The Wrinkle in Facial Injections and Implants: Safety Questions

by Diana Zuckerman, PhD, Beth Nichols, MSW, and Megan Cole

 
In the eternal search for eternal youth, some new technique or product is always being touted as the next best thing. Women and men seek out long-lasting non-surgical procedures that will reduce wrinkles and make them look younger or better. There are many different types of facial injections (some permanent and some temporary) and implants, each having a variety of brand names.What you need to know is that none of these have been tested long-term and many of them are being used by doctors and consumers in ways that have not been approved of by the Food and Drug Administration (FDA). Another source of concern is that because there is a lot of money to be had in making people look younger or “more beautiful,” many medical professionals and others who lack proper training or board certification are giving these injections.Below is an overview of several types of facial injections and implants:

Permanent versus temporary fillers: Having a temporary wrinkle-filler means that it will not last forever, but it doesn’t tell you how long it will last. Depending on the type, they generally last as little as a few months or as long as “up to five years.”  (Remember, “up to five years” could mean it lasted that long for one person, but it might last for less for just a few months for you – ask for the average or the minimum amount of time that it lasts.)  Eventually, these products are absorbed by the body and the procedure must be repeated. In comparison, permanent wrinkle-fillers are just that: permanent (or at least, long-lasting). Permanent wrinkle-fillers are not absorbed by the body so if they work correctly they do not have to be replaced.

Botulinum toxin-based injectable: often known by the brand name Botox. Although this is not a filler (meaning that it does not “fill” wrinkles), it is an injectable that temporarily paralyzes wrinkle-causing muscles.

Human-based collagen: a popular wrinkle-filler, often seen under the brand names of CosmoDerm, CosmoPlast, and Cymetra. It builds volume in facial areas such as the lips, above and below the eyes, crow’s feet, and smile and frown lines. The results of these are not permanent and generally last four or more months.

Bovine-based collagen fillers: another common filler. Popular brand names include Zyderm and Zyplast. This form of collagen comes from cows and like human-based collagen fillers, may be used to add volume to facial areas such as the lip area, above and below the eye, crow’s feet, and smile and frown lines. The results are not permanent and generally last four or more months.

Fat transfer: a doctor may extract fat cells from one part of your body and inject them into your lips, around your eyes, into crow’s feet, or into your smile or frown lines. Results are not predictable, though it may last longer than other non-permanent injectable procedures.

Calcium Hydroxylapatite: a common filler seen under the brand name Radiesse. The filler is a water-based solution that reduces the appearance of wrinkles and skin folds around the mouth and nose. It is non-toxic and non-allergenic, unlike many other fillers. Results are said to last up to six month or more and though it is only approved for medical purposes, it is often used off-label for cosmetic purposes.

Hyaluronic acid-based fillers: include brand names such as Restylane and Juvederm. These are fillers containing something known as hyluronic acid. This is a naturally-occurring acid found in human tissue and is used as a filler to treat smile and frown lines, crow’s feet, and lips. They are said to have longer-lasting results than collagen fillers, though the results are not permanent.

Polytetrafluoroethylene (PTFE) and expanded polytetrafluoroethylene (ePTFE): a facial implant commonly known by the brand names Gore-Tex and SoftForm. They are manufactured from an artificially made material that is not biodegradable in the body. Previously used for vocal cord defects and joint implants, they are now being used for cosmetic purposes, to get rid of wrinkles, and to help the body create new tissue that helps the face stay wrinkle-free. This is a “permanent” procedure, meaning that the results are long-lasting-unlike many other procedures that last a few years at most.

Silicone injections: offered in liquid form and injected into the face; silicone injections are “permanent” wrinkle fillers. However, due to major safety concerns, liquid silicone injections are not approved by the FDA for any type of cosmetic use.

Synthetic poly-l-lactic acid: an artificial material made from natural sources. The brand name is Sculptra, which may treat skin folds, indented chins, hollowed cheeks, and sunken eyes. Results may last up to two years.

Synthetic polymethylmethacrylate microspheres (PMMA) in bovine-based collagen: under the brand name Artecoll in Europe and ArteFill in the U.S.; This is an artificial collagen that is supposed to help fill skin folds, such as smile lines (also called “naso-labial folds”). Results are immediate and build over time, and are said to last up to five years.[27],[28]

We will discuss five of the most popular of these treatments.  The news is not especially good.

Consumer protections exist but don’t always work as well as they should. Injectable substances are subject to approval by the U.S. Food and Drug Administration (FDA). Most are labeled as Class III medical devices, which means that they require pre-market approval (PMA) before being sold to the general public. For instance, Botox needed to be tested in clinical trials and proven safe and effective before it could be approved for sale. Those FDA safeguards sound impressive. Loopholes, however, are large enough for millions of unsuspecting consumers to pass through.

The major loophole, called off-label use, is that products proven safe and effective for one use or one type of patient then get used in other ways for other types of patients. For example, once a product is found safe and effective for wrinkles, it can be used for lip augmentation-even though it may never have been tested for that purpose. And if a product is tested only on very healthy white women, it may not be as safe for less healthy women, or men, or certain racial or ethnic groups.

Certain products require skill to minimize the risks, but once it is approved, any kind of physician can offer the service. Sometimes, physicians who are not well trained in a specific procedure may offer the procedure anyway, and harm can result. Finally, since many cosmetic injectables are available in Canada, Mexico and elsewhere, patients sometimes leave the country for these procedures or doctors bring them into the United States illegally, making safety claims that are not true. A lot of money is to be made in the quest for the “fountain of youth,” most of it at the expense of patients unaware of the potential consequences.

Botox

Botox, or Botulinum Toxic Type A, is a protein produced by the same bacteria that causes botulism, a severe food poisoning.[1] Botox was first approved for medical use in 1989 to treat eye-muscle disorders and then for a neurological disorder that causes severe neck and shoulder contractions.[2] Approved in 2002 by the FDA for cosmetic use on frown lines, Botox is the Number One non-surgical procedure in the United States today, according to the American Society for Aesthetic Plastic Surgery 2010 statistical report. [3] It cited more than 1.6 million Botox treatments in 2009, an increase of more than 1,200 percent since 2000, when 118,000 were performed. Of these procedures, 94% are conducted on females.[3]

The procedure involves injecting a small dose of the toxin into selected muscles, thus blocking a chemical that signals the muscle to contract and, in effect, paralyzing the muscle.[4] Botox injections last about 3 to 6 months. They are an effective treatment for wrinkles, but should not be injected more than once every 3 months. The most common adverse effects are headaches, droopy eyelids, and nausea. These usually are temporary but can last several weeks or even several months-the same as the cosmetic benefits. There is also the risk of severe, debilitating headaches that can last more than a month. Another troublesome issue, which Dr. David Becker of the Weill Cornell Medical College has raised, is that excessive use could lead to the creation of wrinkles when untreated muscles overcompensate for the paralysis in treated ones.[5] In addition, psychologists worry that overuse can damage a person’s ability to make facial expressions that are an essential part of communication.[6]

The FDA approved Botox based on its effectiveness for one type of wrinkles: the frown lines between the eyebrows. Physicians can use it legally, however, for other wrinkles. Such off-label use is common in medicine and assumes that a physician can use his or her own knowledge and experience to make the best decisions for patients. In many such cases, however, physicians trust that the use will be safe and effective, even though there may be no data to back up that hope. Although not approved for wrinkles other than frown lines between the eyebrows, many people are getting Botox injections to take care of wrinkles in other areas of the face. Botox may not be safe or effective if used in those areas, such as near the eyes.

Lately, concern has been growing over the sometimes casual attitudes toward a treatment that involves injecting a toxin into the face. Botox parties are as casual as Tupperware parties used to be. The American Society of Plastic Surgeons has concerns about the frequency of partygoers’ injections; it cites the need for proper consultations and sterile environments in order to ensure safety, the very things that may be missing from a social gathering.[7] The price of injections offered at parties is tempting to patients, however, since it is usually lower than the average scheduled appointment fee of $405.[8][3]

Injectable Silicone

Injectable silicone is perhaps one of the most controversial treatments of this kind. First used to increase breast size in the 1940s and 1950s, liquid silicone injections were found to cause infections, granulomas (lumps), deformities and even death when the silicone migrated to the lungs and other parts of the body. Nevada was the first state to ban liquid silicone injections because the problems were so evident in Las Vegas showgirls.[9] A federal ban then followed: the marketing of injectable liquid silicone for cosmetic purposes was prohibited by the FDA in 1991, in response to safety concerns. Since then, the FDA has approved clinical studies to determine the safety and efficacy of injectable silicone. However, no studies are yet complete, as long-term follow-up is necessary to properly evaluate the product.[29] Nevertheless, liquid injectable silicone (LIS) continued to be used in this country as well as in Mexico, Canada, and parts of Europe. The FDA considers silicone injections dangerous, but a legal loophole-arising from approval of two LIS products (Adatosil and Silikon 1000) for treating detached retinas-has resulted in their being legal since 1994.[10] Since the FDA law allows doctors to administer a “legally marketed device” to their patients, [11] doctors may inject liquid silicone into the face as an off-label use.

Within the past decade, reports have surfaced about the rising popularity of silicone parties. As with Botox parties, those who attend are eager for a quick, affordable way to look younger and curvier; unlike Botox parties, however, they are usually very secretive and typically more devastating for the “patients.” These parties have been especially popular in Florida, where many unlicensed doctors from South America are treating mainly women and transsexuals, usually for only a few hundred dollars.[12] When complications arise, such as severe reactions, the patients must pay thousands to plastic surgeons and dermatologists to try to get the silicone removed. Several deaths have been reported.

Silicone injections are less dangerous when performed by a well-trained physician using sterile procedures, but even then problems can occur. Since no studies have been done, it is not known how often immediate or long-lasting problems arise from silicone injections. Certainly, some new patients are satisfied and recommend the procedure to their friends. But what happens to that permanent filling years later? As faces age, wrinkles move slightly, and what was a filled-in wrinkle can instead be a permanent raised ridge of silicone, several inches long, near the wrinkle. Because problems with silicone often require surgery, three Swiss medical associations as well as the Swiss government health agency have issued a warning against the use of silicone, the wrinkle filler Artecoll (also called Artefill), and other permanent treatments for cosmetic purposes. Noting the risk for disfiguring later complications, including visible nodules and swelling, they concluded that the benefits do not outweigh the risks.

ArteFill (Artecoll)

ArteFill, a “wrinkle filler” that won FDA approval for the correction of “smile lines” –the “folds” from the nose to the mouth– in 2006, is another permanent injected material used to plump up wrinkles and enhance the lips.[13] ArteFill (known as Artecoll outside the U.S.) is a Class III device composed of 75 percent bovine collagen and 25 percent tiny Plexiglas beads.[14] When problems arise, surgical removal may be necessary.  ArteFill is injected through a tunneling technique with a hypodermic needle. The plunger is depressed and deposits the Artecoll while pulling out of the skin, leaving a small cylindrical mass of ArteFill. Each microbead is coated in bovine collagen to keep from clumping together; after the body gradually absorbs the collagen, it replaces it with its own collagen and causes a plumping up of the wrinkles or lips.

Artecoll has been used for nearly a decade in Canada and Europe. In the United States, Artes Medical, Inc. sought FDA approval of ArteFill in 2003, based on a one-year study of 117 women and 11 men. An FDA Advisory panel recommended approval, but the FDA did not immediately agree. Meanwhile, Artecoll came under increasing scrutiny and criticism from Swiss and Canadian doctors. Three Swiss medical societies issued a warning against its use in the face because of reports that it causes granulomas, which lead to unsightly bumps that usually have to be removed surgically.[15] Many Canadian doctors are against its use for lip augmentation for the same reasons. A large portion of the medical community believes Artecoll can cause inflammatory reactions that lead to scar tissue, making removal of the beads nearly impossible without causing some lip disfigurement.[16] In 2003, the Canadian company that sells Artecoll claimed that only 10 cases out of 8,000 patients worldwide have reported nodules within two years, [17] but interviews with Canadian doctors indicate many more problems. Plastic surgeons explain that they don’t report lumpy lips because it doesn’t seem sufficiently important, but that means that there is no way to determine how many patients who have used this cosmetic treatment look worse instead of better, and in some cases have disfiguring lumps and nodules.[18]

In October of 2006, ArteFill was approved by the FDA for “smile lines”). This decision was based on data from a 12-month study conducted at medical centers throughout the U.S. It compared the outcomes of patients treated with ArteFill to the outcomes of patients treated with Zyderm and Zyplast-two other FDA approved “skin fillers” used as controls. After six months, patients treated with ArteFill did not have reappearing wrinkles, unlike those with the control treatment. After one year, the ArteFill patients were again evaluated, and showed signs of continued safety and wrinkle correction. Then, a five-year post-market follow-up of these ArteFill patients showed continued and improved wrinkle correction, in comparison their pre-treatment condition. The company reported that no serious or unanticipated device-related adverse events occurred.[26]

What have other studies shown? The manufacturer’s own initial studies indicated that within the first year, 16 percent of the 128 patients had complications, including persistent swelling, lumpiness, flu-like symptoms, and blurred vision. Unfortunately, as the Swiss government and published studies have pointed out, large unsightly bumps can appear several years later.[19] It also is important to recognize that the company finds the best physicians possible to use and evaluate its new products, and they are carefully trained. Once a product is sold, any physician can use it, and many will not be as skilled or carefully trained.

Yet another major concern deserves attention: ArteFill has not been tested on African or Asian Americans, two groups known to be at increased risk of scarring and autoimmune disease. It is important that these minority groups realize that there is no evidence that the product is safe for them.

Gore-Tex

When first introduced as alternatives to face-lifts, Gore-Tex implants received a lot of attention. That’s right – the same material used to waterproof jackets and boots is being used in cosmetic surgery. Having been used successfully in 1971 as a surgical implant for damaged arteries and other vascular parts, Gore-Tex has become widely accepted in surgery and cosmetic enhancements.

In the past decade, Gore-Tex implants have been used for lip augmentations or enlargements, and now the company claims that its Subcutaneous Augmentation Material (S.A.M.) will get rid of wrinkles while helping the body create the tissue it needs to stay wrinkle-free.[20] Gore S.A.M. is made from a chemical compound known as e-PTFE (the same substance that is used for Teflon) and is described as a permanent yet reversible way to achieve the results of a face-lift without undergoing complicated surgery. Gore S.A.M. has primarily been used to reduce or eliminate smile lines (the folds that run from the side of the nose to the corners of the mouth). The FDA approved the use of e-PTFE for facial augmentation and lip reconstruction but initially specified it not be used for wrinkles or lip augmentation.[21] A form of Gore-Tex (Softform) was approved for research only in 1997. Gore-Tex products have not been specifically approved as safe or effective for wrinkles, lip augmentation, or other types of “facial rejuvenation,” and the long term risks have not been studied.

A typical Gore-Tex implantation entails a small incision in the face or lip just under the skin. The surgeon lifts up the tissue to create a small cavity or hole for the implant, then trims the implant material to fit facial contours and inserts the implant, securing it in place. Some incisions require stitches; swelling can be treated with a cold compress; and bruising will sometimes occur.[22]

Although the company points out that millions of implants have been used and there have been no allergic reactions,[23] the absence of objective research on these patients makes these reports questionable. Other problems have been reported, such as irritation, slow healing, discomfort, and the implants’ being visible under the skin and poking out because of the constant movement of the mouth. Infections also have occurred, requiring the implants to be removed and replaced. [24] In light of the similarity to Teflon, it is important to note that Teflon implants were used in the 1980′s for jaw joint problems, and were removed from the market after causing permanent irreversible damage to the jaw bones and skulls of many patients.

Since 2003, the Environmental Protection Agency (EPA) has demonstrated increasing concern about a chemical processing aid known as PFOA, which is used to make several products, including Gore-Tex. EPA is concerned that PFOA exposure may cause health problems. [25] EPA has imposed penalties against the companies that use PFOA for withholding information about the harmful effects of PFOA on human health and the environment, but what are the potential risks of Gore-Tex when it is implanted in the human body for many years? Nobody knows; no research exists.

Juvéderm

Juvederm, another injectable “wrinkle filler,” was approved by the FDA in 2006 to remove smile lines. Although unapproved for this, it is also used to plump up patients’ lips and to fill in hollow places and facial scars. There are two types of Juvederm: (1) Juvederm Ultra, which is approved to correct moderately deep facial wrinkles, and (2) Juvederm Ultra Plus, which is denser and approved for much deeper facial folds or wrinkles.[30]

Juvederm was first introduced in Europe in 2000, then in Canada in 2002. However, there are potential risks and side effects. As explained on the product’s label, most side effects are mild or moderate, and do not last a long time (generally, seven days or less). The most common side effects are redness, pain/tenderness, firmness, swelling, lumps/bumps, itching, and discoloration. However, individuals with a history of skin disease, severe allergies, scarring, or pigmentation disorder must be especially careful and consult with a physician before considering Juvederm.[31]

Based on clinical studies, the FDA’s 2006 summary on safety and effectiveness concluded that Juvederm’s injectable gel implants were generally effective and safe, as indicated by the lack of severe adverse events and the short duration of treatment responses observed in the studies.[32]

FDA approval for Juvederm was based on a U.S. study that followed 144 individuals for 24 weeks. These individuals were followed after receiving Juvederm in one of their smile lines and Zyplast (another wrinkle filler already approved by the FDA) in the other smile line. Negative facial reactions were generally mild to moderate in severity and were similar for both Juvederm and Zyplast in terms of duration and frequency, generally lasting for seven days or less. Individuals receiving Juvederm had better results and maintained their improved look for a longer period of time. Ultimately, at the end of the study, 84% of participants preferred Juvederm while only 10% preferred Zyplast.[33][32]

Cost per treatment ranges from $600 to $1000. Studies conducted by Juvederm’s manufacturer, Allergen, report that the results last 9 to 12 months.[30] A study done in 2008 found similar results.[34] As with most wrinkle-fillers, this could be a costly venture for individuals hoping to sustain the look and keep wrinkles away over time.

Conclusion

Injectables are an increasingly popular cosmetic procedure. They pose these safety issues:

  • FDA does not require studies of minority groups; it doesn’t even require studies to specify the race of those individuals studied.
  • FDA does not require long-term safety data, but some of these products have long-term consequences.
  • The FDA neither studies nor approves some of these products for the specific cosmetic purposes that are now popular.
  • Complication rates may be much higher when these procedures are done by physicians who are not Board-certified or well-trained for the specific procedures.
  • A poor cosmetic outcome is not considered a serious risk, but it is an important risk considering that the only benefits are also cosmetic. Those who pay for treatment and end up looking worse are very unhappy, and those that are disfigured are often devastated.

Patients want a long-lasting solution to their wrinkles, but injections of permanent substances such as silicone and Artecoll raise important long-term safety questions. When considering the approval of new products, the FDA should carefully consider information provided by other countries that are now warning against their use because of concerns that the risks outweigh the benefits. It is also very important to acknowledge that the clinical trials conducted by companies for FDA approval are short-term studies that represent the best-case scenario under the best-trained physicians the company can find. Once a product is sold, any physician (or even dentists) can use it, and since this is a cash business, many physicians prefer this to their own specialties. Patients may not even think to ask what kind of training a physician has; they assume he or she is well trained or wouldn’t be doing the procedure. Unfortunately, that assumption may not be correct.

Over time, the substances used–Botox, injectable silicone, ArteFill, Gore-Tex, and Juvederm–will change, as will the popular brands. BUT, keep in mind that whatever the next new fountain of youth may be, you can be pretty sure it hasn’t been tested for very long. We really don’t know the long-term effects of these products, or how your body will absorb or adjust to these products as you age, so be a cautious and even skeptical consumer!

To view recent and related testimony by the NRC from a 2008 “FDA Advisory Panel Meeting on Dermal Fillers,” please visit http://www.center4research.org/2008/11/statement-of-diana-zuckerman-phd-at-the-fda-advisory-panel-meeting-on-dermal-fillers/


 

Footnotes

[1] “FDA APPROVES BOTOX TO TREAT FROWN LINES,” April 15, 2002. http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01147.html
[2] ibid
[3]“American Society of Plastic Surgeons (ASPS) (2010). 2010 Report of the 2009 Statistics: National Clearinghouse of Plastic Surgery Statistics. Retrieved from <http://www.plasticsurgery.org/Documents/Media/statistics/2009-US-cosmeticreconstructiveplasticsurgeryminimally-invasive-statistics.pdf>
[4] “FDA APPROVES BOTOX TO TREAT FROWN LINES,” April 15, 2002. http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01147.html
[5] “Botox ‘may cause new wrinkles.’” http://news.bbc.co.uk/2/hi/health/2772263.stm
[6] Klaish, N. (May, 2003). Beyond Botox. Health, pgs.119-125.
[7] “A Party May Not Be Best Setting for Botoxâ Injections,” April 16, 2002. http://www.plasticsurgery.org/news_room/press_releases/A-Party-May-Not-Be-Best-Setting-for-Botox-Injections.cfm
[8] “Experts Frown On Botox Parties.” http://www.nyp.org/news/2002/healthnews/botox.html
[9] http://www.facialwasting.org/pages/869165/index.htm
[10] http://www.fda.gov/bbs/topics/NEWS/NEW00499.html
[11] http://www.lipaugmentation.com/microimplants.htm#Injectable%20Silicone%20gel:
[12] http://www.msnbc.com/news/576924.asp
[13] “Recommendations for Physicians,” Swiss Federal Health Agency. December, 2001.
[14] “Filler material may cause nodules, lumps in lips,” Cosmetic Surgery Times. June 15, 2002
[15] “Recommendations for Physicians,” Swiss Federal Health Agency. December, 2001.
[16] http://www.lipaugmentation.com/microimplants.htm#ArtecollTM:
[17] http://www.canderm.com/page.asp?intNodeID=8035
[18] Lemperle G., Gauthier-Hazan, N., and Lemperle, M. (1998). PMMA-Microspheres (Artecoll) for long-lasting correction of wrinkles: Refinements and statistical results. Aesthetic Plastic Surgery, 22, pgs.356-365.
[19] Reisberger E., Landthaler M., and Wiest L., Schroder, J., & Stolz, W. (January, 2003), Foreign body granulomas caused by polymethylmethacrylate microspheres: Successful treatment with allopurinol. Archives of Dermatology, 139, pgs. 17-20.
[20] http://www.goremedical.com/Products/SAM/index.htm
[21] Conrad K., & MacDonald, M.R. (June, 1996). Wide polytef (Gore-Tex) implants in lip augmentation and nasolavial groove correction. Archives of Otolaryngology and Head & Neck Surgery, 122, pgs. 664-670.
[22] http://www.talksurgery.com/
[23] http://www.drbader.com/
[24] Conrad K., & MacDonald, M.R. (June, 1996). Wide polytef (Gore-Tex) implants in lip augmentation and nasolavial groove correction. Archives of Otolaryngology and Head & Neck Surgery, 122, pgs. 664-670.
[25] Environmental Protection Agency. (April, 2003). OPPT Fact Sheet: PFOA Q’s and A’s. www.epa.gov/oppt/pfoa/pfoafcts.pdf
[26] Cohen SR, Berner CF, Busso M, Clopton P, Hamilton D, Romano JJ, et al (2007) Five-Year Safety amd Efficacy of a Novel Polymethylmethacrylate Aesthetic Soft Tissue Filler for the Correction of Nasolabial Folds. Dermatological Surgery 33(s2):222-230. Retrieved from <http://www3.interscience.wiley.com/journal/118489667/?CRETRY=1&SRETRY=0>
[27] Miller MD SR (2010 Jan.) Injectable Fillers Overview. Retrieved from <http://www.yourplasticsurgeryguide.com/injectables-and-fillers/injectable-fillers.htm#brand>
[28] American Society of Plastic Surgeons (ASPS) (2010) Brand Name Products and Treatments. Retrieved from <http://www.plasticsurgery.org/Patients_and_Consumers/Procedures/Brand_Name_Procedures_and_Treatments.html>
[29] Medical News Today (2008 Sept. 1) Silicone Injections for Cosmetic Use. Retrieved from <http://www.medicalnewstoday.com/articles/119860.php>
[30] Geronemus RG (2007) The Patient’s Guide: Wrinkles-Juvederm. Retrieved from <http://www.wrinkles.org/juvederm.aspx>
[31] Food and Drug Administration (FDA) (2006). Juvederm 30HV: Patient Information Labeling. Retrieved from http://www.accessdata.fda.gov/cdrh_docs/pdf5/P050047d.pdf
[32] Food and Drug Administration (FDA) (2006 June 2). Juvederm: Summary of Safety and Effectiveness. Retrieved from http://www.accessdata.fda.gov/cdrh_docs/pdf5/P050047b.pdf
[33] Allergan, Inc. (2010). Juvederm: Safety Considerations. Retrieved from <http://www.juvederm.com/views/what-is-juvederm/safety-considerations/?p=juvederm-stories>
[34] Pinsky MA, Thomas JA, Murphy DK, & Walker PS (2008). Juvederm injectable gel: a multicenter double-blind, randomized study of safety and effectiveness. Aesthetic Surgery Journal 28(1):17-23. Retrieved from < http://www.ncbi.nlm.nih.gov/pubmed/19083502>

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Updated June 2010

Diana Zuckerman, PhD, Beth Nichols, MSW, and Megan Cole

In the eternal search for eternal youth, some new technique or product is always being touted as the next best thing. Women and men seek out long-lasting non-surgical procedures that will reduce wrinkles and make them look younger or better. There are many different types of facial injections (some permanent and some temporary) and implants, each having a variety of brand names.

What you need to know is that none of these have been tested long-term and many of them are being used by doctors and consumers in ways that have not been approved of by the Food and Drug Administration (FDA). Another source of concern is that because there is a lot of money to be had in making people look younger or “more beautiful,” many medical professionals and others who lack proper training or board certification are giving these injections.
Below is an overview of several types of facial injections and implants:
Permanent versus temporary fillers: Having a temporary wrinkle-filler means that it will not last forever, but it doesn’t tell you how long it will last. Depending on the type, they generally last as little as a few months or as long as “up to five years.”  (Remember, “up to five years” could mean it lasted that long for one person, but it might last for less for just a few months for you – ask for the average or the minimum amount of time that it lasts.)  Eventually, these products are absorbed by the body and the procedure must be repeated. In comparison, permanent wrinkle-fillers are just that: permanent (or at least, long-lasting). Permanent wrinkle-fillers are not absorbed by the body so if they work correctly they do not have to be replaced.
Botulinum toxin-based injectable: often known by the brand name Botox. Although this is not a filler (meaning that it does not “fill” wrinkles), it is an injectable that temporarily paralyzes wrinkle-causing muscles.
Human-based collagen: a popular wrinkle-filler, often seen under the brand names of CosmoDerm, CosmoPlast, and Cymetra. It builds volume in facial areas such as the lips, above and below the eyes, crow’s feet, and smile and frown lines. The results of these are not permanent and generally last four or more months.
Bovine-based collagen fillers: another common filler. Popular brand names include Zyderm and Zyplast. This form of collagen comes from cows and like human-based collagen fillers, may be used to add volume to facial areas such as the lip area, above and below the eye, crow’s feet, and smile and frown lines. The results are not permanent and generally last four or more months.
Fat transfer: a doctor may extract fat cells from one part of your body and inject them into your lips, around your eyes, into crow’s feet, or into your smile or frown lines. Results are not predictable, though it may last longer than other non-permanent injectable procedures.
Calcium Hydroxylapatite: a common filler seen under the brand name Radiesse. The filler is a water-based solution that reduces the appearance of wrinkles and skin folds around the mouth and nose. It is non-toxic and non-allergenic, unlike many other fillers. Results are said to last up to six month or more and though it is only approved for medical purposes, it is often used off-label for cosmetic purposes.
Hyaluronic acid-based fillers: include brand names such as Restylane and Juvederm. These are fillers containing something known as hyluronic acid. This is a naturally-occurring acid found in human tissue and is used as a filler to treat smile and frown lines, crow’s feet, and lips. They are said to have longer-lasting results than collagen fillers, though the results are not permanent.
Polytetrafluoroethylene (PTFE) and expanded polytetrafluoroethylene (ePTFE): a facial implant commonly known by the brand names Gore-Tex and SoftForm. They are manufactured from an artificially made material that is not biodegradable in the body. Previously used for vocal cord defects and joint implants, they are now being used for cosmetic purposes, to get rid of wrinkles, and to help the body create new tissue that helps the face stay wrinkle-free. This is a “permanent” procedure, meaning that the results are long-lasting-unlike many other procedures that last a few years at most.
Silicone injections: offered in liquid form and injected into the face; silicone injections are “permanent” wrinkle fillers. However, due to major safety concerns, liquid silicone injections are not approved by the FDA for any type of cosmetic use.
Synthetic poly-l-lactic acid: an artificial material made from natural sources. The brand name is Sculptra, which may treat skin folds, indented chins, hollowed cheeks, and sunken eyes. Results may last up to two years.
Synthetic polymethylmethacrylate microspheres (PMMA) in bovine-based collagen: under the brand name Artecoll in Europe and ArteFill in the U.S.; This is an artificial collagen that is supposed to help fill skin folds, such as smile lines (also called “naso-labial folds”). Results are immediate and build over time, and are said to last up to five years.[27],[28]
We will discuss five of the most popular of these treatments.  The news is not especially good.
Consumer protections exist but don’t always work as well as they should. Injectable substances are subject to approval by the U.S. Food and Drug Administration (FDA). Most are labeled as Class III medical devices, which means that they require pre-market approval (PMA) before being sold to the general public. For instance, Botox needed to be tested in clinical trials and proven safe and effective before it could be approved for sale. Those FDA safeguards sound impressive. Loopholes, however, are large enough for millions of unsuspecting consumers to pass through.
The major loophole, called off-label use, is that products proven safe and effective for one use or one type of patient then get used in other ways for other types of patients. For example, once a product is found safe and effective for wrinkles, it can be used for lip augmentation-even though it may never have been tested for that purpose. And if a product is tested only on very healthy white women, it may not be as safe for less healthy women, or men, or certain racial or ethnic groups.
Certain products require skill to minimize the risks, but once it is approved, any kind of physician can offer the service. Sometimes, physicians who are not well trained in a specific procedure may offer the procedure anyway, and harm can result. Finally, since many cosmetic injectables are available in Canada, Mexico and elsewhere, patients sometimes leave the country for these procedures or doctors bring them into the United States illegally, making safety claims that are not true. A lot of money is to be made in the quest for the “fountain of youth,” most of it at the expense of patients unaware of the potential consequences.
Botox
Botox, or Botulinum Toxic Type A, is a protein produced by the same bacteria that causes botulism, a severe food poisoning.[1] Botox was first approved for medical use in 1989 to treat eye-muscle disorders and then for a neurological disorder that causes severe neck and shoulder contractions.[2] Approved in 2002 by the FDA for cosmetic use on frown lines, Botox is the Number One non-surgical procedure in the United States today, according to the American Society for Aesthetic Plastic Surgery 2010 statistical report. [3] It cited more than 1.6 million Botox treatments in 2009, an increase of more than 1,200 percent since 2000, when 118,000 were performed. Of these procedures, 94% are conducted on females.[3]
The procedure involves injecting a small dose of the toxin into selected muscles, thus blocking a chemical that signals the muscle to contract and, in effect, paralyzing the muscle.[4] Botox injections last about 3 to 6 months. They are an effective treatment for wrinkles, but should not be injected more than once every 3 months. The most common adverse effects are headaches, droopy eyelids, and nausea. These usually are temporary but can last several weeks or even several months-the same as the cosmetic benefits. There is also the risk of severe, debilitating headaches that can last more than a month. Another troublesome issue, which Dr. David Becker of the Weill Cornell Medical College has raised, is that excessive use could lead to the creation of wrinkles when untreated muscles overcompensate for the paralysis in treated ones.[5] In addition, psychologists worry that overuse can damage a person’s ability to make facial expressions that are an essential part of communication.[6]
The FDA approved Botox based on its effectiveness for one type of wrinkles: the frown lines between the eyebrows. Physicians can use it legally, however, for other wrinkles. Such off-label use is common in medicine and assumes that a physician can use his or her own knowledge and experience to make the best decisions for patients. In many such cases, however, physicians trust that the use will be safe and effective, even though there may be no data to back up that hope. Although not approved for wrinkles other than frown lines between the eyebrows, many people are getting Botox injections to take care of wrinkles in other areas of the face. Botox may not be safe or effective if used in those areas, such as near the eyes.
Lately, concern has been growing over the sometimes casual attitudes toward a treatment that involves injecting a toxin into the face. Botox parties are as casual as Tupperware parties used to be. The American Society of Plastic Surgeons has concerns about the frequency of partygoers’ injections; it cites the need for proper consultations and sterile environments in order to ensure safety, the very things that may be missing from a social gathering.[7] The price of injections offered at parties is tempting to patients, however, since it is usually lower than the average scheduled appointment fee of $405.[8][3]
Injectable Silicone
Injectable silicone is perhaps one of the most controversial treatments of this kind. First used to increase breast size in the 1940s and 1950s, liquid silicone injections were found to cause infections, granulomas (lumps), deformities and even death when the silicone migrated to the lungs and other parts of the body. Nevada was the first state to ban liquid silicone injections because the problems were so evident in Las Vegas showgirls.[9] A federal ban then followed: the marketing of injectable liquid silicone for cosmetic purposes was prohibited by the FDA in 1991, in response to safety concerns. Since then, the FDA has approved clinical studies to determine the safety and efficacy of injectable silicone. However, no studies are yet complete, as long-term follow-up is necessary to properly evaluate the product.[29] Nevertheless, liquid injectable silicone (LIS) continued to be used in this country as well as in Mexico, Canada, and parts of Europe. The FDA considers silicone injections dangerous, but a legal loophole-arising from approval of two LIS products (Adatosil and Silikon 1000) for treating detached retinas-has resulted in their being legal since 1994.[10] Since the FDA law allows doctors to administer a “legally marketed device” to their patients, [11] doctors may inject liquid silicone into the face as an off-label use.
Within the past decade, reports have surfaced about the rising popularity of silicone parties. As with Botox parties, those who attend are eager for a quick, affordable way to look younger and curvier; unlike Botox parties, however, they are usually very secretive and typically more devastating for the “patients.” These parties have been especially popular in Florida, where many unlicensed doctors from South America are treating mainly women and transsexuals, usually for only a few hundred dollars.[12] When complications arise, such as severe reactions, the patients must pay thousands to plastic surgeons and dermatologists to try to get the silicone removed. Several deaths have been reported.
Silicone injections are less dangerous when performed by a well-trained physician using sterile procedures, but even then problems can occur. Since no studies have been done, it is not known how often immediate or long-lasting problems arise from silicone injections. Certainly, some new patients are satisfied and recommend the procedure to their friends. But what happens to that permanent filling years later? As faces age, wrinkles move slightly, and what was a filled-in wrinkle can instead be a permanent raised ridge of silicone, several inches long, near the wrinkle. Because problems with silicone often require surgery, three Swiss medical associations as well as the Swiss government health agency have issued a warning against the use of silicone, the wrinkle filler Artecoll (also called Artefill), and other permanent treatments for cosmetic purposes. Noting the risk for disfiguring later complications, including visible nodules and swelling, they concluded that the benefits do not outweigh the risks.
ArteFill (Artecoll)
ArteFill, a “wrinkle filler” that won FDA approval for the correction of “smile lines” the “folds” from the nose to the mouth in 2006, is another permanent injected material used to plump up wrinkles and enhance the lips.[13] ArteFill (known as Artecoll outside the U.S.) is a Class III device composed of 75 percent bovine collagen and 25 percent tiny Plexiglas beads.[14] When problems arise, surgical removal may be necessary.  ArteFill is injected through a tunneling technique with a hypodermic needle. The plunger is depressed and deposits the Artecoll while pulling out of the skin, leaving a small cylindrical mass of ArteFill. Each microbead is coated in bovine collagen to keep from clumping together; after the body gradually absorbs the collagen, it replaces it with its own collagen and causes a plumping up of the wrinkles or lips.
Artecoll has been used for nearly a decade in Canada and Europe. In the United States, Artes Medical, Inc. sought FDA approval of ArteFill in 2003, based on a one-year study of 117 women and 11 men. An FDA Advisory panel recommended approval, but the FDA did not immediately agree. Meanwhile, Artecoll came under increasing scrutiny and criticism from Swiss and Canadian doctors. Three Swiss medical societies issued a warning against its use in the face because of reports that it causes granulomas, which lead to unsightly bumps that usually have to be removed surgically.[15] Many Canadian doctors are against its use for lip augmentation for the same reasons. A large portion of the medical community believes Artecoll can cause inflammatory reactions that lead to scar tissue, making removal of the beads nearly impossible without causing some lip disfigurement.[16] In 2003, the Canadian company that sells Artecoll claimed that only 10 cases out of 8,000 patients worldwide have reported nodules within two years, [17] but interviews with Canadian doctors indicate many more problems. Plastic surgeons explain that they don’t report lumpy lips because it doesn’t seem sufficiently important, but that means that there is no way to determine how many patients who have used this cosmetic treatment look worse instead of better, and in some cases have disfiguring lumps and nodules.[18]
In October of 2006, ArteFill was approved by the FDA for “smile lines”). This decision was based on data from a 12-month study conducted at medical centers throughout the U.S. It compared the outcomes of patients treated with ArteFill to the outcomes of patients treated with Zyderm and Zyplast-two other FDA approved “skin fillers” used as controls. After six months, patients treated with ArteFill did not have reappearing wrinkles, unlike those with the control treatment. After one year, the ArteFill patients were again evaluated, and showed signs of continued safety and wrinkle correction. Then, a five-year post-market follow-up of these ArteFill patients showed continued and improved wrinkle correction, in comparison their pre-treatment condition. The company reported that no serious or unanticipated device-related adverse events occurred.[26]
What have other studies shown? The manufacturer’s own initial studies indicated that within the first year, 16 percent of the 128 patients had complications, including persistent swelling, lumpiness, flu-like symptoms, and blurred vision. Unfortunately, as the Swiss government and published studies have pointed out, large unsightly bumps can appear several years later.[19] It also is important to recognize that the company finds the best physicians possible to use and evaluate its new products, and they are carefully trained. Once a product is sold, any physician can use it, and many will not be as skilled or carefully trained.
Yet another major concern deserves attention: ArteFill has not been tested on African or Asian Americans, two groups known to be at increased risk of scarring and autoimmune disease. It is important that these minority groups realize that there is no evidence that the product is safe for them.
Gore-Tex
When first introduced as alternatives to face-lifts, Gore-Tex implants received a lot of attention. That’s right – the same material used to waterproof jackets and boots is being used in cosmetic surgery. Having been used successfully in 1971 as a surgical implant for damaged arteries and other vascular parts, Gore-Tex has become widely accepted in surgery and cosmetic enhancements.
In the past decade, Gore-Tex implants have been used for lip augmentations or enlargements, and now the company claims that its Subcutaneous Augmentation Material (S.A.M.) will get rid of wrinkles while helping the body create the tissue it needs to stay wrinkle-free.[20] Gore S.A.M. is made from a chemical compound known as e-PTFE (the same substance that is used for Teflon) and is described as a permanent yet reversible way to achieve the results of a face-lift without undergoing complicated surgery. Gore S.A.M. has primarily been used to reduce or eliminate smile lines (the folds that run from the side of the nose to the corners of the mouth). The FDA approved the use of e-PTFE for facial augmentation and lip reconstruction but initially specified it not be used for wrinkles or lip augmentation.[21] A form of Gore-Tex (Softform) was approved for research only in 1997. Gore-Tex products have not been specifically approved as safe or effective for wrinkles, lip augmentation, or other types of “facial rejuvenation,” and the long term risks have not been studied.
A typical Gore-Tex implantation entails a small incision in the face or lip just under the skin. The surgeon lifts up the tissue to create a small cavity or hole for the implant, then trims the implant material to fit facial contours and inserts the implant, securing it in place. Some incisions require stitches; swelling can be treated with a cold compress; and bruising will sometimes occur.[22]
Although the company points out that millions of implants have been used and there have been no allergic reactions,[23] the absence of objective research on these patients makes these reports questionable. Other problems have been reported, such as irritation, slow healing, discomfort, and the implants’ being visible under the skin and poking out because of the constant movement of the mouth. Infections also have occurred, requiring the implants to be removed and replaced. [24] In light of the similarity to Teflon, it is important to note that Teflon implants were used in the 1980′s for jaw joint problems, and were removed from the market after causing permanent irreversible damage to the jaw bones and skulls of many patients.
Since 2003, the Environmental Protection Agency (EPA) has demonstrated increasing concern about a chemical processing aid known as PFOA, which is used to make several products, including Gore-Tex. EPA is concerned that PFOA exposure may cause health problems. [25] EPA has imposed penalties against the companies that use PFOA for withholding information about the harmful effects of PFOA on human health and the environment, but what are the potential risks of Gore-Tex when it is implanted in the human body for many years? Nobody knows; no research exists.
Juvéderm
Juvederm, another injectable “wrinkle filler,” was approved by the FDA in 2006 to remove smile lines. Although unapproved for this, it is also used to plump up patients’ lips and to fill in hollow places and facial scars. There are two types of Juvederm: (1) Juvederm Ultra, which is approved to correct moderately deep facial wrinkles, and (2) Juvederm Ultra Plus, which is denser and approved for much deeper facial folds or wrinkles.[30]
Juvederm was first introduced in Europe in 2000, then in Canada in 2002. However, there are potential risks and side effects. As explained on the product’s label, most side effects are mild or moderate, and do not last a long time (generally, seven days or less). The most common side effects are redness, pain/tenderness, firmness, swelling, lumps/bumps, itching, and discoloration. However, individuals with a history of skin disease, severe allergies, scarring, or pigmentation disorder must be especially careful and consult with a physician before considering Juvederm.[31]
Based on clinical studies, the FDA’s 2006 summary on safety and effectiveness concluded that Juvederm’s injectable gel implants were generally effective and safe, as indicated by the lack of severe adverse events and the short duration of treatment responses observed in the studies.[32]
FDA approval for Juvederm was based on a U.S. study that followed 144 individuals for 24 weeks. These individuals were followed after receiving Juvederm in one of their smile lines and Zyplast (another wrinkle filler already approved by the FDA) in the other smile line. Negative facial reactions were generally mild to moderate in severity and were similar for both Juvederm and Zyplast in terms of duration and frequency, generally lasting for seven days or less. Individuals receiving Juvederm had better results and maintained their improved look for a longer period of time. Ultimately, at the end of the study, 84% of participants preferred Juvederm while only 10% preferred Zyplast.[33][32]
Cost per treatment ranges from $600 to $1000. Studies conducted by Juvederm’s manufacturer, Allergen, report that the results last 9 to 12 months.[30] A study done in 2008 found similar results.[34] As with most wrinkle-fillers, this could be a costly venture for individuals hoping to sustain the look and keep wrinkles away over time.
Conclusion
Injectables are an increasingly popular cosmetic procedure. They pose these safety issues:
  • FDA does not require studies of minority groups; it doesn’t even require studies to specify the race of those individuals studied.
  • FDA does not require long-term safety data, but some of these products have long-term consequences.
  • The FDA neither studies nor approves some of these products for the specific cosmetic purposes that are now popular.
  • Complication rates may be much higher when these procedures are done by physicians who are not Board-certified or well-trained for the specific procedures.
  • A poor cosmetic outcome is not considered a serious risk, but it is an important risk considering that the only benefits are also cosmetic. Those who pay for treatment and end up looking worse are very unhappy, and those that are disfigured are often devastated.
Patients want a long-lasting solution to their wrinkles, but injections of permanent substances such as silicone and Artecoll raise important long-term safety questions. When considering the approval of new products, the FDA should carefully consider information provided by other countries that are now warning against their use because of concerns that the risks outweigh the benefits. It is also very important to acknowledge that the clinical trials conducted by companies for FDA approval are short-term studies that represent the best-case scenario under the best-trained physicians the company can find. Once a product is sold, any physician (or even dentists) can use it, and since this is a cash business, many physicians prefer this to their own specialties. Patients may not even think to ask what kind of training a physician has; they assume he or she is well trained or wouldn’t be doing the procedure. Unfortunately, that assumption may not be correct.
Over time, the substances used Botox, injectable silicone, ArteFill, Gore-Tex, and Juvederm will change, as will the popular brands. BUT, keep in mind that whatever the next new fountain of youth may be, you can be pretty sure it hasn’t been tested for very long. We really don’t know the long-term effects of these products, or how your body will absorb or adjust to these products as you age, so be a cautious and even skeptical consumer!
To view recent and related testimony by the NRC from a 2008 “FDA Advisory Panel Meeting on Dermal Fillers,” please visit http://www.center4research.org/2008/11/statement-of-diana-zuckerman-phd-at-the-fda-advisory-panel-meeting-on-dermal-fillers/

Footnotes

[1] “FDA APPROVES BOTOX TO TREAT FROWN LINES,” April 15, 2002. http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01147.html
[2] ibid
[3]“American Society of Plastic Surgeons (ASPS) (2010). 2010 Report of the 2009 Statistics: National Clearinghouse of Plastic Surgery Statistics. Retrieved from <http://www.plasticsurgery.org/Documents/Media/statistics/2009-US-cosmeticreconstructiveplasticsurgeryminimally-invasive-statistics.pdf>
[4] “FDA APPROVES BOTOX TO TREAT FROWN LINES,” April 15, 2002. http://www.fda.gov/bbs/topics/ANSWERS/2002/ANS01147.html
[5] “Botox ‘may cause new wrinkles.’” http://news.bbc.co.uk/2/hi/health/2772263.stm
[6] Klaish, N. (May, 2003). Beyond Botox. Health, pgs.119-125.
[7] “A Party May Not Be Best Setting for Botoxâ Injections,” April 16, 2002. http://www.plasticsurgery.org/news_room/press_releases/A-Party-May-Not-Be-Best-Setting-for-Botox-Injections.cfm
[8] “Experts Frown On Botox Parties.” http://www.nyp.org/news/2002/healthnews/botox.html
[9] http://www.facialwasting.org/pages/869165/index.htm
[10] http://www.fda.gov/bbs/topics/NEWS/NEW00499.html
[11] http://www.lipaugmentation.com/microimplants.htm#Injectable%20Silicone%20gel:
[12] http://www.msnbc.com/news/576924.asp
[13] “Recommendations for Physicians,” Swiss Federal Health Agency. December, 2001.
[14] “Filler material may cause nodules, lumps in lips,” Cosmetic Surgery Times. June 15, 2002
[15] “Recommendations for Physicians,” Swiss Federal Health Agency. December, 2001.
[16] http://www.lipaugmentation.com/microimplants.htm#ArtecollTM:
[17] http://www.canderm.com/page.asp?intNodeID=8035
[18] Lemperle G., Gauthier-Hazan, N., and Lemperle, M. (1998). PMMA-Microspheres (Artecoll) for long-lasting correction of wrinkles: Refinements and statistical results. Aesthetic Plastic Surgery, 22, pgs.356-365.
[19] Reisberger E., Landthaler M., and Wiest L., Schroder, J., & Stolz, W. (January, 2003), Foreign body granulomas caused by polymethylmethacrylate microspheres: Successful treatment with allopurinol. Archives of Dermatology, 139, pgs. 17-20.
[20] http://www.goremedical.com/Products/SAM/index.htm
[21] Conrad K., & MacDonald, M.R. (June, 1996). Wide polytef (Gore-Tex) implants in lip augmentation and nasolavial groove correction. Archives of Otolaryngology and Head & Neck Surgery, 122, pgs. 664-670.
[22] http://www.talksurgery.com/
[23] http://www.drbader.com/
[24] Conrad K., & MacDonald, M.R. (June, 1996). Wide polytef (Gore-Tex) implants in lip augmentation and nasolavial groove correction. Archives of Otolaryngology and Head & Neck Surgery, 122, pgs. 664-670.
[25] Environmental Protection Agency. (April, 2003). OPPT Fact Sheet: PFOA Q’s and A’s. www.epa.gov/oppt/pfoa/pfoafcts.pdf
[26] Cohen SR, Berner CF, Busso M, Clopton P, Hamilton D, Romano JJ, et al (2007) Five-Year Safety amd Efficacy of a Novel Polymethylmethacrylate Aesthetic Soft Tissue Filler for the Correction of Nasolabial Folds. Dermatological Surgery 33(s2):222-230. Retrieved from <http://www3.interscience.wiley.com/journal/118489667/?CRETRY=1&SRETRY=0>
[27] Miller MD SR (2010 Jan.) Injectable Fillers Overview. Retrieved from <http://www.yourplasticsurgeryguide.com/injectables-and-fillers/injectable-fillers.htm#brand>
[28] American Society of Plastic Surgeons (ASPS) (2010) Brand Name Products and Treatments. Retrieved from <http://www.plasticsurgery.org/Patients_and_Consumers/Procedures/Brand_Name_Procedures_and_Treatments.html>
[29] Medical News Today (2008 Sept. 1) Silicone Injections for Cosmetic Use. Retrieved from <http://www.medicalnewstoday.com/articles/119860.php>
[30] Geronemus RG (2007) The Patient’s Guide: Wrinkles-Juvederm. Retrieved from <http://www.wrinkles.org/juvederm.aspx>
[31] Food and Drug Administration (FDA) (2006). Juvederm 30HV: Patient Information Labeling. Retrieved from http://www.accessdata.fda.gov/cdrh_docs/pdf5/P050047d.pdf
[32] Food and Drug Administration (FDA) (2006 June 2). Juvederm: Summary of Safety and Effectiveness. Retrieved from http://www.accessdata.fda.gov/cdrh_docs/pdf5/P050047b.pdf
[33] Allergan, Inc. (2010). Juvederm: Safety Considerations. Retrieved from <http://www.juvederm.com/views/what-is-juvederm/safety-considerations/?p=juvederm-stories>
[34] Pinsky MA, Thomas JA, Murphy DK, & Walker PS (2008). Juvederm injectable gel: a multicenter double-blind, randomized study of safety and effectiveness. Aesthetic Surgery Journal 28(1):17-23. Retrieved from < http://www.ncbi.nlm.nih.gov/pubmed/19083502>

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