cosmoderm or Zyderm I. Other techniques to correct older or dynamic lips include botulinum toxin, non-ablative or ablative laser resurfacing and chemical peeling.

Hylaform and Captique are less inflammatory than Restylane for which erythema, induration and lip edema may last as long as one week. Nodules and asymmetry may occur which can be corrected by touch-up and massage.10

It is important not to overfill lips, especially when patients ask for it. This is especially important at the medial tubercle of the upper lip as it may present a “duck-bill” appearance. (Figure 11)
4) Marionette Lines – Filling the marionette lines lift the corners of the mouth offsetting the sad or aging oral appearance. The lines are formed by the muscle depressor anguli oris and the platysma with a loss of overlying volume. Filling the depression involves injecting the line and the medial triangle from the lateral lower lip skin and vermilion to the modeolus. A stiff hyaluronic acid filler such as Restylane will deliver volume as well as lift the lip commissures. The clinician can use a combination of retrograde linear threading and fanning technique to give the necessary mid and deep volume filling. It is important to keep the injection under and medial to the fold as a lateral injection will increase the appearance of the fold. The patient with significant elastosis would benefit from injecting multiple layers using serial puncture technique as well to give full filling and prevent deep lumps. (Figure 12)
5) Facial Shaping – Deeper volume filling can be used for facial shaping. Though large volume results are best achieved with fat or Sculptra, hyaluronic acids can be used for limited areas such as brow elevation, tear troughs and localized cheek defects. The brow and cheeks are to be injected in deep dermis and subcutaneous tissue while tear trough deformities of the lower eyelids are approached with an HA injection along the bony orbital rim below the orbicularis muscle but not penetrating the orbital septum. This injection should be reserved for those with extensive filling experience. (Figure 13)

Hyaluronic acid fillers are today the most popular skin agent for filling wrinkles and grooves caused by facial aging. It, though, should be considered one of many tools available to the physician for correction of facial aging skin.