cosmetic - ascentx medical

COSMETIC

ArteFill: A Long-Lasting Injectable WrinkleFiller Material–-Summary of the U.S. Food andDrug Administration Trials and a ProgressReport on 4- to 5-Year Outcomes

Steven R. Cohen, M.D.Carl F. Berner, M.D.Mariano Busso, M.D.

Mathew C. Gleason, M.D.Douglas Hamilton, M.D.

Ralph E. Holmes, M.D.James J. Romano, M.D.

Peter P. Rullan, M.D.Millard P. Thaler, M.D.

Zeena Ubogy, M.D.Thomas R. Vecchione, M.D.

San Diego, San Francisco, Los Angeles,and Chula Vista, Calif.; Bellevue,

Wash.; Miami, Fla.; and Mesa, Ariz.

Summary: ArteFill, the successor product to Artecoll, is an injectable wrinklefiller composed of polymethylmethacrylate microspheres and bovine collagen,which offers long-lasting and probably permanent augmentation of wrinkles andskin contour deformities. The pivotal U.S. Food and Drug Administration studyconsisted of 251 subjects at eight centers in the United States who receivedinjections of ArteFill or bovine collagen dermal filler (control) in 1334 wrinklesof the glabella, nasolabial folds, radial upper lip lines, and corners of the mouth.The efficacy data generated by masked observers using a photographic FacialFold Assessment Scale demonstrated a significant improvement with ArteFillcompared with collagen at 6 months (p � 0.001) in the nasolabial folds. In theArteFill group, 12-month follow-up was obtained for 111 subjects (86.7 percent)and showed persistence of significant wrinkle correction. A subgroup of 69patients who received ArteFill were recalled 4 to 5 years later. Five patientsreported six late adverse events that occurred from 2 to 5 years after the initialinjection; four of the adverse events were mild cases of lumpiness and two weresevere. The total number of late adverse events was six of 272 (2.2 percent)wrinkles injected. Among the 272 wrinkles evaluated at 5 years, two events (0.7percent) in one patient were rated as severe (a nodular, minimally inflammatoryto noninflammatory reaction in both nasolabial folds). Investigator Facial FoldAssessment ratings at 4 to 5 years were improved from baseline by 1.67 points(p � 0.001). (Plast. Reconstr. Surg. 118 (Suppl.): 64S, 2006.)

Over the past several decades, numerous at-tempts have been made to develop safebiological or synthetic materials to perma-

nently fill wrinkles and scars.1,2 Virtually all biolog-ical materials, however, are ultimately resorbed,and previously used synthetic materials have beenassociated with side effects, such as migration,granuloma formation, and late allergic reactions.3,4

To overcome some of the problems associated withartificial skin fillers, Artecoll was developed in Ger-many in 1994 to be a permanent, injectable im-

plant. As of this article’s acceptance for publicationin Plastic and Reconstructive Surgery, ArteFill, a prod-uct of Artes Medical, had not yet been approved bythe U.S. Food and Drug Administration. ArteFillhas the same composition as Artecoll, but nano-particles have been further reduced and thesphere size is more uniform.5 To avoid confusionin the present article, Artecoll is referred to asArteFill.6 Once approved by the U.S. Food andDrug Administration, Artecoll will be marketed asArteFill in the United States and internationally.

ArteFill consists of homogenous polymethyl-methacrylate microspheres evenly suspended ina solution of partly denatured 3.5% collagen,

From the Division of Plastic Surgery and Department ofDermatology, University of California; Department of Der-matology, University of Miami; Dermatology Institute ChulaVista; and Papillon Cosmetic Dermatology Center.Received for publication January 6, 2006; accepted May 12, 2006.Presented in part at Plastic Surgery 2005: Annual Meetingof the American Society of Plastic Surgery, in Chicago, Illi-nois, September 24 through 28, 2005.Copyright ©2006 by the American Society of Plastic Surgeons

DOI: 10.1097/01.prs.0000234873.00905.a4

As of this article’s acceptance for publicationin Plastic and Reconstructive Surgery, ArteFill, aproduct of Artes Medical, had not yet beenapproved by the FDA.

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which serves as a vehicle for deep-dermalimplantation.7 All microspheres have a definedsize of 30 to 42 �m in diameter; are completelypolymerized; and have a smooth, round surface.Because of the smooth surface of the polymeth-ylmethacrylate microspheres, each microspherebecomes encapsulated by the patient’s own col-lagen fibers, thereby preventing dislocation.

ArteFill consists of 20 volume percent polym-ethylmethacrylate microspheres evenly sus-pended in 80 volume percent U.S. bovine colla-gen solution per syringe. After deep dermalinjection of ArteFill, the collagen carrier is de-graded by the body within 1 to 3 months andcompletely replaced by the body’s own collagenat a similar rate, ensuring a steady augmentationresult. Because the polymethylmethacrylate mi-crospheres are nonbiodegradable and too largeto migrate or to be phagocytosed by macro-phages, the tissue augmentation is expected tobe permanent, consisting of 80 volume percentautologous connective tissue.

Artecoll, ArteFill’s predecessor, has been ap-proved and available in over 50 countries in theworld since 1994. Since its introduction in 1994,an estimated 400,000 patients have been treated,with a reported complication rate of 0.01percent.6,8 On February 28, 2003, the U.S. Foodand Drug Administration General and PlasticSurgery Devices Advisory Panel recommendedthat ArteFill be approved, with conditions, formarketing in the U.S. ArteFill is expected tobecome the first permanent injectable wrinklefiller to gain U.S. Food and Drug Administrationapproval.

The need to closely monitor and report anylong-term benefits and late adverse events whendiscussing a permanent filler material is criticalto the successful application of a product such asArteFill. The purpose of the present report is tosummarize the U.S. Food and Drug Administra-tion United States Clinical Trial and to updatethe readership on the 4- to 5-year outcomes fol-lowing injection of ArteFill.

MATERIALS AND METHODSThe purpose of the U.S. Food and Drug Ad-

ministration study was to compare the safety andefficacy of ArteFill injections with those of colla-gen (Zyderm II or Zyplast) in the glabellar frownlines, nasolabial folds, radial upper lip lines, andcorners of the mouth (marionette). The primaryobjectives of the study were to compare the cos-metic correction provided by ArteFill at the end of6 months to that of Zyderm/Zyplast over the same

time period and to explore the safety of ArteFill at6 and 12 months as an injectable implant for cor-rection of contour deformities of the dermis of theface. The secondary objectives of the study were tocharacterize the physician’s assessment of successwith respect to how closely the treatment met thephysician’s expectations for correction and tocharacterize the subject’s assessment of satisfac-tion with respect to the subject’s personal expec-tations. Although physicians were not masked as tothe identity of the treatment, subjects were nottold which treatment they received until after theyhad completed the 6-month evaluation.

The study was performed at eight centers(four plastic surgery centers and four dermatologycenters), with institutional review board approvaland informed consent from all subjects. The studywas controlled and randomized, with potentialsubjects agreeing to be assigned to either the Ar-teFill or control group. The subjects and evalua-tors were masked and unaware of which injectionmaterial they received (double-blinded). Inclu-sion and exclusion criteria were strict and havepreviously been published.9

Efficacy was measured by three masked ob-servers using the Facial Fold Assessment Scale torate wrinkles on the subject’s photographs.10 In-vestigator assessment of success was recorded at 1,3, and 6 months using the following scale: 1 �completely successful, 2 � very successful, 3 �moderately successful, 4 � somewhat successful,and 5 � not at all successful. Subject assessment ofsatisfaction was recorded at 1-, 3-, and 6-monthintervals using the following scale: 1 � very satis-fied, 2 � satisfied, 3 � somewhat satisfied, 4 �dissatisfied, and 5 � very dissatisfied.

4- to 5-Year Follow-Up DataAll study participants were invited to return for

4- to 5-year follow-up. As an inducement, a smallfinancial payment ($100) was offered. A subgroupof 69 patients who received ArteFill returned 4 to5 years after their initial treatment. These 69 pa-tients underwent clinical and photographic eval-uation and were again rated for efficacy using theFacial Fold Assessment Scale. Safety informationand adverse events were also recorded at 4- to5-year follow-up. The data in the present reportwere tabulated as of September 9, 2005, the cutoffdate for this portion of the study. A vigorous effortis still underway to follow up as many of the orig-inal study patients as possible; thus, ultimately, afinal report will be submitted on a larger numberof patients.

Volume 118, Number 3S • Progress Report on ArteFill

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Injection TechniqueBefore injection, topical anesthetic cream/

ointment and, for the upper lip, local anesthesiawas used when indicated by the investigator. Thedermal layer used for ArteFill implantation isshown in Figure 1. The method of implantingArteFill is more technique sensitive than that forinjecting collagen. The “tunneling technique,”moving the needle in a linear fashion back andforth just beneath the wrinkle, was used. Becausethe viscosity of ArteFill is three times higher thanthat of Zyplast, a higher constant pressure wasapplied throughout the injection procedure. A26-gauge, half-inch-long needle was used. Thethickness of the needle and skin were used to help

determine depth of injection. The thickness offacial skin varies between 0.2 mm (eyelids), 0.4mm (nasolabial folds), and 0.8 mm (glabellarfrown lines).11 The thickness of the skin in a deepcrease is diminished to approximately one-fourthof its normal thickness. At the start of the proce-dure, the needle was tested by squeezing a smallquantity of ArteFill out of the tip. ArteFill was thenimplanted deeply intradermally (e.g., into the re-ticular dermis just above the junction betweendermis and subcutaneous fat). If ArteFill was in-jected into the papillary dermis, causing a blanch-ing effect, the injection was stopped and the nee-dle was placed at a deeper level. At the end ofimplantation, the implant was evenly massagedwith the fingertip, and slight pressure was appliedto any detected lump. Subjects were advised thatthere would be some swelling for the first 12 to 24hours and that areas of light pink coloration alongthe injection sites might be present for 2 to 5 days.They were also advised to minimize mimetic ac-tivity for 1 to 2 days.

Statistical AnalysisAdverse events were described by counts of

events and counts of subjects experiencing ad-verse events. Counts of elevated immunoglobulinG levels were also provided. Tests for treatmentgroup differences in number of treatments andquantity of product were made using independentt tests. Nonparametric tests were used for ratingsvariables. Groups were compared with Mann-Whitney U tests for improvements in observer-rated and investigator-rated Facial Fold Assess-ment Scale scores and for investigator successratings and subject satisfaction ratings. Within-group tests for improvements in the ArteFill treat-ment group were made using Wilcoxon matched-pairs signed ranks data to accommodate the 12-month observations. Rater reliability for observerFacial Fold Assessment Scale ratings was evaluatedusing intraclass correlation.

RESULTSThere were 251 subjects entered into the

study. One hundred twenty-eight subjects receivedArteFill (11 men and 117 women), and 123 sub-jects (11 men and 112 women) received the col-lagen control. The mean age of the ArteFill sub-jects was 53.2 years (range, 28 to 82 years) and themean age of the controls was 51.2 years (range, 29to 78 years). Of these 251 subjects, 247 had at leastone follow-up visit (98.4 percent) and 233 (92.8percent) had 6-month follow-up visits. In the Ar-

Fig. 1. The dermal plane of ArteFill implantation. (Above) Thedermal thickness is diminished under a wrinkle. Initial implanta-tion of ArteFill using a threading technique. (Center) ArteFill set-tles into the deep dermis and (below), if necessary, ArteFill is re-injected into the deep dermis to “fill” the wrinkle.

Plastic and Reconstructive Surgery • September 1 Supplement, 2006

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teFill group, 12-month follow-up was obtained for111 subjects (86.7 percent). Because ArteFill treat-ment was offered to all subjects in the collagengroup at 6-month follow-up, no 12-month fol-low-up could be obtained for the collagen group.Of the 116 collagen subjects who completed the6-month follow-up evaluation, 106 (91 percent)were treated with ArteFill.

ArteFill was injected into the glabellar frownsof 81 subjects, nasolabial folds of 108 subjects,upper lip lines of 69 subjects, and mouth cornersof 86 subjects; whereas collagen was injected intothe glabellar frowns of 86 subjects, nasolabial foldsof 104 subjects, upper lip lines of 59 subjects, andmouth corners of 87 subjects. In total, 1334 wrin-kles were injected: 320 glabellar frowns, 420 na-solabial folds, 253 lip lines, and 341 mouth cornerswere treated in the 251 subjects.

The number of treatments to each of the facialareas (i.e., glabellar frowns, nasolabial folds, radialupper lip lines, and corner of mouth lines) werenot significantly different (p � 0.316 to p � 0.974)between ArteFill and the controls (Fig. 2). Almosttwice as much collagen as ArteFill was used at eachof the four injection sites (Fig. 3), a statisticallysignificant difference (p � 0.001 in each case).

Results of Primary ObjectivesAlthough adverse reactions were uncommon

in either group, more redness and swelling andmore lumpiness at the injection site was noted in

the collagen group. There were a total of 27 ad-verse events in the ArteFill group compared with38 in the collagen controls. These numbers werenot statistically significant. One subject underwent“incidental” removal and/or drainage in the Ar-teFill group related to excision of an actinic ker-atosis in the vicinity of the previous ArteFill injec-tion, and two subjects in the collagen grouprequired removal and/or drainage for abscesses(Table 1).

Serum immunoglobulin G levels were elevatedin one subject undergoing ArteFill implantationafter 1 month. Levels were elevated in one subjectat 1, 3, and 6 months after collagen injection.There was no clinically significant findings inthese patients.

Table 2 summarizes improvement over time inthe masked observers’ Facial Fold AssessmentScale ratings. Observations 1 month after injectionshowed no statistically significant difference be-tween the two groups for nasolabial folds, upperlip lines, or mouth corners, whereas the controltreatment was more effective (p � 0.004) thanArteFill for glabellar folds. By 3 months, themasked observers’ ratings showed a statisticallysignificantly greater improvement in the nasola-bial folds (p � 0.001) and the corner of the mouthwrinkles (p � 0.001) in the ArteFill group whencompared with collagen. Averaged across facialareas, the overall result was also significant (p �0.001). At 6 months after injection, the ArteFillgroup was statistically better (p � 0.001) than the

Fig. 2. During the 4 weeks after initial treatment, additional treatments were permitted. The number of treatmentsshown in this graph (mean � SE) did not differ significantly between ArteFill and control (p � 0.974, p � 0.316, p �

0.705, and p � 0.608, respectively). (Reprinted from Cohen, S. R., and Holmes, R. E. Artecoll: A long-lasting injectablewrinkle filler material. Report of a controlled, randomized, multicenter clinical trial of 251 subjects. Plast. Reconstr.Surg. 114: 964, 2004.)


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collagen injection in the nasolabial fold and over-all (p � 0.001). Facial Fold Assessment Scale re-liability among the three masked raters rangedfrom 0.835 for the glabellar frowns to 0.900 for thecorner of the mouth lines.

Results of Secondary ObjectivesTable 3 summarizes improvement in investigators’

Facial Fold Assessment Scale ratings over time. Unlikemasked observers, who rated from photographs, in-vestigators were not masked and rated their live expe-

Fig. 3. The quantity of ArteFill injected (mean � SE) was significantly lower than control for each facial area (p � 0.001ineachcase).(ReprintedfromCohen,S.R.,andHolmes,R.E.Artecoll:Along-lastinginjectablewrinklefillermaterial.Reportof a controlled, randomized, multicenter clinical trial of 251 subjects. Plast. Reconstr. Surg. 114: 964, 2004.)

Table 1. Adverse Events from ArteFill and Control Injections

No. of Events

ArteFill Control

Event ReportedRemoval orDrainage* Reported

Removalor Drainage*

Increased sensitivity 4 1Sensitization reactions 0 6Visibility of puncture site 0 2Granuloma or enlargement of the implant 0 1Persistent swelling or redness 7 13 (1§)Abscess 0 3 2Infection 0 1Rash, itching more than 48 hr after injection 2 2Lumpiness at injection site � 1 mo after injection 8

(1†) 1‡ 4(1§)

Blurred vision (temporary) 1 0Recurrence of existing herpes labialis 1 0Flu-like symptoms 1 1§Other local complications 1 1§Other systemic complications 1§ 0Severe illness, trauma, death 0 1§Total adverse events 26 1 36 2Total subjects with adverse events 21 1 16 2Total subjects evaluated 128 128 123 123Subjects with adverse events (%) 16.4 0.8 13.0 1.6Reprinted from Cohen, S. R., and Holmes, R. E. Artecoll: A long-lasting injectable wrinkle filler material. Report of a controlled, randomized,multicenter clinical trial of 251 subjects. Plast. Reconstr. Surg. 114: 964, 2004.*Adverse events with removal or drainage are included in total reported.†Used contrary to protocol (lip augmentation).‡Pathologic examination showed no foreign body reaction. Diagnosis: seborrheic keratosis, not related to implant.§Not related to implant.


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rience with subjects against the reference photographsof the Facial Fold Assessment Scale. At 1 month, sig-nificantly greater improvement in glabellar folds wasseen with control than with ArteFill (p � 0.034),whereas significantly greater improvement in mouthcorners was seen with ArteFill than with control (p �0.041). By 3 months, all facial areas except for glabellarfolds (p � 0.317) showed significantly greater improve-ment with ArteFill than with control (p � 0.001 in eachcase). The overall average was also significantly greater

for ArteFill (p � 0.001). By 6 months, all four facialareas and the overall average showed significantlygreater improvement with ArteFill than with control (p� 0.001).

Investigator success ratings over time are summa-rized in Figure 4. As shown in the figure, the ratings forthe two groups were similar at 1 month. However, by3 months and 6 months, significantly more success wasnoted in the ArteFill group than in the control group(p � 0.007 to p � 0.001). By 6 months, ArteFill ratings

Table 2. Improvement in Masked Observers Ratings Using the Facial Fold Assessment Scale

ArteFill Control

Time Treatment Area No. Mean SD SE No. Mean SD SE p

1 Month Glabellar folds 64 0.17 0.69 0.09 77 0.49 0.68 0.08 0.004Nasolabial folds 91 0.75 0.76 0.08 91 0.74 0.73 0.08 0.713Upper lip lines 58 0.31 0.55 0.07 53 0.48 0.60 0.08 0.205Mouth corners 71 0.46 0.74 0.09 76 0.30 0.65 0.07 0.179Overall 109 0.53 0.59 0.06 108 0.59 0.55 0.05 0.422

3 Months Glabellar folds 65 0.25 0.80 0.10 75 0.35 0.60 0.07 0.348Nasolabial folds 87 0.81 0.81 0.09 88 0.15 0.79 0.08 �0.001Upper lip lines 53 0.18 0.64 0.09 51 0.25 0.52 0.07 0.454Mouth corners 64 0.45 0.80 0.10 77 0.01 0.66 0.07 0.001Overall 102 0.53 0.61 0.06 107 0.02 0.48 0.05 �0.001

6 Months Glabellar folds 71 0.34 0.79 0.09 79 0.32 0.68 0.08 0.971Nasolabial folds 92 0.77 0.87 0.09 91 0.00 0.90 0.09 �0.001Upper lip lines 55 0.08 0.62 0.08 50 0.22 0.48 0.07 0.176Mouth corners 69 0.26 0.76 0.09 79 0.09 0.74 0.08 0.316Overall 107 0.50 0.67 0.06 110 0.16 0.57 0.05 �0.001

12 Months Glabellar folds 69 0.41 0.73 0.09Nasolabial folds 90 0.95 0.95 0.10Upper lip lines 56 0.24 0.64 0.09Mouth corners 70 0.17 0.81 0.10Overall 108 0.55 0.71 0.07

Reprinted from Cohen, S. R., and Holmes, R. E. Artecoll: A long-lasting injectable wrinkle filler material. Report of a controlled, randomized,multicenter clinical trial of 251 subjects. Plast. Reconstr. Surg. 114: 964, 2004.

Table 3. Improvement in Investigator Ratings Using the FFA Scale

ArteFill Control

Time Treatment Area No. Mean SD SE No. Mean SD SE p

1 Month Glabellar folds 67 1.16 0.79 0.10 79 1.56 1.07 0.12 0.034Nasolabial folds 91 1.66 0.92 0.10 93 1.59 1.05 0.11 0.405Upper lip lines 61 1.47 0.74 0.09 54 1.32 0.90 0.12 0.338Mouth corners 74 1.50 0.97 0.11 76 1.16 0.94 0.11 0.041Overall 111 1.50 0.68 0.06 111 1.47 0.79 0.07 0.593

3 Months Glabellar folds 67 1.14 0.90 0.11 74 0.90 1.07 0.12 0.317Nasolabial folds 88 1.84 0.94 0.10 89 0.51 0.99 0.11 �0.001Upper lip lines 58 1.28 0.69 0.09 51 0.43 0.89 0.12 �0.001Mouth corners 68 1.40 1.25 0.15 75 0.48 0.77 0.09 �0.001Overall 106 1.50 0.83 0.08 108 0.59 0.73 0.07 �0.001

6 Months Glabellar folds 73 1.12 0.95 0.11 82 0.46 1.04 0.12 �0.001Nasolabial folds 96 1.91 1.01 0.10 96 0.01 0.86 0.09 �0.001Upper lip lines 60 1.34 0.95 0.12 54 0.05 0.98 0.13 �0.001Mouth corners 72 1.28 1.41 0.17 80 0.02 0.83 0.09 �0.001Overall 112 1.51 0.95 0.09 115 0.17 0.74 0.07 �0.001

12 Months Glabellar folds 69 1.29 1.01 0.12Nasolabial folds 91 2.07 1.06 0.11Upper lip lines 58 1.41 1.02 0.13Mouth corners 72 1.51 1.23 0.14Overall 109 1.68 0.94 0.09

Reprinted from Cohen, S. R., and Holmes, R. E. Artecoll: A long-lasting injectable wrinkle filler material. Report of a controlled, randomized,multicenter clinical trial of 251 subjects. Plast. Reconstr. Surg. 114: 964, 2004.


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were generally in the very successful range, whereascollagen ratings were generally in the somewhat suc-cessful range.

A similar presentation for subject ratings of satis-faction is shown in Figure 5. No significant differencesbetween treatment groups was noted at 1 month. By 3months, the subjects in the ArteFill group reportedsignificantly greater satisfaction than those in the con-trol group (p � 0.038 to p � 0.001). At 6 months, thesubjects in the ArteFill group continued to report sig-

nificantly greater satisfaction than the control groupsubjects (p � 0.001 in each case). By 6 months, themeans for the ArteFill group were generally in theSatisfied range while the means for the control groupwere generally in the Dissatisfied range.

12-Month ArteFill Efficacy AnalysisData on improvement at 12-months in Facial

Fold Assessment Scale ratings was available for the

Fig. 4. The investigators’ success ratings (means � SE) for ArteFill and control were similar at 1 month (p � not significant ineach case except for mouth corners p � 0.011) and significantly higher for ArteFill than control at both 3 and 6 months (p �

0.001 in each case except 3-month glabellar folds, where p � 0.007). ArteFill success ratings remained high at 12 months.(Reprinted with permission from Cohen, S. R., and Holmes, R. E. Artecoll: A long-lasting injectable wrinkle filler material. Reportof a controlled, randomized, multicenter clinical trial of 251 subjects. Plast. Reconstr. Surg. 114: 964, 2004.)

Fig. 5. The subjects satisfaction ratings (means and standard errors) for ArteFill and control were similar at 1 month(p �NS in each case) and significantly higher for ArteFill at 3 and 6 months (p �0.001 in each case except for 3-monthglabellar where p � 0.038). Satisfaction ratings for ArteFill/Artecoll remained high at 12 months. Reprinted withpermission from Cohen, S. R., and Holmes, R. E. Artecoll: A long-lasting injectable wrinkle filler material. Report of acontrolled, randomized, multicenter clinical trial of 251 subjects. Plast. Reconstr. Surg. 114: 964, 2004.


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ArteFill group only, per protocol, because of cross-over of collagen subjects to the ArteFill treatmentat 6 months. Ratings from masked observers andfrom investigators were included.

Single group tests were computed for maskedobserver ratings to determine whether efficacycould be detected 12 months after treatment. Theresults showed significant improvement in FacialFold Assessment Scale ratings for the each of thefour facial areas and the overall average (p � 0.047to p � 0.001).

Similar tests were computed for investigatorFacial Fold Assessment Scale ratings. Theseshowed significant results in all four of the treat-ment areas and overall (p � 0.001 in each case).These ratings for masked observer and investiga-tor demonstrated effectiveness 12 months afterArteFill treatment.

Investigator ratings of success and subject rat-ings of satisfaction in the ArteFill group at 12months are presented in Figures 4 and 5, respec-tively. The success and satisfaction ratings re-mained high for the ArteFill group at 12 months.

5-Year Results and Statistical AnalysisA subgroup of 69 patients who received Arte-

Fill were recalled 4 to 5 years later. These 69 pa-tients underwent clinical and photographic eval-uation and were again rated for efficacy using theFacial Fold Assessment Scale. Safety informationand adverse events were also recorded at 4- to5-year follow-up. Five patients reported six lateadverse events: four of the adverse events weremild and two were severe. Among the 272 wrinklesevaluated at 5 years, two events (0.7 percent) inone patient were rated as severe (a nodular min-imally to noninflammatory reaction in both naso-labial folds). The patient was treated with steroidinjections, and the event is in the process of re-solving, having been rated recently as mild. Thepatient is happy with the result and may or may notreturn for further treatment of the event. Theother four patients had mild events reported aslumpiness in the left glabellar fold in one, the leftradial wrinkle line in one, the left marionette linein one, and the left nasolabial fold in one. In onepatient with mild lumpiness in the left marionetteline, the lump was simply excised by a small in-traoral incision. These six late adverse events werereported to the investigators from 2 to 5 years afterthe initial injection.

Investigator Facial Fold Assessment Scale rat-ings at 4 or 5 years were improved from baselineby 1.67 points (p � 0.001); 81.8 percent of subjects

reported that they were either satisfied or verysatisfied; 95.5 percent reported that they were atleast somewhat satisfied; 88.6 percent were ratedas very successful or completely successful by in-vestigators; and 97.7 percent were rated as at leastmoderately successful. Forty-three of the 69 pa-tients had no other surgical procedures (i.e., mid-face lift) following ArteFill injection 4 to 5 yearsearlier. Facial Fold Assessment Scale ratings inthese patients were conducted by three blindedobservers (Fig. 6). Masked observer Facial FoldAssessment Scale ratings at 5 years were improvedfrom baseline by 1.22 points (p � 0.001).

DISCUSSIONThe results of this study show ArteFill to be a

safe and effective soft-tissue filler. Although Arte-Fill had fewer adverse events reported throughoutthe 12-month safety study period compared withcollagen (Zyderm/Zyplast) in a 6-month study pe-riod, these results were not statistically significant.ArteFill was more effective than collagen for cor-rection of nasolabial folds in masked observer rat-ings at the 6-month effectiveness study period. Nostatistically significant difference was noted be-tween masked observer ratings for ArteFill andcollagen in the other injection sites; however, thequantity of ArteFill used was nearly half that ofcollagen. Investigators’ success ratings for ArteFillwere superior to those for collagen at 6 months foreach of the four injection sites. Subjects’ satisfac-tion ratings for the ArteFill group were also higher

Fig. 6. Forty-three patients evaluated at 4- to 5-year follow-upshowed further improvement in the masked observers’ FacialFold Assessment Scale ratings for the nasolabial folds.


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than for collagen in each of the injection sites at6 months after implantation.

Apreliminaryproductusedinhumansbythesameinventor, before Artecoll, was called Arteplast.12 Theoriginal suspension consisted of 30- to 42-�m-diameterpolymethylmethacrylate microspheres in gelatin. Thefirst clinical trials were conducted under the supervi-sion of the Ethical Commission of Frankfurt Universityin1989.Onehundredeighty-sevenvolunteersreceivedArteplast subdermally. In this group, plus the 400 sub-jects who received Arteplast up until its replacement byArtecoll in 1994, a total of 15 (2.5 percent) developedforeign body granulomas from 6 to 18 months afterinjection.6 The majority of these were treated with in-tralesional steroid injection and rarely with surgicalexcision. In 1994, a new purification and washing tech-nique was introduced.6 The sieving process waschanged from a nylon fabric mesh to a metal mesh,and a complex washing and ultrasound procedure wasdevised that removed virtually all nanoparticles andelectrical surfacecharges,whichwerethoughttobethecause of foreign body reactions and granuloma for-mation. Another change made at the same time wasthe use of collagen as a carrier to replace the gelatincarrier, which is resorbed too quickly and thereby per-mits clumping of the particles. The improved product,named Artecoll, was brought onto the market by RofilMedical International, Breda, Holland, in 1994 andhas since been used in an estimated 400,000 patients,with a reported granulomatous reaction rate of lessthan 0.01 percent.6,8

In evaluating the literature on safety of permanentinjectable fillers, it is critical for the clinician to differ-entiate between Arteplast, Artecoll, and ArteFill. Arte-plast, Artecoll, and ArteFill have been confused witheach other in the past, making accurate communica-tion about the safety and efficacy of ArteFill difficult.13

Electron microscopic views of polymethylmethacrylatemicrospheres contained in Artecoll demonstrate sig-nificant reduction of polymethylmethacrylate micro-particles smaller than 30 �m, compared with Arteplast(Fig. 7). ArteFill has been further refined to meet strin-gent U.S. Food and Drug Administration quality re-quirements by removing microparticles smaller than20 �m, which now account for less than 1 percent bynumber. In another words, among 100 microspheres,there is less than one phagocytosable (�20 �m) par-ticle on average. The partially denatured collagen isproduced from bovine hides from a closed herd lo-cated in the United States. The collagen is the sameas in Artecoll, 80 percent denatured and only 20 per-cent native, which makes the collagen less allergenicand reduces the positive skin test to approximately0.1 percent.5

BiocompatibilityThe chemical inertness and biocompatibility

of polymethylmethacrylate has been well accepted

Fig. 7. Comparison of scanning electron microscopic images ofpolymethylmethacrylate bone cement (above) and Artecoll polym-ethylmethacrylate 32- to 40-�m-diameter microspheres (center)and ArteFill (below). Note relative absence of nanoparticles on thesurface of ArteFill microspheres compared with Artecoll and Arte-plast, resulting from improvements in washing procedures. Nano-particles may be one of the stimuli for inflammatory reactions.


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since Judet14 introduced the first hip prosthesismade from polymethylmethacrylate in 1947. An-imal experiments have demonstrated that an im-portant key to biocompatibility in the skin is theabsolutely round shape, smooth surface, and sizeof the polymethylmethacrylate microspheres.15,16

In comparison, other synthetic fillers such as Te-flon or silicone particles have irregular surfacesthat are more prone to cause chronic granuloma-tous reactions.17 Microscopically, the predomi-nant cells seen in the reaction to Teflon or siliconeparticles are foreign body giant cells. In contrast,in the rare case of foreign body reaction to Arte-Fill, histologically, the true granulomas showbroad bands of collagen fibers between micro-spheres, which are pushed apart, with rare lym-phocytes, macrophages, and giant cells.18 Thesegranulomas almost always respond to intralesionalinjection with corticosteroids.6,19 In those casesthat do not respond to steroids, surgical excisionmay be required.

Most materials that are used as biological fill-ers to increase the thickness of the dermis in awrinkle line are phagocytosed within a fewmonths. Therefore, a lasting effect can beachieved only by using either an autogenous ma-terial that becomes vascularized and survives as agraft or with nonresorbable synthetic substances.There are approximately 6 million polymethyl-methacrylate microspheres in each 1 cc of ArteFill.Beneath the wrinkle crease, the microspheres actas a matrix and stimulate fibroblasts to encapsu-late each individual microsphere. Collagen is usedas a carrier substance that prevents clumping dur-ing injection and stimulates tissue ingrowth. The20 volume percent polymethylmethacrylate mi-crospheres provide the scaffold for the 80 volumepercent autologous connective tissue deposition.The ArteFill serves as a filler that seems to providestructural support to the wrinkle crease, prevent-ing further folding and allowing the dermis toregenerate in the wrinkle fold.

Treatment AreasThe glabellar lines posed little problem with

injection because the dermis is thick and the un-derlying connective tissue provides good supportof the implant (Fig. 8). Slight overcorrection maybe necessary and deeper lines may require repeatinjections. It is difficult to explain the lack of sta-tistical difference found between collagen andArteFill in the glabellar frown region usingmasked observer ratings. Initial overcorrectionwas common for collagen treatment. However,

there was a general reluctance among U.S. clinicaltrial investigators to inject as much ArteFill as col-lagen in each of the four study areas because of itspermanent effect, which may account for the ab-sence of clear-cut statistical significance, with theexception of nasolabial folds. Nevertheless, sub-ject satisfaction ratings and investigator successratings were higher for ArteFill at the 6-monthpoint in each of the four study areas.

The results of nasolabial fold augmentationwith ArteFill were excellent (Figs. 9). Nasolabialcreases are best supported by two to three strandsof ArteFill implanted parallel and medial to thefold. During the first several days after implanta-tion, ArteFill can be moved laterally by facial mus-cle movement. Care must be taken not to place theArteFill too superficially. Otherwise, in patientswith thin skin, the implant may appear erythem-atous for several weeks and the implant may bevisualized as small white granules. A second ses-sion is often necessary for not only the nasolabialfolds but other treatment areas as well.

Fig. 8. Glabellar lines before (above) and 6 months after (below)treatment with ArteFill. (Reprinted from Cohen, S. R., and Holmes,R. E. Artecoll: A long-lasting injectable wrinkle filler material. Re-port of a controlled, randomized, multicenter clinical trial of 251subjects. Plast. Reconstr. Surg. 114: 964, 2004.)


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Radial lip lines extend upward or downwardfrom tiny notches in the vermilion-cutaneous bor-der. Care must be taken in injecting the verticalwrinkles of the lip to avoid lumps. In younger pa-tients with nice projection of the white roll, eachwrinkle can be treated individually. In patients withfour or more vertical lines and in whom the projec-tion of the white roll is diminished, ArteFill can beinjected transversely along the entire white roll andbeneath the individual vertical lines (Fig. 10). Thereis a natural pocket between the white roll and theorbicularis oris muscle, which is easily filled centrip-etally from the corners of the mouth. Injection intothe upper and lower lips may be painful, and field ornerve blocks with local anesthesia are recom-mended. ArteFill is presently not intended for in-jection into the vermilion of the lip.

Wrinkles at the corners of the mouth and mar-ionette lines may be difficult to treat but often yieldexcellent results. First, the lower white roll itself is

treated horizontally approximately 1 cm in lengthfrom the corner. Next, five to 10 vertical and hori-zontal threads of ArteFill should be implanted usinga criss-crossing technique. This supports the regionand slightly lifts the corners of the mouth. The skinis thin in this area, and superficial injection may leadto telangiectasias. Preferably, ArteFill should be im-planted in many different tunnels in two or moresessions. Injection of ArteFill into the orbicularis orismuscle is to be avoided, as it may result in the for-mation of nodules that can be palpated in the wetmucosa. The marionette lines that extend verticallyfrom the corners of the mouth down to the man-dibular border can be improved by linear threadingcombined with deep intradermal criss-cross injec-tion of ArteFill.

5-Year OutcomesClinical and photographic review of the 69

patients who returned at 4 to 5 years for follow-up

Fig. 9. Nasolabial fold before (left), 3 months after (center), and 5 years after (right) treatment with ArteFill.

Fig. 10. Upper lip lines, marionette lines, and nasolabial folds before (left), 3 months after (center), and 5 years after (right) treatmentwith ArteFill.


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substantiated our earlier impressions of the dura-tion of ArteFill. At 5 years, the results actuallylooked better then they did during the periodfrom 3 months to 1 year after injection (Figs. 9through 12). It is difficult to know the exact mech-anism, but because ArteFill may be considered apartially living implant, there seems to be a grad-ual increase in the amount of collagen depositionaround the microspheres. From a safety point ofview, it is critical to continue rigorous follow-up ofthese patients or any patient receiving a poten-tially permanent injection. As of September 9,2005, when this phase of the study was statisticallyanalyzed, five patients reported six late adverseevents: four of the adverse events were mild andtwo were severe. Among the 272 wrinkles evalu-ated at 5 years, two events (0.7 percent) in onepatient were rated as severe (a nodular minimallyinflammatory to noninflammatory reaction inboth nasolabial folds). The patient was treated

with steroid injections, and the event is in theprocess of resolving, having been rated recently asmild. The patient is happy with the result and mayor may not return for further treatment of theevent. In conclusion, it appears that late adverseevents were rare with the use of ArteFill and canbe successfully treated with corticoid injections.The other four patients had mild events reportedas lumpiness in the left glabellar fold in one, theleft radial wrinkle line in one, the left marionetteline in one, and the left nasolabial fold in one. Inone patient with mild lumpiness in the left mar-ionette line, the lump was simply excised by a smallintraoral incision. These six late adverse eventswere reported to the investigators from 2 to 5 yearsafter the initial injection.

CONCLUSIONSThe ability to measure the effect of cosmetic

treatments, such as wrinkle fillers, has suffered

Fig. 11. Before (left), 6 months after (center), and 5 years after (right) injection of ArteFill into nasolabial folds.

Fig. 12. Before (left), 3 months after (center), and 5 years after (right) injection of ArteFill into nasolabial folds.


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from the lack of a validated objective rating scale.The authors hope that the successful use of aphotographic Facial Fold Assessment Scale for thisU.S. Food and Drug Administration study will en-courage development and adoption of similarscales for cosmetic treatment evaluations.

This study has demonstrated the safety of ArteFillrelative to collagen control, as measured by relativerates of adverse events. It has demonstrated the effec-tiveness of ArteFill relative to collagen control for treat-ment of nasolabial folds, as measured by the objectiverating scale using masked raters. The effectiveness ofArteFill was demonstrated for all areas treated, usingthe important outcome measures of investigator suc-cess rating and subject satisfaction.

Ratings of wrinkle depth using the Facial FoldAssessment Scale by masked observers showed im-provement from baseline by 1.22 points (p �0.001) at 5 years after injection. In conclusion, itappears that improvements from ArteFill are sta-ble for at least 4 to 5 years, and at this point in time,the development of late adverse events appears tobe relatively uncommon.

Steven R. Cohen, M.D.FACESplus Aesthetic Facility

8899 University Center Lane, Suite 350San Diego, Calif. [email protected]

ACKNOWLEDGMENTSThe study was sponsored by Artes Medical, Inc., San

Diego, California. The authors are indebted to PaulClopton, M.S., Research Service, Veterans Affairs Med-ical Center, San Diego, for invaluable statistical work,and PaxMed International, San Diego, for diligent andthorough management of this study. They are also hum-bly appreciative of Professor Gottfried Lemperle’s adviceand generous availability to the researchers.

DISCLOSURESSteven R. Cohen, M.D., and Ralph E. Holmes, M.D.,

have served on the medical advisory board to Artes Medical,Inc., the manufacturer of ArteFill, and currently serve as con-sultants to the company. Carl F. Berner, M.D., Stephen R.Cohen, M.D., Mathew C. Gleason, M.D., Ralph E. Holmes,M.D.,PeterP.Rullan,M.D.,MillardP.Thaler,M.D.,ZeenaUbogy, M.D., and Thomas R. Vecchione, M.D., are share-holders in Artes Medical, Inc. Mariano Busso, M.D., James J.Romano, M.D., and Douglas Hamilton, M.D., have no fi-nancial interest in any of the products, devices, or drugs men-tioned in this article.

REFERENCES1. Alster, T. S., and West, T. B. Human-derived and new syn-

thetic injectable materials for soft-tissue augmentation: Cur-rent status and role in cosmetic surgery. Plast. Reconstr. Surg.105: 2515, 2000.

2. Kinney, B. M., and Hughes, C. E., III. Soft tissue fillers: Anoverview. Aesthetic Surg. J. 21: 469, 2001.

3. Rubin, J. P., and Yaremchuk, M. J. Complications and tox-icities of implantable biomaterials used in facial reconstruc-tive and aesthetic surgery: A comprehensive review of theliterature. Plast. Reconstr. Surg. 100: 1, 1997.

4. Knapp, T. R., Kaplan, E. N., and Daniels, J. R. Injectable collagenfor soft tissue augmentation. Plast. Reconstr. Surg. 60: 398, 1977.

5. Lemperle, G. Personal communication from the inventor ofArteFill/Artecoll and Chief Medical Officer, Artes Medical,Inc., San Diego, California, December 28, 2005.

6. Lemperle, G., Romano, J. J., and Busso, M. Soft tissue aug-mentation with artecoll: 10-year history, indications, tech-nique, and potential side effects. Dermatol. Surg. 29: 573, 2003.

7. Lemperle, G., Hazan-Gauthier, N., and Lemperle, M. PMMA mi-crospheres(Artecoll) for skinandsoft-tissueaugmentation:Part II.Clinical investigations. Plast. Reconstr. Surg. 96: 627, 1995.

8. Lemperle, S. Personal communication from the Chief Ex-ecutive Officer, Artes Medical, Inc., San Diego, California,January 5, 2006.

9. Cohen, S. R., and Holmes, R. E. Artecoll: A long-lastinginjectable wrinkle filler material. Report of a controlled,randomized, multicenter clinical trial of 251 subjects. Plast.Reconstr. Surg. 114: 964, 2004.

10. Lemperle, G., Holmes, R. E., Cohen, S. R., and Lemperle, S.M. A classification of facial wrinkles. Plast. Reconstr. Surg. 108:1736, 2001.

11. Tan, C. Y., Statham, B., Marks, R., and Payne, P. A. Skin thicknessmeasurement by pulses ultrasound: Its reproducibility, validation,and variability. Br. J. Dermatol. 106: 675, 1982.

12. Lemperle, G., Ott, H., Charrier, U., Hecker, J., and Lem-perle, M. PMMA microspheres for intradermal implantation:Part I. Animal research. Ann. Plast. Surg. 26: 57, 1991.

13. McClelland, M., Egbert, B., Hanko, V., Berg, R. A., and DeLustro,F. Evaluation of Artecoll polymethylmethacrylate implant for softtissue augmentation: Biocompatibility and chemical characteriza-tion. Plast. Reconstr. Surg. 100: 1466, 1997.

14. Judet, J. Protheses en resins acrylic. Mem. Acad. Chir. 73: 561,1947.

15. Morhenn, V. B., Lemperle, G., and Gallo, R. L. Phagocytosisof different particulate dermal filler substances by humanmacrophages and skin cells. Dermatol. Surg. 28: 484, 2002.

16. Lemperle, G., Morhenn, V. B., Pestonjamasp, V., and Gallo,R. L. Migration studies and histology of injectable PMMAmicrospheres of various sizes in mice. Plast. Reconstr. Surg.113: 1380, 2004.

17. Lemperle, G., Morhenn, V. B., and Charrier, U. Human histologyand persistence of various injectable filler substances for soft tissueaugmentation. Aesthetic Plast. Surg. 27: 354, 2003.

18. Requena, C., Izquierdo, M. J., Navarro, M., et al. Adversereactions to injectable aesthetic microimplants. Am. J. Der-matopathol. 23: 197, 2000.

19. Manuskiatti, W., and Fitzpatrick, R. E. Treatment response ofkeloidal and hypertrophic sternotomy scars: Comparisonamong intralesional corticosteroid, 5-fluorouracil, and585-nm flashlamp-pumped pulsed-dye laser treatments. Arch.Dermatol. 138: 1149, 2002.


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