I
Ft Dermatologic Therapy, Vol. 1 9, 2006, 1 4 1 -1 50 Pinted in the United States . All rights reserued
Copyright
@
Blackwell Publishing, Inc., 2006
DERMATOLOGIC THERAPY ISSN 1396-0296
Hyaluronic acid fillers
G
crrrrrmrorund. GARy
D. MoNuErr* & KvrE M. CornvraNt
*Total Skin and Beauty Dermatology Centen Department of Dermatology, Department of Ophthalmology, Uniuersity of Alabama at Birmingham, and TOchsner Clinic, New Orleans, Louisiana
tircnsdCopy B: +612 !t!19{}'500 mu.opyrfltrcor,ru
ABSTRACT: Although hyaluronic acids are a relatively new treatment for facial lines and wrinkles, they have provided numerous advances in the area of cosmetic surgery. This article discusses the
inherent properties of hyaluronic acid fillers that make them ideal for treatment of facial lines. It encompasses a review of the current literature on U.S. Food and Drug Administration-approved hyaluronic acid fillers and the role that each of these fillers currently has in facial cosmetics. This article also discusses the potential pitfalls and adverse effects that can be associated with using hyaluronic acids for filling facial lines. Finally, it serves as an overview of current techniques for clinical assessment of patients as well as administration and treatment of facial lines and wrinkles. KEIWORDS: Captique, filler, hylaform, hyaluronic acid, restylane, review, wrinkles
Hyaluronic acid background The development of temporary yet noninvasive techniques for wrinkle and volume correction has spawned a worldwide industry of soft tissue and skin fiIlers. Beginning with the release of Zyderm bovine in the early 1980s, numerous techniques for correction of nasolabial furrows, forehead, and glabella wrinkles and lip augmentation have been developed. The qubst for other temporary agents that are biocompatible without the necessity of skin testing for allergy led to the development of hyaluronic acid (FIA) 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 the various FIA flller products, their differences and their uses as soft tissue flllers. Hyaluronic acid is a naturally occurring linear polysaccharide found in the extracellular matrix of connective tissue, sy,novial fluid, and other tissues. Hyaluronic acid structure consists of polyanionic disaccharide units of glucouronic acid and N-acetyl-glucosamine connected by alternating p Address correspondence and reprint requests to: Gary D: Monheit, MD, Department of Dermatology, Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, AL, or e-mail:
[email protected] (Gary Monheit, MD),
[email protected] (Kyle Coleman, MD).
1-3 and p 1-4 bonds (see FIG. 1). There is no antigenic specificity for species or tissues; and thus, these agents have a low potential for allergic or immunogenic reaction. In humans, FIA 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 "biofllrri' around bacteria. There are high concentrations of these acids in soft connective tissue extracellular matrix, vitrous of eye, hyaline cartilage, qmovial joint fluid, disc nucleus, umbilical cord, and skin dermis. Hyaluronic acids have speciflc physical and biochemical properties in normal tissue that
make them ideal structural compounds. When HAs are incorporated into aqueous solution, hydrogen bonding occurs between adjacent carboxyl and N-acetyl groups; this feature allows HAs to maintain conformational stiffness and retain water. One gram of HA can bind up to 6 L of water (1). As a physical background material, it has functions in 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 scavenging of free radicals. Hyaluronic acid was first isolated 70 years ago. Its name is derived from hyalos (Greek for glassy) for its space filling and viscoelastic properties. Natural HA has a half-life in tissue of only 1 to 2 days before undergoing aqueous dilution and
141
Monheit &Coleman
FIG.
l.
Hyaluronic acid.
enzyme degradation in the liver to carbon dioxide and water. Ascorbic acid and iron derivatives are
essential cofactors
in this
degradation reaction
(2). For use as an effective dermal flller, one to two
days is insufficient; and a longer tissue residue time is required. Cross-linking native HA forms larger, more stable molecules with similar biocompatibiliry and viscoelastic filling properties yet longer residue time in tissues. The bonding creates a larger macromolecule, which trapsforms the hylan fluid to a more cohesive gel. Because of the structure of HAs, the gel is hygroscopic, meaning it swells by absorbing water from the surrounding atmo-
sphere. Particulate cross-linking thus creates water-insoluble gels that will remain stable in tissue as they are slowly resorbed over a period of months. The physical properties of these bonded molecules give each hylan flller its unique qualities. These properties include: 1) Gel hardness or rheological (flow) properties as measured by energy stored in the gel. This is deferred as the gel passes through a syringe and is then released as it is restored to an expanded
FIG.2. Cross-linking creates
a
water-insoluble
Bel,
stabilizing the molecule.
viscoelastic state.
2) Particle size within the gel 3) Concentration of HA particles and gel per milliliter 4) Swelling-the gel's abilityto resist dilution, thus a factor in the flller longevity 5) The ratio of soluble to insoluble HA - particulated versus fluid components (see FIG. 2).
These properties determine the behavior of each
individual HA product and determine how each
FIG. 3. Physical characteristics ofHA-based fllers.
produces clinical effects for soft tissue augmentation. Medically useful FIA was first isolated and purifled in 1962; it was licensed by the Food and Drug Administration (FDA) to Pharmacea as Healon@
skin fillers available in the United
for ophthalmic use. In the
1980s, cross-linking was perfected to support the stability and visco
elastic properties as a "hyaluronan." Biomatrix developed Hylaform (Iname d Corporation) (hylan B) as the flrst FIA skin flller; this product was released in Europe 1996 (see FIG. 3).
142
At present, there are four, FDA-approved HA States:
Hylaform, Hylaform Plus, Captique (Inamed Cor-
poration), and Restylane (Medicis Aesthetics, Inc.). Hylaform and Hylaform Plus are derived from the body of rooster combs, purifled and cross-linked with divinyl sulfone. Hylaform has a high degree of cross-linking and has an HA
Hyaluronic acidfillers
or
immunogenicity found
in
either product.
Restylane has a higher concentration of FIA than Hylaform at 20 mg/ml. Initial European studies of Restylane revealed excellent correction of the nasolabial folds with sustained correction in over
60% of patients over 6 months (4). An Italian study in which injections were placed at multiple
FIG.4. The modified infraorbital nerve block ls used for perioral andlip filling.
concentration of 5.5 mg/ml. Hylaform has been available worldwide since 1998 and recently in the United States sinc.e 2004.
Clinical phase
III
studies of Hylaform were
completed in the United States in 2002 (3). These double-blinded, randomized studies were carried out in eight sites with over 300 patients tested and demonstrated at least equal results compared to bovine collagen (Zyplast) for correction of nasolabial folds for up to 4 months. There were very few adverse events with no evidence of immunogenic or allergic reactions with very little inflammatory response to the compound. Since then, the filler has been used with favorable results for the treatment of facial wrinkles, folds and grooves, acne scars, and is being used as a volume lip flller. Hyalform plus is a variant on Hylaform. It has larger particle size than its predecessor and may require a 27-gauge needle for administration. It was approved in the United States in October of 2004. In a prospective, double-blind, randomized,
multicenter study, patients randomly received Hylaform Plus in one nasolabial fold and Hylaform gel in the other. The FDA concluded that Hylaform Plus was comparable to Hylaform gel in correcting nasolabial folds at 12 weeks. In addition, no severe adverse events were observed (see FIG.4). Restylane is a bacterial derived, cross-linked
HA gel produced from cultures of Streptococcus equi. lt was the fust nonanimal stabilized HA approved in the United States; Restylane contains trace amounts of bacterial proteins and exists as small particles. Although Hylaform is avian derived and Resrylane is from a bacterial source, there have been no reports of signiflcant allergy
sites including glabellar lines, nasolabial folds, marionette lines, lips, and depressed acne scars resulted in good patient satisfaction with moderate improvement at I months (5). The major U.S. study on Restylane by Narins et al. was a randomized double-blind split-face study with Resrylane and Zyplast for efficacy and safety. At 6 months, Restylane was found to be superior to Zyplast in 60% of patients, and less volume of Restylane was required to reach full correction than Zyplast (6). Side effects noted for Restylane in all major studies included erythema, induration, edema, and bruising. The induration and swelling were most problematic during the flrst few days but could last up to a week; howeveg these usually
resolved without much difficulty. Reported inflammatory reactions of the lips have sometimes been symptomatic enough to require a short course of systemic corticosteroids. Captique is the newest HA approved
in the United States. It was approved for use in December 2004 for correction of moderate to severe wrinkles around the nose and mouth. It is a nonanimal stabilized FIA and contains small amounts of bacterial derived proteins. It is manufactured by Genzyme, distributed by Inamed and is claimed to have a unique cross-linking. The only literature on this material is derived from studies of Hylaform, which is produced using the same process. The difference is the bacterial instead of avian source. All FDA studies referred to in the Captique package insert are based on the Hylaform studies. There have been a number of reports documenting occasional allergic hypersensitivity reactions to both Restylane and Hylaform (7-9). Friedman presented a retrospective review of Restylane reactions in 2000, which included patients worldwide (10). The larger series revealed I out of 1400 developed a documented hypersensitivity reaction with localized induration and swelling at the treatment site. None of the patients developed systemic allergic responses. Comparing this report to prior adverse event reporting, there were less hypersensitivity reactions in 2000, which was thought to be due to the reformulation of Restylane in 1999 with less 143
Monheit & Colernan
Table
l.
Hyaluronic acid fillers
USA Restylane
Hlaform HylaformPlus Captique Europe
Table
2. Primary indications for hyaluronic acid
fillers Photoaging wrinkles Nasolabial folds Lip rhytids Marionette lines
Volume enhancement Lip filling and contouring Chin and cheek augmentation Tear trough treatment
Restylane, Fineline, and Perlane
Hyacel Hylaform, Hyladerm Iuvederm, Hydrafill Surgiderm, Surgilips Achyal, Hyal2000, Hylan SES Matredur, Rofilan Esthelis
Viscontour
protein. Special attention was given to reactions of necrosis in the glabella area that have also been reported in the past from Zyplast. This reaction is thought to be the lesult of embolization of particulate material in the subdermal plexus of vessels.
Although the previously mentioned reviewed in the United States, many more HA fillers are on the market in Europe (Table 1). These are of variable concentration, gel viscosity, particulate size, and some include adjunctive agents. Although they have CE approval, very few have rigorous clinical testing. Without FDA approval, there is significant risk for a U.S. clinician to import and use these products. Some, however, are now undergoing clinical investigation in the United States for potential FDA approval. Iuvederm is a HA filler developed by Corneal Industries (Paris, France) with CE approval since 2000. It presently is undergoing clinical investigation in the United States by Inamed Pharmaceuticals and is marketed in Europe under the name Hydrafil. Iuvederm differs from the other FDA-approved FIA products in that it is a homogeneous gel rather than particulatebased, theoretically giving it less potential for inflammation and degradation. It is available in three forms: Iuvederm-18 for superficial wrinkles, Iuvederm-24 used in the mid and upper dermis, and Iuvederm-3O, which is longer lasting for medium and deeper dermal injections. 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 over the particulate state. The clinical advantages of longevity and decreased inflammation reactions are yet to be established. F{A fillers are available
144
Patient treatment with HA fillers In evaluating a patient for an HA filler, one must first begin with an understanding of patient desires and assess whether or not the product can
fulfill their wishes (11). One must evaluate the area to be treated (eyelid skin vs. nasolabial), prior treatments, allergies, pain tolerance, downtime, and the patient's financial situation. With those variables in mind, the clinician then must objectively evaluate the wrinkle, depth of the fold or groove to be treated, volume of filler needed, skin t)4)e, as well as any pre-existing asymmetry. Choosing the correct filler is important for achieving natural results. Restylane or Hylaform will usually give natural and biocompatible results for nasolabial folds or lip volume filling, but will not produce good results for treatment of flne lines in eyelids or vertical flne lines on lips. HAs are too viscous for superficial augmentation and will produce visible nodules if injected too superflcially. Less viscous agents such as Zyderm or Cosmoderm are more appropriate for the upper dermis. Deeper grooves or folds are better treated with the larger-particle Hylaform Plus than with Hylaform, but can also be treated with Restylane or Captique (Table2). Layering of superficial and deep flllers will often give a better result than using a single agent, especially when the wrinkle or furrowhas both superficial and deep component. After a fi:ll pretreatment consultation and the decision for the appropriate HA filler is made, the patient's face is cleansed with disinfectant and pretreatment photographs are taken. It is impor-
tant for the patient to be seated in an upright position to visualize the gravitational effect of the wrinkles and folds. The patient's head should be supported with a headrest to minimize inadvertent movements. Magniflcation can be useftrl to aid in the appreciation of subtle contour abnormalities. Food and Drug Administration-approved HA preparations do not contain lidocaine, thus separate anesthesia is necessary. The choices include topical anesthetics, field block, and peripheral nerve block (12). These may be accompanied by anxiolytics if needed and "talkesthesia."
Hyaluronic acidfillers Table
3. Commonly used topical anesthetic agents
Commonly used topical anesthetic agents Betacaine enhanced gel, BetaCaine Plus
LMx4andLMx5 EMtA (lidocaine pritocaine) cream Ice of other cryoesthetic agents
Vibratory counterstimulation
end up in the subcutaneous tissue and produce minimal result. This technique is repeated until the volume defect is fully corrected. One shottld ensure that full correction is achieved while avoiding overcorrection. Injecting too superficially can produce nodules and sausage-like deformity on the skin surface with induration that may last for weeks.
Topical anesthetics can provide adequate anesthesia for many patients, especially with limited treatment of the nasolabial folds or marionette lines. Lip augmentation or treatment of multiple
in the perioral region invariably requires lidocaine iniection for infraorbital and mental areas
nerve blocks. The proper technique of regional block for lip injection includes an infraorbital nerve block, which will provide 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. Using this technique, excellent anesthesia of the perioral area can be obtained (Table 3).
Hyaluronic acids are generally injected through a 30 gauge needle, although the larger particle materials may require a 27-garge needle. Hyaluronic acids require more pressure on the plunger of I-cc syringes than when injecting collagen because of the intrinsic rheological properties of the gel as it is deformed through the needle. The
HA then expands within the tissue, giving
a
greater volume swell than seen with collagen. The
needle bevel can be either up or dor,rrn, but the physician must direct the flller into the mid to deep dermis. This can be monitored by the back pressure felt on the plunger. Injecting into the subcutaneous tissue will waste the material. When the physician feels the filler release too quickly through the needle, it is likely positioned in the fat. The needle should then be pulled back until appropriate positioning is established. Injection techniques include linear threading,
serial puncture, and fanning. Although serial puncture is most commonly used for collagen injections, retrograde linear threading is often used for HA injections, especially when filling nasola-
bial furrows and lips. The needle is placed in mid to deep dermis at a 30-60-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. If placed too high, a blanch or peau d'orange will occur. Filler placed too deep will
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 furrow the lower lip and marionette, deeper lip filling, and brow augmentation. Serial puncture through multiple sites in and around the defect is also useful for injecting HAs. This approach is helpful for the deep fllling of tear troughs and touching up lips and nasolabial folds. A combination of serial injection and linear threading can combine the benefits of both techniques (see FIG.5).
After injection, the physician should gently to smooth irregularities
massage the treated area
or nodules and move material to the most esthetic position. An ice pack used after injections helps
relieve discomfort and reduces swelling. After treatments, the patient should be advised to minimize movement of the treated areas and to avoid alcohol and anticoagulants. It is important to remember that HA fillers are hygroscopic and may increase correction 10-157o after injection unlike collagen, which loses volume in the ensuing weeks (see FIG.6, FIG. 7). Areas most amenable to HA fillers include nasolabial furrows, marionette lines, and forehead and glabellar folds not amenable to botulinum toxin; these fillers are also have excellent results in lip and brow augmentation. The following approaches are used in specific areas:
1. Nasolabial furrows are formed by the junction of the orbicularis oris, levator labii superioris, and zygomaticus major muscles. Furrows can vary from deep grooves to superficial wrinkles, dependent on whether these are induced by strong facial muscles or by overlying folds as a result of skin and superficial musculoaponeurotic system ptosis. Each requires different injection techniques and variable viscosity of filler. a. Deep furrows.
i. Restylane or Hylaform Plus.
ii. Linear threading and fanning the superior tri. angle combined with serial puncture.
145
Monheit & Coleman
/--1 --{J
Ar
//"/
-\.)
I
t. &
., 7
!
FIG.
5. Injection
FIG.
6.
146
techniques. (a) Serial puncture. (b) Linear threading. (c) Fanning, (d) Cross-hatching.
Nasolabial fold. (a) Pre; (b) post.
Hyaluronic acidfillers
FIG.7.
Captique. (a) HA Injection before. (b) Three months postiniection.
b. Superficial wri4kles i. Restylane, Hylaform, or Captique.
ii. Linear threading and/or 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. Minimize punctures to reduce the incidence of bruising.
2. Lips - HA flller treatments are performed for lip augmentation in younger patients and lip reshaping for the older patient who has a loss of volume. Collagen (Zyplast/Cosmoplast) can be used at the vermilion and for the correction of the radial grooves (ZydermlCosmoderm). The lower lips should be filled alongwith the upper lips. The central lower lip normally protrudes
slightly beyond the upper lip. The upper lip should be about 75-B0To of the volume of the lower lip. Lip injections are painful and a full perioral nerve block should be performed as described previously. Lips are fllled in three distinctive planes:
1) The vermilion border. 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 flller because of its hygroscopic property and the natural viscoelastic feel and appearance. Fine vertical lines may develop nodules if treated with presently approved FIAs. A more superficial filler such
as Cosmoderm or Zyderm I is more forgiving and can be used to slightly overcorrect, as these mate-
rials tend to subside after injection. Other techniques to correct older or dynamic lips include botulinum toxin, nonablative or ablative laser resurfacing, and chemical peeling. Hylaform and Captique seem to be less inflammatory than Restylane for which erythema, induration, and lip edema may last as long as 1 week.
Nodules may occur with all HA lip injections; these can usually be corrected by massage or intralesional steroid injections if the problem persists. Asymmetry can easily be rectifled by injecting additional material (see FIG. B, FIG.9). It is important not to overfill lips, even if patients ask for it. This is especially important at the medial tubercle of the upper lip as it may present a "duck-bill" appearance. Additional treatment can always be used later if needed. 3. Marionette lines - fllling 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 injectingthe line andthe medial triangle from the lateral lower lip skin and vermilion to the modeolus. A stiff FIA filler such as Restylane will deliver volume as well as lift the lip commissures. The physician 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 actually increase
147
Monheit &Coleman
FIG. B. Hyalform is an ideal Posttreatment.
lip filler with immediate, natural results, and little inflammation. (a) Pretreatment.
(b)
4. Facial shaping - deeper-volume filling can be
used for facial shaping. However, large volume contourfillingis best achieved with fat or Sculptra, HAs can be used for limited areas such as
brow elevation, tear troughs, and localized cheek defects. The browand cheeks are injected
in the deep dermis and subcutaneous
tissue.
Tear trough deformities of the medial and infe-
rior lower eyelids can be improved with
an
HA injection along the bony orbital rim below
the orbicularis muscle without penetrating the orbital septum. This injection technique should be reserved for those with extensive fiIling experience (see FIG. 11). In conclusion, HA flllers are currently the most
popular skin agents for f,lling wrinkles and grooves caused by facial aging; and many new products will soon be available for use in the FIG,9. Overcorrection of upper lip, creating'duck bill" appearance.
the appearance of the fold. The patient with significant elastosis may beneflt from injecting in multiple layers using the serial puncture technique as well to give complete filling and prevent deep lumps (see FIG. 10).
148
United States. They are, however, but one of many tools available to the physician for correction of facial aging skin. In order to achieve the best results, it is important to remember the inherent properties of each filler. Recognizing when to use a hyaluronic and the beneflts to each particular flller is the flrst step. Understanding the various techniques for administering these fillers in different areas of the face will help develop a mastery of these products and their use in cosmesis.
Hy al uro ni c aci d fi.lle rs
FIG. 10. Marionette lines (a) pre; (b) post.
FIG. 11. TeartroughdeformitytreatedwithCaptique.Injectionismadedeeptoortricularisalongtheorbitalrim.(a)pre;(b)post.
References 1. Sutherland I. Novel and established applications of microbial polysaccharides. Trends Biotechnol 1988: l6: 41-46. 2. Fink RM, Lengfelder E. Flyaluronic acid degradation by ascorbic acid ar-rd influence of iron. Free Rad Res Comm 1987: 3: 85-92.
3. Morrheit GD. "Hylaform: a new hyaluronic acid filler" in Soft Tissue Augmentation. Facial Plast Surg 2004: 20: 153r57. 4. Olenius M. The first clinical study using a nerv biodegradable implant for treatment of lips, wrinkles, and folds. Aesthetic Plast Surg I9BB: 22:97-107. 5. Duranti F, Salti G, Bovani B, Calandm M, Rosati ML. Inject-
able hyaluronic acid gel for soft tissue augmentation:
a
149
funheitaColeman clinical and histological study. Dermatol Surg l99B: 24: 1317-1325.
?,
Rutin M, Smith
10. Freidman PM, Mafimg EA, IGuvar AN, Gerronemus RG.
Safety data non-injectable non-animal stabilized hyaluronic acid gel br soft tissue augmentation. Dermatol Surg 2ffi2:28:491-494. ll. Monheit GD. "Management of the nasolabial fold," in soft tissue augmentation. In: Cumrthers J, Cumrthers A, eds. .Procedures in Cosmetic Dermatology. london: Elsevier, 2fi)5: 128-130. 12. Grekin RC, Auletta MI. Iocat anesthesia in dermatologic surgery. JAmAcad Dermatol l99B: 19:599-614.
RS,
Brandt F,.Ieyden L lorenc
S.
588-595.
frriibn'm,'Alster IS. Cutaneous hypersensitivity neaction
,.b,iniecEb{g hyaluronic acid gel. Dermatol Surg 2000: 26: l35-r37. 0r
it
possible? Dermatol Surg 2O02: 28: 359-360.
A randomize4 double-blin{ multicenter comparison of the efficacy,a.d tole€bility of Restylane versus Zyplast for lhe @Etredoi'rof nasolabial folds. Dermatol Surg 20Gl: 29:
6. Narins
Z;.
9. Midrcels P. Human anti-hyaluronic acid antibodies: is
E
NJ' Maxwell CA, Patanaik R. Adverse reactions to derusal fiUers: review. Dermatol Surg 2fi)5: 3l: l6f6-f625.
150