COSMETIC
`
`A Brief Overview and History of Temporary
`Fillers: Evolution, Advantages, and Limitations
`
`Steven Fagien, M.D.
`Arnold W. Klein, M.D.
`Boca Raton, Fla.; and Los Angeles,
`Calif.
`
`Summary: Facial soft-tissue augmentation by injection has become increasingly
`popular as a minimally invasive option for patients seeking cosmetic facial
`enhancement. Surgical rejuvenation procedures of the face often relate to a less
`than comprehensive solution to many of the changes that occur with age.
`Indeed, the surgical “lift,” while providing the opportunity for soft-tissue repo-
`sitioning, often fails to provide volumetric restoration to the face that is lost with
`aging. Appreciating the necessity of replacing depleted soft tissue has allowed
`for a more comprehensive approach to total facial rejuvenation. Hundreds of
`filling agents are available worldwide, and the enormity of options has led to
`confusion about which agents work best, where, and why. The vast array of
`available soft-tissue filling agents can be distilled into two simple categories:
`nonpermanent and permanent. In this article, the authors mostly limit their
`discussion, consistent with the mission of this supplement, to the evolution of
`nonpermanent filling agents, providing a rationale for their emergence and
`(Plast. Reconstr. Surg. 120 (Suppl.): 8S, 2007.)
`their individual use.
`
`We have come to understand facial aging
`
`much better in recent years through a
`combination of revelations,
`including
`the actual anatomic and physical changes that
`occur with time and the failure of traditional
`surgical methods to address changes. In addi-
`tion, photographic comparative imaging and
`morphing techniques, as described and demon-
`strated by Lambros,1 have shed more light on the
`reality of facial change. As has been the case in
`aesthetic medicine, historically, the cure has re-
`lated more to available options and the often
`ill-conceived concepts of causation. Although fa-
`cial aging has been attributed primarily to soft-
`tissue descent, we now realize that qualitative
`and quantitative influences, including a deple-
`tion of components present in youth and volume
`loss, may have comparable relevance. Soft-tissue
`loss is now better understood and acknowledged
`as a necessary component that must be ad-
`dressed in a comprehensive reversal of facial
`aging. Moreover, the causes of facial volume loss
`and shifts are many and include contributions
`from chronic facial animation that were previ-
`
`From private practice and Aesthetic Eyelid Plastic Surgery,
`and Department of Medicine and Dermatology, University of
`California, Los Angeles.
`Received for publication March 3, 2006; accepted August
`31, 2006.
`Copyright ©2007 by the American Society of Plastic Surgeons
`DOI: 10.1097/01.prs.0000248788.97350.18
`
`ously less appreciated.1 The ability now both to
`address volume depletion and to modify its
`cause (for instance, with chemodenervation) has
`yielded a more powerful approach to nonsurgi-
`cal facial rejuvenation.
`
`HISTORY AND EVOLUTION
`One of the earliest agents used for soft-tissue
`augmentation was autologous fat, which was first
`used more than 100 years ago.2 Interest in autol-
`ogous fat transfer has been renewed by improved
`applications and techniques, but unlike most of
`the agents discussed in this article, autologous fat
`transfer is used primarily for subcutaneous volume
`augmentation.3,4 Of historical interest, most of
`the early dermal-filling materials were potentially
`long-lasting (even “permanent”) and were not
`necessarily native to the intended site. Paraffin, for
`instance, was used at the turn of the nineteenth
`century, but it fell into disfavor by the 1920s be-
`
`FDA Status and Approved Uses: For a com-
`plete list of the FDA status and approved uses
`for the fillers mentioned in this article, please
`see the information throughout the article or
`visit the following Web sites: www.plasticsurgery.
`org/media/press_releases/Injectables-at-a-
`Glance.cfm or www.surgery.org/download/
`injectablechart.pdf.
`
`8S
`
`www.PRSJournal.com
`
`Exhibit 1004
`Prollenium v. Allergan
`
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`

`Volume 120, Number 6S • History of Temporary Fillers
`
`cause of the appearance of severe granulomas.
`Nevertheless, its use continued in Asia throughout
`the 1960s. Pure injectable silicone was utilized by
`a relatively small group of physicians with mark-
`edly mixed reviews.5– 8 Others, albeit intuitively
`and anecdotally, without a strong scientific basis for
`their claims, felt that permanent agents such as these
`could cause severe facial distortion over time, hence
`their personal preferences for nonpermanent filling
`substances. Due in part to concerns about its use, the
`U.S. Food and Drug Administration eventually
`banned silicone for cosmetic procedures.9 Ulti-
`mately, we have come to a greater understand-
`ing of the benefits and limitations of a host of
`filling agents, including the appropriate applica-
`tion and what factors, such as technique, might con-
`tribute to untoward events. This is also true for sil-
`icone, with experienced injectors showing good
`results while minimizing complications.10–12 Re-
`cently, ophthalmologic 1000 centistokes of silicone
`was used in an off-label manner as a filling
`substance.13
`
`“COLLAGEN” PRODUCTS
`In 1958, Gross and Kirk at Harvard Medical
`School showed the potential for collagen ex-
`tracted from calf skin to produce a solid gel by
`gentle warming.14 In the early 1970s, a group of
`investigators at Stanford began work on a poten-
`tially useful injectable bovine collagen implant.
`This ultimately led to the development and ap-
`proval of the Zyderm (Allergan, Irvine, Calif.) bo-
`vine collagen implant in 1977.15 The early claims
`were that this filler could result in “collagen re-
`placement” and more long-lasting results. Expe-
`rience indicated otherwise. This led to the devel-
`opment of a more robust (cross-linked) form of
`the product called Zyplast, followed by the for-
`mulation of Zyderm 2, a more viscous form of the
`original Zyderm formulation that is used to treat
`moderate fine lines, wrinkles, and scars. These
`(pioneer) products paved the way for a better
`appreciation of what could be accomplished with
`filling agents in an outpatient setting by injection
`alone, with minimal downtime. Improved injec-
`tion methods, including serial puncture for im-
`plantation and lip augmentation, also contributed
`to the success (better results and improved per-
`sistence) of these products. The lack of satisfactory
`persistent correction with bovine collagen was
`more often technique-related than product-re-
`lated, although the reality was still that these
`agents, in most individuals, would last for only
`several months at best. The bovine collagen prod-
`ucts, which were really the first widely used, com-
`
`mercially available, injectable soft-tissue augmen-
`tation agents, suffered many of the casualties of
`being “first generation.” Physicians also often used
`ancillary (staff) help to implant these products,
`and little attention was paid to the details of im-
`plantation, which often yielded suboptimal re-
`sults. In addition, the rare occurrence of severe
`localized allergic reactions also raised many ques-
`tions regarding their usage. Satisfactory results
`could be obtained with these injectable collagen
`agents, however, and complaints were related
`mostly to the lack of persistence and the inability
`to substantially improve facial volume. There was
`also the requirement
`for skin testing, which
`evolved into double skin testing as physicians’ un-
`derstanding of collagen reactions became more
`sophisticated. Complications due to allergenicity
`were also most disconcerting, and these occur-
`rences were sometimes quite difficult to manage
`(Fig. 1). Many of these problems were related to
`the lack of physician appreciation of the most
`applicable facial regions and injection techniques
`associated with these products. The theoretic bio-
`compatibility of bovine collagen rested on the fact
`that the ultrastructure of type I collagen is quite
`similar among animal species. The risk of aller-
`genicity due to different species specifications was
`said to be addressed by modifications of the “ex-
`posed” protein segments through a variety of pro-
`cessing techniques. Processing of bovine collagen
`involves conceptual removal of the nonhelical
`amino and carboxyl telopeptides in an attempt to
`reduce the immunogenicity to make the bovine
`collagen more compatible with human tissue.
`Cross-linking was also considered to render the
`collagen fragments more resistant to enzymatic
`degradation and to seclude other heterogeneous
`segments. Although severe allergic reactions were,
`fortunately, relatively rare, there has been incon-
`sistent reporting, and best estimates of a severe
`reaction place it in the 5 percent range. Satisfac-
`tory results could be achieved, and the era of in-
`jectable bovine collagen facilitated an awakening
`of the field of soft-tissue augmentation. Other an-
`imal protein collagen-like products were intro-
`duced into the market, including porcine-derived
`collagen (Fibrel) and other bovine products avail-
`able outside of the United States. The require-
`ment for in-office formulation (Fibrel) and the
`lack of superiority over the then-available bovine
`products led to the continued use of the latter.
`Concerns regarding the allergenicity of the
`bovine products led to the concept of creating a
`nonallergenic human collagen. The first agent
`commercially available in the United States was
`
`9S
`
`

`

`Plastic and Reconstructive Surgery • November Supplement 2007
`
`Fig. 1. Collagen reactions. (Left) Acute ulcerative reaction to Zyplast placed into the nasolabial fold. This resolved spontaneously
`without intervention in 5 months. (Right) Chronic granulomatous reaction reportedly to Zyderm placed into the upper lip rhytides
`2 years earlier. The patient denied that any other product had ever been injected into the lip for augmentation. Intervention included
`intralesional injection of corticosteroids to cause focal dermal atrophy. Both patients had negative single skin tests to bovine collagen.
`
`Autologen (Autogenesis Technologies, Acton,
`Mass.). Research and development culminated in
`the ability to extract human dermis with intact
`collagen fibers for injection from skin obtained
`during any surgical procedure. With autologous
`dermal tissue matrix, there was no need for skin
`testing and concerns about allergic inflammation
`and potential communicable diseases were elim-
`inated. However, a relatively laborious process was
`required for skin harvest and procurement of the
`injectable Autologen (autologous human tissue
`dermal matrix). The skin was sent in sterile con-
`tainers for processing, which involved steriliza-
`tion with a proprietary technology that ex-
`tracted decellularized dermal
`components,
`including collagen fibers, in a viable injectable
`form.16 –20 The required process of custom pro-
`duction for each individual patient was rather
`costly and heralded the typical inconsistencies
`of products that lacked mass production. Fur-
`thermore, the product did not contain the li-
`docaine found in the bovine agents; many phy-
`sicians found it painful to inject, and it lacked
`the ease of use compared with the familiar bo-
`vine collagen. The viscosity of the early proto-
`types of this product also varied, and good re-
`sults required a level of precision that at the time
`was not commonly practiced.
`The interest in a readily available injectable
`human tissue matrix spawned the idea for a ca-
`daver-based allogeneic agent. Dermalogen (Col-
`lagenesis, Inc., Beverly, Mass.), identical to Au-
`tologen in structure and substance, was created,
`but the source, rather than being autologous, was
`skin obtained from approved tissue banks.21,22 One
`
`10S
`
`advantage was mass production, which allowed for
`greater quality assurance, mostly with regard to
`consistency, and lower costs. In contrast, the
`source of Autologen was limited, and turnaround
`of the product to the physician occurred despite
`slight variations in specifications.
`The earlier prototypes of Dermalogen and Au-
`tologen were not
`fibrillar-purified agents but
`rather dermal extracts with distinctly different
`flow characteristics compared with the bovine
`products.23 Dermalogen was refined in several
`ways. It was available in a 4% (40 mg/dl) range of
`concentration and could be injected through 27-
`gauge needles into the dermis. When a precision
`technique was used to administer the product, the
`results were highly satisfactory (Fig. 2).
`As with the introduction of most injectable
`products, rare reactions were seen early in the
`evolution that were related to product impuri-
`ties; these problems were eventually rectified.
`Although the many obstacles of the first human
`collagen injectable product were eventually over-
`come, its widespread use was limited as many
`awaited the introduction of newer agents that
`could both eradicate dermal defects and restore
`facial volume loss. In many ways, however, Der-
`malogen paved the way for other agents that could
`also satisfy the requirements of safety and efficacy
`with negligible adverse events and avoidance of
`skin testing.
`To address the concerns about allergenicity,
`CosmoDerm and CosmoPlast (Inamed Division of
`Allergan, Santa Barbara, Calif.), human tissue an-
`alogs to Zyderm and Zyplast, were introduced. In
`March of 2003, the U.S. Food and Drug Admin-
`
`

`

`Volume 120, Number 6S • History of Temporary Fillers
`
`Fig. 2. (Left) This patient presented for treatment of (mostly) upper lip rhytides and lip augmentation. (Right) Two months after final
`treatment with Dermalogen, with 1 ml administered in three sessions. The result lasted approximately 6 months.
`
`istration approved the CosmoDerm family of in-
`jectable dermal fillers (Allergan). CosmoDerm 1,
`CosmoDerm 2, and CosmoPlast were the first ap-
`proved bioengineered human collagen dermal
`fillers and the first approved fillers, according to
`the manufacturer, that were nonallergenic and
`did not require skin testing before use. Cosmo-
`Derm 1 has a collagen concentration of 3.5 per-
`cent and CosmoDerm 2 has a collagen concen-
`tration of 6.5 percent. Both are used to correct fine
`to moderate lines, wrinkles, and scars. Cosmo-
`Plast, which is cross-linked, is a more robust for-
`mulation and is indicated to treat deeper lines and
`folds.
`Another collagen-based product is Cymetra
`(micronized human cadaveric dermis; AlloDerm;
`LifeCell Corporation, Palo Alto, Calif.). The man-
`ufacturer claims a longevity of 3 to 9 months, but
`this injectable agent is costly. It costs about twice
`as much as collagen and typically requires multi-
`ple office visits. Fascian is an injectable human
`cadaveric fascia made by Biosystems (Beverly Hills,
`Calif.). First introduced in 1999, the manufacturer
`claimed that it lasted from 6 to 8 months. Most
`physicians, however, feel that its persistence is
`more comparable to the longevity of bovine col-
`lagen. In addition, both Cymetra and Fascian are
`relatively more difficult to use. In our experience,
`syringes are easily clogged by the product and the
`result can be irregular and “lumpy.” In addition,
`Cymetra and Fascian have not enjoyed popularity
`similar to that of other “collagen” agents for many
`reasons, including larger particle size, which re-
`quires larger needles that make precise intrader-
`mal injection difficult. Ultimately, they have not
`proven superior with regard to persistence. A new
`cross-linked porcine collagen, Evolence (Colbar
`LifeScience, Herzliya, Israel, acquired in July of
`
`2006 by Johnson & Johnson, Inc.), has shown
`promise, as there appears to be a renewed interest
`in collagen-based products with greater persis-
`tence due to cross-linking and other methods. In
`its first U.S. clinical trials, Evolence was matched
`against Zyplast for the treatment of nasolabial
`folds and showed equal efficacy in the short term
`and superiority to Zyplast beyond 6 months. Iso-
`lagen (Isologen Technologies, Inc., Paramus,
`N.J.), consisting of cultured autologous fibro-
`blasts, has also been reintroduced. With this filler,
`a dermal specimen is harvested from behind the
`ear and sent to the Isologen laboratory, where the
`fibroblasts are cultured and packaged for injec-
`tion into the patient. A test dose is required and
`it is reportedly quite expensive. There is no con-
`sensus regarding the validity of many anecdotal
`claims relating to both the real science and per-
`sistence. One study, however, reported that after
`two to three treatments the effects may last for up
`to 22 months.24
`
`HYALURONIC ACID PRODUCTS
`The concept of using hyaluronic acid for tissue
`augmentation was the result of years of research by
`Balazs and coworkers.25 Its use was justified be-
`cause it is a structural and elastic component of
`skin as well as partly responsible for maintaining
`skin hydration. Native hyaluronic acid, however,
`has a short residence time in the skin and likely
`lasts for only several days after injection. Clinically,
`hyaluronic acid had been used as a viscoelastic
`injectable material during intraocular surgery, to
`protect delicate structures such as the cornea dur-
`ing instrumentation of the anterior segment. Sev-
`eral derivatives of hyaluronic acid, including ani-
`mal and bacteria fermented products, had been
`introduced in both the ophthalmology and ortho-
`
`11S
`
`

`

`Plastic and Reconstructive Surgery • November Supplement 2007
`
`Fig.3. (Left)Thisyoungwomandesiredlipaugmentation.(Right)Postoperativeview,after1mlofRestylanewasappliedtotheupper
`and lower lips. This result lasted 4 months. Reproduced with permission from Steven Fagien, M.D.
`
`Fig. 4. (Left) This patient presented for treatment of early lower facial volume loss manifesting as extended marionette lines, peri-
`mental hollows, and reduced lip volume and definition. (Right) Postoperative view, after 2 ml (total) of Restylane was applied to these
`regions. Reproduced with permission from Steven Fagien, M.D.
`
`pedic fields, with no obvious concerns about al-
`lergenicity in lieu of the transient residence time.
`The concept of cross-linking, which was well
`known in the collagen industry, was then applied
`to the hyaluronic acid products in an attempt to
`improve persistence by fortifying the molecule
`against enzymatic degradation. In the late 1980s,
`investigators reported the potential for injectable
`cross-linked hyaluronan to have a prolonged res-
`idence time in tissue and yet have the same bio-
`compatibility as hyaluronan. In 1991, Piacquadio
`initiated a study of cross-linked hyaluronic acid
`(hylan B) for tissue augmentation.26
`
`The Food and Drug Administration’s approval
`of Restylane (nonanimal stabilized hyaluronic
`acid; Medicis, Scottsdale, Ariz.) in December of
`2003 began a new era of injectable soft-tissue
`agents in the United States. This product proved
`to have several advantages over the existing “col-
`lagen” products, mostly due to its greater persis-
`tence and because it was an off-the-shelf agent that
`could be used for volume augmentation. “Non-
`animal stabilized hyaluronic acid” simply indicates
`that the product is derived from a nonanimal
`source and is essentially “stabilized” by cross-link-
`ing. Several independent manufacturers of hyal-
`
`12S
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`

`Volume 120, Number 6S • History of Temporary Fillers
`
`Fig. 5. (Left) This patient presented in her forties with complaints of the recent onset of obvious nasolabial folds, oral commissures,
`and aging changes around the chin. (Right) Postoperative view, after 2.0 ml of Restylane was injected into the nasolabial folds and
`oral commissures, in addition to treatment around the chin. Reproduced with permission from Steven Fagien, M.D.
`
`Fig. 6. (Left) This patient presented with a significant depression along the central chin region and lower facial aging. (Right) Post-
`operative view, after 2 ml of Restylane was injected into mentum, upper and lower lips, and perimental hollows. Reproduced with
`permission from Steven Fagien, M.D.
`
`uronic acid products utilize proprietary cross-link-
`ing methods; these products have also been shown
`to be more resistant to enzyme degradation and,
`hence, have an improved residence time (com-
`pared with “free hyaluronic acid”) when injected
`into the dermis. The following is an abbreviated
`list of these agents (in alphabetical order): AcHyal
`(Tedec Meiji Farma, S.A., Madrid, Spain), Hydra
`Fill (Allergan), Hylaform and Hylaform Plus
`(Genzyme, Framingham, Mass.; distributed by
`Allergan), Captique (Genzyme and Allergan),
`Juve´derm, Juve´derm Ultra Plus, and Juve´derm
`Ultra (Allergan), Perlane (Q-Med, Uppsala, Swe-
`den), Purogen (Mentor, Santa Barbara, Calif.),
`Restylane (Medicis), Restylane Lip, Restylane Fine
`Line, and Restylane SubQ (Q-Med and Medicis),
`and Rofilan Gel (Rofil Medical International,
`Breda, The Netherlands).
`
`To date, Restylane has been the frontrunner
`in the vast sea of available hyaluronic acid filler
`products for a variety of reasons, including its ear-
`lier Food and Drug Administration approval, sat-
`isfactory safety margin, and beneficial effects.
`Guidelines on the most effective applications and
`usage were recently reported based on the con-
`sensus of a large group of experienced injectors
`across the aesthetic specialties.27,28
`Erroneously, however, there appeared to be
`the notion that persistence and enhanced aes-
`thetic effect could simply be accomplished by in-
`creasing concentration and/or
`cross-linking.
`What is also critical is a low-protein load of the
`source material from which the agent is derived.
`Furthermore, severely high concentrations of hy-
`aluronic acid, as well as the nature and concen-
`tration of the cross-linking agent, can affect the
`
`13S
`
`

`

`Plastic and Reconstructive Surgery • November Supplement 2007
`
`Fig. 7. (Left, above and below) This patient wished to improve the appearance of her deepened nasolabial folds and oral commis-
`sures. (Above, right) One-month postoperative view, after 2 ml of Restylane was injected into multiple planes (deep, mid-dermis, and
`superficial dermis) because of the depth of the folds and prior mediocre treatments. A satisfactory early result is seen. (Below, right)
`Four-month postoperative view, after resorption of the deeper injected product with persistence and visibility of the superficially
`placed product. This reflects an error in the superficial injection, which can result in a dramatically enhanced residence time. Re-
`produced with permission from Steven Fagien, M.D.
`
`biocompatibility of the agent. A multitude of hy-
`aluronic acid agents are now currently available
`worldwide with variations that define their unique
`individual characteristics, including source deri-
`vation (animal versus bacterial), cross-linking
`(both chemical method and degree), concentra-
`tion, amount of free hyaluronic acid (non– cross-
`linked), and particle size/uniformity (structure).
`Practical and theoretic differentiations include su-
`perior applicability of certain products to differ-
`ent regions, residence time and persistence, pa-
`tient comfort and the requirement for anesthetic,
`rheological and flow characteristics, gel hardness,
`and injectability. With appropriate and precise in-
`jection protocols, highly satisfactory results can be
`achieved with a variety of hyaluronic acid products
`primarily for the treatment of facial furrows and
`volume depletion (Figs. 3 through 6).
`
`It has always been our contention that a good
`injector can use any of these temporary products
`and get comparable results (including persis-
`tence) once he or she completely understands the
`nuances of each agent and applies the agent with
`appropriate precision. For example, a fine-line
`variety of hyaluronic acid (smaller-particle hyal-
`uronic acid) is more applicable to more superficial
`rhytides. Although this is not recommended by
`the manufacturer, by carefully using a 32-gauge
`needle, Restylane can be applied at the most dif-
`ficult (superficial) sites. Some evidence indicates
`that this decreases the bead size, thereby making
`Restylane useful for superficial applications. This
`phenomenon holds true for most of the collagen
`products as well. To date, however, the smaller-
`particle agents have not been impressive with re-
`gard to persistence. They have shown little to no
`
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`Volume 120, Number 6S • History of Temporary Fillers
`
`superiority to collagen products placed with pre-
`cision and herald the risk of visibility (detection)
`and palpability. These agents are all, however, less
`advantageous to the deeper dermis, and residence
`time/persistence is dramatically reduced in the
`subcutaneous space.
`More recently, we have observed a resurgence
`of the use of “collagen” for the superficial/papil-
`lary dermis. Hyaluronic acid agents have simply
`not worked well in most of these situations, and in
`fact are at the center of complaints about the use
`of hyaluronic acid. Visible and palpable nodulari-
`ties are a manifestation of attempting to place a
`viscous, clear, amorphous gel in the superficial
`dermis. The residence time, for all agents in this
`space, can seem like “forever” and has forced
`many to either enzymatically degrade (hyaluron-
`idase) or surgically excise or drain the material to
`satisfy patients. A particular phenomenon is one
`in which hyaluronic acid products are injected
`into multiple planes of a particular facial region in
`an attempt to augment the soft tissue at many
`dermal levels. Since the residence time and per-
`sistence for most fillers is greater the more super-
`ficially it is placed, when the deeper placed prod-
`uct dissipates (sooner), despite an initially highly
`satisfactory result, the residual superficial compo-
`nent remains and can become quite visible (Fig.
`7). Collagen from any source (bovine, human, or
`other) that can be administered through a fine
`needle is far more utilitarian, effective, and for-
`giving in this superficial plane. On the other hand,
`for volume augmentation, the collagens that were
`once used for this purpose due to a “lack of op-
`tions” have proven to be dramatically less effective
`than the hyaluronic acids and, certainly, the more
`permanent materials in this space. Commonly,
`practitioners use a combination of agents to op-
`timize results, for instance, by using the “collagen”
`products in the superficial dermis and the hyal-
`uronic acid product in the deep dermis to der-
`mal/subcutaneous junction. In the final analysis,
`we have realized that instead of replacing existing
`products with newer agents, the most comprehen-
`sive approach utilizes a palate of products, with
`each appropriate for the required effect and used
`in harmony for facial dermal and volume aug-
`mentation to yield the best results.
`
`CONCLUSIONS
`As we have established, soft-tissue augmenta-
`tion is a vital component of facial rejuvenation.
`The aesthetic market continues to be flooded with
`agents touted as being an improvement over ex-
`isting products. What we have learned is that
`
`newer is not necessarily better, and sometimes,
`when we look back at some of the older practices
`that were essentially intuitive or were spawned
`from a lack of options (after we survive the dis-
`traction of the “latest and greatest”), we learn
`about their limitations. Further clinical experi-
`ence with most of these agents will eventually dic-
`tate what agents work best, and a clearer algorithm
`for product choice will become more evident.
`
`Steven Fagien, M.D.
`660 Glades Road, Suite 210
`Boca Raton, Fla. 33431
`sfagien@aol.com
`
`DISCLOSURES
`Steven Fagien, M.D., serves as a consultant and
`investigator to Allergan, Medicis, Dermik Aesthetics, and
`Mentor, Inc. He is an investigator for Anika Therapeu-
`tics and a shareholder in Collagen Matrix Technologies.
`Arnold W. Klein, M.D., serves as a consultant and
`investigator to Allergan and Medicis.
`
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`3. Coleman, S. R. Facial contouring with Liposculpture. Clin.
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`4. Lambros, V. S. Fat injection for facial rejuvenation. Aesthetic
`Surg. J. 17: 190, 1997.
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