COSMETIC
`
`Practical Use of Juve´derm: Early Experience
`
`Kevin C. Smith, M.D.
`Niagara Falls, Ontario, Canada
`
`Background: This article is intended to provide practical information on the use
`of Juve´derm Ultra and Juve´derm Ultra Plus injectable gel fillers and to highlight
`differences between the injection techniques and uses of these fillers and those
`of gel-particle suspensions. The author’s purpose was to provide early infor-
`mation to clinicians who perform aesthetic surgery.
`Methods: The author discusses the properties of the Juve´derm family of prod-
`ucts, compares these with particulate gel fillers, and makes recommendations
`for achieving optimal outcomes with Juve´derm as well as dermal fillers in
`general.
`Results: When correcting relatively fine and superficial lines, or for first-time
`treatment of the lips, Juve´derm Ultra is preferred. Juve´derm Ultra Plus is useful
`for correction of deeper wrinkles and folds. Cohesive, homogenous gel fillers
`such as Juve´derm require gentle, gradual injection, which facilitates very accu-
`rate delivery to the site while minimizing the risk of disengagement of the needle
`from the Luer lock hub of the syringe. These fillers appear to remain in the
`desired location and do not flow away from the injection point into unintended
`areas, so that a somewhat smaller amount of filler is required for a given degree
`of correction. Both the Juve´derm preparations tend to blend in with the treated
`area in a shorter period of time compared with gel-particle suspensions. Finally,
`cohesive gels appear to be associated with a lesser degree of swelling in the
`24-hour period after the procedure, particularly in the lips.
`Conclusions: Juve´derm Ultra and Juve´derm Ultra Plus are new-generation hy-
`aluronic acid fillers used to treat superficial lines and deeper folds, respectively.
`(Plast.
`They require administration by gentle, gradual, and precise injection.
`Reconstr. Surg. 120 (Suppl.): 67S, 2007.)
`
`Hyaluronic acid dermal fillers, alone or in
`
`combination with botulinum toxin type A,
`have been shown to be effective in treat-
`ing deep resting rhytides and folds.1–5 Juve´derm
`Ultra and Juve´derm Ultra Plus (Allergan, Inc.,
`Irvine, Calif.) injectable gels have been on the
`market in most European countries and Canada
`since 2003, and in some markets longer, and
`were introduced to the U.S. market in 2007. They
`are cohesive, homogenous gels made from hyal-
`uronic acid, which is derived from bacterial fer-
`mentation, and are cross-linked using the butane-
`diol-diglycidyl-ether chemistry which is also used in
`the preparation of particulate gel suspension fill-
`ers. Juve´derm Ultra and Juve´derm Ultra Plus were
`formulated with the goals of providing optimal
`flow, predictable delivery of product to the treated
`area, and prolonged duration of cosmetic benefit.
`
`From Niagara Falls Dermatology and Skin Care Center.
`Received for publication July 18, 2007; accepted July 31,
`2007.
`Copyright ©2007 by the American Society of Plastic Surgeons
`DOI: 10.1097/01.prs.0000285107.16836.16
`
`Juve´derm is produced using a proprietary modu-
`lation of the butane-diol-diglycidyl-ether cross-
`linking chemistry as well as the post–cross-linking
`processing of the components used in the
`preparation.6 About 10% non–cross-linked hyal-
`uronic acid is included in the formulations to op-
`timize the flow properties of the material.
`Juve´derm Ultra and Juve´derm Ultra Plus are
`both designed for injection into the middle to
`deep dermis for correction of superficial facial
`lines and scars.7,8 The more viscous Juve´derm
`Ultra Plus formulation is optimized for deep
`dermal injection and also for placement of de-
`pots of material (e.g.,
`in the supraperiosteal
`
`FDA Status and Approved Uses: Juve´derm 30,
`24HV, and 30HV are injectable gels approved
`by the FDA and indicated for injection into
`the middle to deep dermis for correction of
`moderate to severe facial wrinkles and folds
`(such as nasolabial folds).
`
`www.PRSJournal.com
`
`67S
`
`Exhibit 1009
`Prollenium v. Allergan
`
`

`

`Plastic and Reconstructive Surgery • November Supplement 2007
`
`Fig. 1. Cheek renewal before (left) and10 days after (right) treatment with Juve´derm Ultra Plus (2.0 ml per cheek). (Photographs
`courtesy of Kent Remington, M.D.)
`
`area) in cases where restoration of volume is
`desired on the upper cheeks or elsewhere (Fig.
`1). Recent data from a large-scale clinical trial in
`nasolabial folds (presented at the 2007 Annual
`Meeting of the American Society for Aesthetic
`Plastic Surgery, April 19 through 24, 2007) dem-
`onstrated that the benefit of treatment with Juve´-
`derm Ultra lasts for up to 9 months or longer,
`while the effect of Juve´derm Ultra Plus may last
`12 months or longer.6 The U.S. Food and Drug
`Administration recently announced a label ex-
`tension for Juve´derm Ultra and Juve´derm Ultra
`Plus, indicating that the cosmetic benefit from
`both products may last for about 1 year—longer
`than clinical studies supporting Food and Drug
`Administration approval of other hyaluronic
`acid fillers.9
`Juve´derm Ultra and Juve´derm Ultra Plus, mar-
`keted by Allergan, are supplied in syringes with a
`volume of 0.8 ml.
`CLINICAL APPLICATIONS
`General Considerations for Injection
`Juve´derm Ultra can be injected through a 30-
`gauge needle, but I usually find it optimal to use
`a 1.25-inch, 27-gauge needle when injecting either
`preparation (the same is true for gel-particle sus-
`pensions). The longer needle allows for a smaller
`number of insertions, which I have found reduces
`the risk of bleeding and bruising and facilitates the
`creation of a long, smooth, linear deposit of ma-
`terial rather than the series of deposits that result
`when a half-inch needle is used.
`
`Treatment of Fine Lines
`When treating very fine and superficial lines
`(e.g., perioral lines, transverse “necklace” lines,
`
`68S
`
`and transverse lines on the forehead), Juve´derm
`Ultra is optimally injected through a 31-gauge nee-
`dle. A particularly effective and well-tolerated
`technique that has evolved in my practice is to load
`0.1-ml aliquots of Juve´derm Ultra into the proxi-
`mal barrel of a 0.3-ml BD-II diabetic syringe with
`a swedged-on 31-gauge, 0.8-cm needle. The
`plunger is put back into the syringe, air is expelled
`from the barrel, and then the needle can be used
`to perform a series of very finely controlled injec-
`tions. There is excellent control of the extrusion
`rate because the very small barrel diameter of this
`syringe provides a high degree of mechanical ad-
`vantage for the injector (Fig. 2). The small amount
`of shear the product is exposed to while passing
`through the 31-gauge, 0.8-cm needle does not
`seem to significantly degrade the duration of cos-
`metic benefit.
`
`Choosing between Juve´derm Ultra and
`Juve´derm Ultra Plus
`In my experience, patients who are new to
`lip enhancement have been more satisfied with
`Juve´derm Ultra, which is somewhat softer and
`more malleable than Juve´derm Ultra Plus. Ex-
`perienced patients and those with thick lips
`(particularly men) appear to do very well with
`Juve´derm Ultra Plus. I have found the latter to
`be optimal for deep dermal injections in areas
`such as the nasolabial folds, for supraperiosteal
`injections in areas such as the prejowl sulcus,
`and for volume restoration in the upper cheeks
`(Fig. 3). Juve´derm Ultra can also be layered over
`Juve´derm Ultra Plus in cases where there is a
`superficial
`line overlying a deeper defect or
`crease, most commonly in the nasolabial folds.
`
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`

`Volume 120, Number 6S • Practical Use of Juve´derm
`
`Fig. 2. Transverse forehead lines before (left) and immediately after (right) use of Juve´derm Ultra administered with a BD-II diabetic
`syringe with a 31-gauge, 0.8 cm needle.
`
`Juve´derm Ultra is the preferred product for use
`in thin-skinned areas such as the tear trough.
`
`Correction of Errors and Complications with
`Hyaluronic Acid Fillers
`Compared with the various non– hyaluronic
`acid fillers, an advantage of using hyaluronic
`acid fillers such as Juve´derm or hyaluronic acid
`gel-particle suspensions is that areas of excess
`fullness, inadvertent superficial placement of
`filler, and some other rare problems can be
`corrected simply by injecting hyaluronidase.10 –12
`When administering any type of filler, it is
`important to carefully examine the treatment
`
`site by visual inspection and palpation to detect
`any pre-existing asymmetries or subcutaneous
`masses, and to discuss these observations with
`the patient. Inspection and palpation are also
`important immediately after treatment. Any ar-
`eas of excess fullness or superficial placement of
`filler should be identified and massaged into the
`correct state before the patient leaves the office.
`Application of water-based ultrasound gel to
`the gloved fingers before pretreatment or post-
`treatment examination or manipulation of the
`treated area can enhance tactile feedback as well
`as improve the sensation experienced by the
`patient during examination.
`
`Fig. 3. Before (left) and 2 weeks after (right) use of Juve´derm Ultra Plus to treat marionette lines and prejowl sulcus. (Photographs
`courtesy of Kent Remington, M.D.)
`
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`Plastic and Reconstructive Surgery • November Supplement 2007
`
`Fig. 4. (Above, left) Initial injection point of a gel-particle suspension hyaluronic acid filler used to treat the nasolabial fold. (Above,
`right) Arrows indicate unwanted migration of the gel-particle suspension away from the intended site. (Center, left) Gel-particle
`suspension can be seen extending toward the vermilion border of the lip. (Center, right) Injection of Juve´derm Ultra Plus into a similar
`location in the nasolabial fold. (Below, left) Injection of Juve´derm Ultra Plus completed. Product can be observed only at the intended
`site. (Below, right) Nasolabial fold correction following gentle massage. No migration is noted for Juve´derm Ultra Plus.
`
`COMPARISON OF INJECTION
`TECHNIQUES AND OUTCOMES WITH
`HYALURONIC ACID GELS AND
`GEL-PARTICLE SUSPENSIONS
`In my experience, one subtle difference be-
`tween the injection of cohesive, homogenous gel
`fillers such as Juve´derm and granular hyaluronic
`
`acid suspensions is that homogenous gels are gen-
`erally easier to inject at a slow and consistent rate
`with steady thumb pressure. The rheological (flow)
`properties of granular suspensions can require a
`relatively high level of pressure on the plunger to
`initiate flow, followed by a somewhat lower thumb
`pressure after flow is established and during extru-
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`Volume 120, Number 6S • Practical Use of Juve´derm
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`Fig. 5. (Above, left) Patient before treatment of nasolabial folds. She had never been treated previously with fillers,
`botulinum toxin type A, lasers, or surgery. (Above, right) One week after injection of Perlane into the right nasolabial fold
`andJuve´dermUltraPlusintotheleftfold.(Below,left)Threemonthsafterinitialinjections.(Below,right)At6monthsafter
`treatment, the nasolabial fold treated with Juve´derm Ultra Plus has maintained clinical improvement.
`
`sion of product. The need for continuous modula-
`tion of thumb pressure to obtain the desired extru-
`sion rate of particulate gel fillers can result in
`variances in flow rate. By contrast, the flow proper-
`ties of Juve´derm facilitate gentle, gradual delivery of
`product to the treated area.
`As with any filler, if too much force is applied,
`excessive hydrostatic pressure in the syringe can
`cause disengagement of the needle from the hub.
`To prevent this, injectors can ensure that the nee-
`dle is firmly attached to the syringe, that injection
`is gradual, and that steady, rather than heavy,
`force is applied to the plunger. I have also found
`that the moderate rate of flow causes more gradual
`distension of tissue, resulting in less patient dis-
`comfort. Gradual, steady flow of product into the
`treated area also facilitates correct placement of
`the filler.
`An important difference, in my experience,
`has been that Juve´derm remains in the area where
`
`it is injected, because of its cohesive nature and
`high viscosity, and does not flow away from the
`injection point to an appreciable degree. Gel-par-
`ticle suspension fillers, on the other hand, are
`slurries, and so tend to behave like fluids during
`the injection process. I have noticed that gel-par-
`ticle suspensions sometimes flow away from the
`injection point, following the path of least resis-
`tance. This can cause filling of unintended areas
`and waste of product (Fig. 4). My experience has
`been that because cohesive gel implants such as
`Juve´derm tend to stay where they are injected, and
`they fill more precisely and more efficiently. Pre-
`cise and efficient filling also logically translates
`into smaller volumes of filler needed to achieve
`the desired degree of correction compared with
`gel-particle suspension hyaluronic acid fillers.
`I have also noticed that Juve´derm blends in
`completely with the treated area within a few days,
`thereby improving patient satisfaction with treat-
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`Plastic and Reconstructive Surgery • November Supplement 2007
`
`ment results. Final integration of gel-particle sus-
`pensions with the treated area often seems to take
`longer, possibly reducing patient satisfaction. The
`relatively short time to integration of Juve´derm
`with the treated area increases the likelihood of
`creating a good “first impression,” which may pos-
`itively influence the patient’s subsequent assess-
`ment of procedures. Photographs comparing the
`duration of cosmetic benefit of Juve´derm Ultra
`Plus with a gel-particle suspension are shown in
`Figure 5.
`I have also noted less swelling during the night
`following the procedure with Juve´derm, particu-
`larly after lip enhancement. I attribute this finding
`to differences in the amounts of free (“non– cross-
`linked”) hyaluronic acid in the products and in
`the rates at which tissue is exposed to this free
`hyaluronic acid. About 10 percent of the hyal-
`uronic acid in Juve´derm is non– cross-linked, and
`this smaller fraction is homogenously distributed
`and sequestered within the mass of cross-linked
`hyaluronic acid. This may result in the free hyal-
`uronic acid component of Juve´derm not being
`exposed as a bolus to the injected tissue. Rather,
`it appears to gradually diffuse from the gel mass
`into the injected area, probably over a period of
`weeks to months.
`By comparison, particle-based products tend
`to contain a considerably larger amount of free
`hyaluronic acid (typically around 20 percent of
`the total hyaluronic acid in the syringe), and all
`of this free hyaluronic acid is found in the ve-
`hicle system (where it is used as a gelling agent
`to keep the particles in suspension). All of this
`free hyaluronic acid is exposed to patient tissues
`within minutes to hours after injection. Thus, it
`may be that the differences in swelling during
`the 24-hour period after injection are related to
`differences in the rate at which tissues in the
`injected area are exposed to the free hyaluronic
`acid of the injected product.
`Guidelines for the use of hyaluronic acid fillers
`of any type are listed below (these guidelines apply
`to all filler injections):
`
`1. Application of firm, steady pressure to the in-
`jected area for 5 full minutes, starting as soon
`as possible after the needle is withdrawn from
`the skin, can significantly reduce the inci-
`dence and severity of bleeding and of late-
`presenting bruises.
`2. Patients should be instructed to go about
`their normal activities, including eating, wash-
`ing, and applying makeup, but to strictly avoid
`massaging or manipulating the treated area.
`
`72S
`
`Disturbance of the site may displace the in-
`jected material and could also increase the
`chance of a bruise developing from a trauma-
`tized blood vessel.
`3. Standardized pretreatment photographs
`should always be obtained. In general, when
`photographing patients before treatment with
`fillers, it is ideal to have symmetrical lighting of
`the patient, either by dual flash or flood lamps
`or simply by being positioned so that ambient
`light falls in a symmetrical manner on the
`patient’s face. To facilitate this procedure, it is
`helpful to place a mark on the floor where
`patients should stand while being photo-
`graphed.
`4. A good practice is to stop after treating one
`side of the face to let patients examine them-
`selves with a large hand mirror. At this point
`in the procedure, patients can easily appre-
`ciate the difference between the treated and
`untreated sides of the face.
`5. It is also wise to see new patients 2 weeks
`after their first treatment in order to ob-
`tain timely feedback about their percep-
`tion of the procedure. Satisfaction can of-
`ten be enhanced by holding the patient’s
`pretreatment photograph beside his or
`her face as the patient looks into a large
`hand mirror. Additional treatments are of-
`ten requested following this before-and-
`after comparison.
`
`SUMMARY AND CONCLUSIONS
`Juve´derm Ultra and Juve´derm Ultra Plus are
`cohesive, homogenous injectable gels made from
`hyaluronic acid derived from bacterial fermenta-
`tion. They have a well-established record of safety
`in Europe, Canada, and elsewhere, and have re-
`cently been introduced in the United States. Their
`proprietary application of butane-diol-diglycidyl-
`ether cross-linking chemistry and post– cross-link-
`ing processing of the gel produces smooth flow,
`predictable delivery, and prolonged duration of cos-
`metic effect of approximately 1 year—longer than
`clinical studies supporting Food and Drug Admin-
`istration approval of other hyaluronic acid fillers.
`An advantage of using hyaluronic acid fillers
`such as Juve´derm and hyaluronic acid gel-particle
`suspensions, compared with the various non– hya-
`luronic acid fillers, is that areas of excess fullness
`or inadvertent superficial placement of filler can
`be corrected by injecting hyaluronidase.
`Based on my experience, there appear to be
`four basic, clinically relevant differences between
`Juve´derm and hyaluronic acid gel-particle suspen-
`
`

`

`Volume 120, Number 6S • Practical Use of Juve´derm
`
`sions. Juve´derm encourages administration by
`gentle, gradual, and precise placement of prod-
`uct. Juve´derm also tends to remain in the treated
`area and does not flow into unintended areas,
`which I attribute to its properties as a cohesive,
`homogenous gel as compared with a fluid-like
`slurry. In addition, there appears to be less noc-
`turnal swelling after the use of Juve´derm, partic-
`ularly after lip enhancement. This observation
`may be explained by the presence of a smaller
`amount of free hyaluronic acid and a slower rate
`at which tissue in the treated area is exposed to
`free hyaluronic acid. Finally, Juve´derm blends
`with the treated area within a few days, contrib-
`uting to rapid patient satisfaction with the feel and
`look of the treated area.
`The foregoing conclusions are based on clin-
`ical experience alone in an effort to provide early
`information about the use of Juve´derm. Addi-
`tional experience and research are needed to
`properly define the validity and relative impor-
`tance of these differences in the clinical setting.
`Trials to further explore the clinical properties of
`Juve´derm are ongoing.
`
`Kevin C. Smith, M.D.
`Dermatology
`201-6453 Morrison Street
`Niagara Falls, Ontario, Canada L2E 7H1
`Dermatology
`175-2315 Whirlpool Street
`Niagara Falls, N.Y. 14305
`www.smithlaser.com
`ksmithderm@gmail.com
`
`DISCLOSURES
`Dr. Smith is a consultant to and serves as an inves-
`tigator and speaker for Allergan, Inc. Editorial assistance
`for this article was provided by Health Learning Systems
`and supported by funding from Allergan, Inc.
`
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`story.aspx?NewsEntityId⫽61178. Accessed June 27, 2007.
`10. Brody, H. J. Use of hyaluronidase in the treatment of gran-
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`acid misplacement. Dermatol. Surg. 31: 893, 2005.
`11. Hirsch, R. J., Lupo, M., Cohen, J. L., and Duffy, D. Delayed
`presentation of impending necrosis following soft tis-
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`ful management with hyaluronidase. J. Drugs Dermatol. 6:
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`12. Lambros, V. The use of hyaluronidase to reverse the effects of
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