`Mary P. Lupo, MD
`
`Nonsurgical procedures have become very popular for the rejuvenation of the aging face.
`Trends now are for less invasive procedures as well as for more preventative intervention
`to slow the damage from ultraviolet light and environmental factors, as well as from intrinsic
`aging. The goal of these procedures is to eliminate or delay the need for corrective surgery.
`The regular use of sunscreens; retinoids and improved cosmeceuticals; injectable neuro-
`toxins; soft-tissue augmentation products; and minimally invasive laser, light, and radio-
`frequency treatments are decreasing and delaying need for invasive procedures. Injectable
`fillers entered mainstream cosmetic medicine with the development of bovine collagen
`injections in the 1980s. The availability of improved fillers that are less allergenic and
`longer lasting has resulted in a renaissance in filler techniques. No single filler has proven
`to be more popular than the category of hyaluronic acids (HA). This article will review the
`use of the hyaluronic acid fillers that are currently approved for use by the Federal Drug
`Administration in the United States and describe the significant differences between them
`to assist the practicing cosmetic physician in choosing and using this category of dermal
`filler.
`Semin Cutan Med Surg 25:122-126 © 2006 Elsevier Inc. All rights reserved.
`
`Today’s cosmetic dermatologist is the specialist in nonsur-
`
`gical rejuvenation of the aging face. Many tools and tech-
`niques are available to achieve this goal. Although the process
`of skin aging is complex and beyond the scope of this review,
`it is sufficient to state that correction of aging skin requires a
`global approach that addresses the sequelae of both intrinsic
`(chronological) as well as extrinsic (primarily solar-induced)
`aging, using combination protocols.1
`Cosmeceuticals have been developed that mitigate the
`signs of photoaging, and this topic is explored more exten-
`sively in this issue. Topical antioxidants are available that
`reduce free radical damage to the skin, stimulate collagen
`production, improve color and texture, and decrease fine
`lines. Additional ingredients may improve the barrier func-
`tion of dehydrated, aging skin.2-4 It must always be remem-
`bered, however,
`that
`topical retinoids remain the gold
`standard in treating the visible signs of photoaging.5 Less-
`aggressive techniques to enhance the appearance of the skin
`include light chemical peels and particle resurfacing also
`known as “microdermabrasion.” These are popular because
`they are “no downtime” procedures.6,7 Injectable neurotoxins
`such as botulinum toxin type A dramatically improve wrin-
`kles that are the result of facial musculature movement.8 La-
`
`Department of Dermatology, Tulane Medical School, New Orleans, LA.
`Address correspondence to Mary P. Lupo, MD, Clinical Professor of Derma-
`tology, Tulane Medical School, New Orleans, Louisiana, 145 Robert
`E Lee Blvd., Suite 302, New Orleans, LA, 70124.
`
`122
`
`1085-5629/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.
`doi:10.1016/j.sder.2006.06.011
`
`ser, pulsed noncoherent light, and other energy sources such
`as radiofrequency energy improve skin coloration, thicken
`dermal architecture, and tighten lax skin without cutting.9,10
`The final, and perhaps most popular, tool to add to combi-
`nation protocols for noninvasive facial rejuvenation is dermal
`fillers.
`
`Filler History
`For more than 20 years, the only fillers approved by the Food
`and Drug Administration (FDA) in the United States were
`forms of bovine collagen. Available in 3 forms, Zyderm I,
`Zyderm II, and the more highly cross linked Zyplast, they
`were our only realistic options for most patients wanting soft
`tissue augmentation. Allergic reaction rates were approxi-
`mately 3% before the adoption of 2 pretreatment skin
`tests.11,12 The availability of human-derived CosmoDermR
`and CosmoPlastR in March, 2003 obviated the need for skin
`testing and was a major breakthrough in esthetic dermatol-
`ogy. Patients could be treated at the time of consultation.
`Still, there was a need for fillers with greater longevity and
`more volume restoration than these collagen based products
`provided. Hyaluronic acid fillers, widely available outside of
`the United States, were the obvious choice to fill this need.
`The visible signs of
`facial aging partially result from
`changes in dentition and bony architecture. Facial fat loss
`and diminished dermal thickness from extrinsic (primarily
`photodamage) and intrinsic (the result of time and genetics)
`aging also contribute to the visible signs of aging. The addi-
`
`Exhibit 1005
`Prollenium v. Allergan
`
`
`
`Hyaluronic acid fillers in facial rejuvenation
`
`123
`
`Figure 1 A 28-year-old woman before restylane injection.
`
`Figure 2 The same woman 1 week after injection into nasolabial fold.
`
`tional loss of the collagen and the glycosaminoglycans (GAG)
`support structures that provide turgidity and support to the
`skin adds further to the appearance of aging. This loss of
`dermal and subcutaneous support results in folds and hol-
`lows that age the face. Filling concavities of the face with
`fillers such as the hyaluronic acids, restores a more youthful
`appearance without the need for cutting and redraping as is
`done with a face lift.
`
`Science of Hyaluronics
`Hyaluronic acid (HA) is one of the most prevalent glycosami-
`noglycans in the dermis, so its utility as a dermal filler is
`obvious. Because HA is not species specific, there is theoret-
`ically no need for skin testing for allergenicity. HA is a poly-
`saccharide composed of repeating units of D-glucuronic acid
`
`Figure 3 A 52-year-old African-American woman before injection.
`
`Figure 4 The same woman after Hylaform Plus and Restylane into
`nasolabial and marionette folds.
`
`
`
`124
`
`M.P. Lupo
`
`Figure 5 A 24-year-old woman.
`
`Figure 6 The same woman immediately after an injection of Hy-
`laform into the lips.
`
`and N-acetyl-glucosamine. It is found in all tissues of verte-
`brates and is very prevalent in human skin. It has been dem-
`onstrated to be decreased in intrinsically aged skin and to be
`altered in photoaged skin.13,14 HA is highly hydrophilic,
`binding much more than its weight in water. To be practical
`as a filler, however, crosslinking of the polysaccharide chains
`is necessary to slow degradation. Hyaluronic acid fillers are
`mainly used in the nasolabial fold, which was the site of
`original testing for FDA approval (Figs. 1 and 2). They are
`also commonly used “off label” in many other areas, includ-
`ing the lips and marionette folds (Figs. 3, 4, 5, and 6). Facial
`reshaping can be achieved by injecting HA into the cheek
`prominence and lateral brow. Advanced injectors place HA
`in the glabela crease, mental crease as well as the ocular
`sulcus and tear trough region.15
`Injection technique varies among injectors, with antegrade
`and retrograde threading as well as serial puncture being
`used. When injecting HA, it is important for the tip of the
`needle to be in the mid to deep dermis to avoid bluish dis-
`coloration or lumping that may be seen with superficial in-
`jections. Placement of HA too deeply in the dermis will com-
`promise the duration and extent of the correction obtained.
`Before injection near the orbital rim, it is important to aspi-
`rate the syringe to avoid inadvertent intravascular injection in
`this highly vascular region.
`At the present time, there are 4 HA fillers approved for use
`in the United States by the FDA. RestylaneR (Medicis Aesthet-
`ics Inc., Scottsdale, AZ), a nonanimal stabilized hyaluronic
`acid (NASHA) of medium viscosity for mid- to deep dermal
`correction, was the first approved in December 2003, fol-
`lowed by the approval of HylaformR, which is derived from
`rooster combs, in April 2004. Hylaform PlusR, formulated for
`deeper dermal injection was approved in October 2004 and
`CaptiqueTM followed in December 2004. A summary of the
`difference of these products is found in Table 1. Differences
`in molecular weight, particle size, and proprietary differences
`in crosslinking have resulted in theoretical variations in
`product behavior and duration. Some published experts be-
`lieve that Hylaform has characteristics that result in de-
`creased swelling and bruising.16 There is widespread anec-
`dotal reporting of greater duration with Restylane. A recent
`
`published report documented higher efficacy and patient sat-
`isfaction with Restylane over Hylaform after 12 weeks.17 An-
`other study showed more durable correction at six months
`with Restylane Perlane (a more viscous NASHA not currently
`available in the United States) over Hylaform.18 I have found
`benefit from layering medium-viscosity products such as Re-
`stylane in the mid dermis with larger particle Hylaform Plus
`in the deep dermis for those with deep nasolabial folds. Hy-
`laform can replace Cosmoderm in the higher dermis if in-
`jected with a fine gauge needle to fill more etched and fine
`skin lines.
`
`Complications
`There is no medical procedure totally devoid of risks. It is
`important to review all known potential side effects with the
`patient to obtain informed medical consent. Clinical trials
`have documented the overwhelming safety profile of all
`forms of HA.19 Transient and self-limiting redness and swell-
`ing are common following injections of HA and this is due to
`the hydrophilic nature of HA. For this reason, correction
`should never be greater than 100%. Pain associated with
`injection of HA may be managed by the use of both topical
`and injected anesthetic agents. This is especially important
`for lip injections where a superficial gingival block in the
`sulcus of the oral cavity provides one hour of anesthesia
`without the extended numbness and occasional morbidity
`seen with a nerve block. Despite adequate anesthesia, pa-
`tients can expect tenderness for 1 to 2 days after injection.
`Rarely do patients require treatment with analgesics.
`Nodule formation is possible after injection of any filler.
`Typically, this results from intermittent over-injection and
`the rate of nodule formation decreases with injector experi-
`ence. If nodule formation is noted, gentle massage may de-
`crease the appearance of the nodule but care should be taken
`to avoid over vigorous massage which will increase bruising.
`Bruising is, by far, the most common complication that is
`disturbing to patients (Fig. 7). Redness, swelling, and tender-
`ness usually fade after 24 hours, but bruising may persist for
`days and sometimes up to 1 week. One possible reason that
`
`
`
`Hyaluronic acid fillers in facial rejuvenation
`
`Table 1 Product Differences
`
`Source
`Concentration
`MW of raw HA
`Median particle size
`Polymer
`
`Restylane
`Bacterial
`20 mg/ml
`1.5–2 M
`300 microns
`Short chain, tight
`configuration
`BDDE
`Crosslink agent
`BDDE, 1,4-butandiol diglycidylether; DVS, divinyl sulfone.
`
`Hylaform
`Avian
`5.5 mg/ml
`4–6 M
`500 microns
`Long chain, loose
`configuration
`DVS
`
`Hylaform Plus
`Avian
`5.5 mg/ml
`4–6 M
`700 microns
`Long chain, loose
`configuration
`DVS
`
`125
`
`Captique
`Bacterial
`5.5 mg/ml
`1.5–2 M
`500 microns
`Short chain, tight
`configuration
`DVS
`
`HA causes more bruising is its structurally similar to heparin.
`Baumann has advocated the use of collagen injection along
`with the HA to reduce bruising.20 She postulates that the
`lidocaine in the Cosmoderm or Cosmoplast has an antibruis-
`ing benefit, but there have been no controlled studies to
`substantiate this hypothesis. Lidocaine is known to decrease
`the activation of eosinophils that may stimulate bruising.21
`Reducing the number of needle sticks in a given treatment
`has decreased bruising in my practice and is one reason I
`recommend threading over serial puncture with HA fillers.
`Finally, true allergic reactions to HA have been reported.22,23
`Treatment with intralesional and topical corticosteroids as
`well as topical immune modulating agents have been tried
`with limited success.23,24 One of the unique benefits of utiliz-
`ing HA fillers is the ability to correct lumps and even elimi-
`nate allergic responses by the injection of hyaluronidase to
`enzymatically degrade the HA filler quickly. Hyaluronidase
`injections are the treatment of choice to reverse allergic reac-
`tions.24,25
`
`The Future
`It is reasonable for the practicing esthetic physician to expect
`additional fillers to be available in the US over the next several
`years. European and Canadian physicians have experience
`with other forms of Restylane such as Perlane for deep dermal
`and subcutaneous correction and Restylane Touch for papil-
`lary dermal correction of fine lines. A smaller particle form of
`Hylaform may come to the U.S. market as well. Another HA
`
`Figure 7 A bruise is evident 3 days after restylane injection.
`
`filler, Juvederm, is widely available and popular outside the
`US and is being evaluated for FDA approval. Discussion of
`this product in this article is not appropriate since it is cur-
`rently undergoing FDA evaluation, but experts report excel-
`lent cosmetic correction with natural softness combined with
`long duration.26,27
`What is clear is that worldwide usage and published re-
`ports confirm the efficacy and safety of hyaluronic acid fillers.
`Popularity of such fillers continues to increase as the aging
`population seeks options to correct the signs of aging without
`surgery. Fillers such as the hyaluronic acids are obviously one
`of the key components to the successful combination treat-
`ment of the aging face.
`
`References
`1. Lupo MP: Photoaging threat advisory: a treatment algorithm. Cosmetic
`Dermatol 18:221-224, 2005
`2. Darr D, Combs S, Dunston S, et al: Effectiveness of antioxidants (vita-
`min C and E) with and without sunscreens as topical photoprotectants.
`Acta Dermatol Venereol 76:264-268, 1996
`3. Tanno O, Ota Y, Kitamura N, et al: Nicotinamide increases biosynthesis
`of ceramides as well as other stratum corneum lipids to improve the
`epidermal permeability barrier. Br J Dermatol 143:524-531, 2000
`4. Elmets CA, Singh D, Tubesing K, et al: Cutaneous photoprotection
`from ultraviolet injury by green tea polyphenols. J Am Acad Dermatol
`44:425-432, 2001
`5. Kligman AM, Grove JL, Hirose R, et al: Topical tretinoin for photoaged
`skin. J Am Acad Dermatol 15:836-859, 1986
`6. Moy LS, Murad H, Moy RL: Glycolic acid peels for the treatment of
`wrinkles and photoaging. J Dermatol Surg Oncol 19:243-246, 1993
`7. Comite SL, Krishtul A, Tan MH: Using microdermabrasion to treat
`sun-induced facial lentigines and photoaging. Cosmetic Dermatol 16:
`40-42, 2003
`8. Klein A: The art and science of treating facial wrinkles with botulinum
`toxin A. J Am Acad Dermatol 53:364-365, 2005
`9. Bitter PH: Noninvasive rejuvenation of photodamaged skin using serial,
`full-faced intense pulsed light treatments. Dermatol Surg 26:835-843,
`2000
`10. Fisher GH, Jacobson LG, Bernstein LJ, et al: Nonablative radiofre-
`quency treatment of facial laxity. Dermatol Surg 31:1237-1241, 2005
`11. Cooperman LS, Mackinnon V, Bechler G, et al: Injectable collagen: a six
`year clinical investigation. Aesthetic Plast Surg 9:145-151, 1985
`12. Klein AW: In favor of double testing. J Dermatol Surg Oncol 15:263,
`1989
`13. Ghersetich I, Lotti T, Campanile G, et al: Hyaluronic acid in cutaneous
`intrinsic aging. Int J Dermatol 33:119-122, 1994
`14. Bernstein EF, Underhill CB, Hahn PJ, et al: Chronic sun exposure alters
`both the content and distribution of dermal glycosaminoglycans. Br J
`Dermatol 135:255-262, 1996
`15. de Maio M: The minimal approach: an innovation in facial cosmetic
`procedures. Aesth Plast Surg 28:295-300, 2004
`
`
`
`126
`
`M.P. Lupo
`
`16. Baumann L: Replacing dermal constituents lost through aging with
`dermal fillers. Semin Cutan Med Surg 20:125-128, 2004
`17. Rao J, Chi GC, Goldman MP: Clinical comparison between two hyal-
`uronic acid-derived fillers in the treatment of nasolabial folds: hylaform
`versus restylane. Dermatol Surg 31:1587-1590, 2005
`18. Carruthers A, Carey W, DeLorenzi C, et al: Randomized, double-blind
`comparison of the efficacy of two hyaluronic acid derivatives, restylane
`perlane and hylaform, in the treatment of nasolabial folds. Dermatol
`Surg 31:1591-1598, 2005
`19. Narins RS, Brandt F, Leyden J, et al: A randomized, double-blind,
`multicenter comparison of the efficacy and tolerability of restylane
`versus Zyplast for the correction of nasolabial folds. Dermatol Surg
`29:588-595, 2003
`20. Baumann L. Cosmoderm/Cosmoplast (human bioengineered collagen)
`for the aging face. Facial Plast Surg 20:125-128, 2004
`21. Okada S, Hagan JB, Kato M, et al: Lidocaine and its analogues inhibit
`
`and activation of human eosinophils.
`IL-5-mediated survival
`J Immunol 160:4010-4017, 1998
`22. Lupton JR, Alster TS: Cutaneous hypersensitivity reaction to injectable
`hyaluronic acid gel. Dermatol Surg 26:135-137, 2000
`23. Lowe NJ, Maxwell CA, Lowe P, et al: Hyaluronic acid fillers: adverse
`reactions and skin testing. J Am Acad Dermatol 45:930-933, 2001
`24. Brody HJ: Use of hyaluronidase in the treatment of granulomatous
`hyaluronic acid reactions or unwanted hyaluronic acid misplacement.
`Dermatol Surg 31:893-897, 2005
`25. Soparkur CNS, Patrinely JR: Managing inflammatory reactions to re-
`stylane. Opthal Plast Reconstr Surg 21:151-153, 2005
`26. Zbili M: Personal experience in the filling of wrinkles and remodeling
`lips with Juvederm. J de Med Esthet Chir Dermatol 29:241-246, 2002
`(translation)
`27. Saylan Z: Facial fillers and their complications. Aesthetic Surg J 23:221-
`224, 2003
`
`