cosmetic artecoll: a long-lasting injectable wrinkle

Cosmetic

Artecoll: A Long-Lasting Injectable WrinkleFiller Material: Report of a Controlled,Randomized, Multicenter Clinical Trial of 251SubjectsSteven R. Cohen, M.D., and Ralph E. Holmes, M.D.San Diego, Calif.

Artecoll, an injectable wrinkle filler composed of poly-methylmethacrylate microspheres and bovine collagen, iswidely available outside the United States. For domesticavailability, a multicenter Investigational Device Exemp-tion study was required by the U.S. Food and Drug Ad-ministration. This study consisted of 251 subjects at eightcenters who received injections of Artecoll or the cur-rently approved collagen dermal filler (control) in 1334wrinkles of the glabella, nasolabial fold, radial upper liplines, and corner-of-the-mouth lines. The treatments wererandomized, and follow-up safety, efficacy, investigatorsuccess rating, and subject satisfaction rating data werecollected at 1, 3, and 6 months. The safety data, measuredas adverse events and immunoglobulin G serum levels,were low and similar for both groups. The efficacy data,measured by masked observers using a photographic fa-cial fold assessment scale, demonstrated a combined sig-nificant improvement with Artecoll compared with colla-gen at 6 months (p � 0.001). At 6 months, the investigatorsuccess ratings and the subject satisfaction ratings for eachof the four injections sites were superior for Artecoll (p �0.001). In the Artecoll group, 12-month follow-up wasobtained for 111 subjects (86.7 percent) and showed per-sistence of significant augmentation. Artecoll had feweradverse events reported throughout the 12-month safetystudy period than the control group did in 6 months,although the difference was not statisticallysignificant. (Plast. Reconstr. Surg. 114: 964, 2004.)

Over the past several decades numerous at-tempts have been made to develop safe biolog-ical or synthetic materials to permanently fillwrinkles and scars.1,2 Virtually all biological ma-terials, however, are resorbed within 1 year,and previously used synthetic materials havebeen associated with side effects such as migra-

tion, granuloma formation, and late allergicreactions.3 To overcome the problems with ar-tificial skin fillers, Artecoll was developed inGermany to be a permanent, injectableimplant.4

Artecoll consists of homogenous polymeth-ylmethacrylate microspheres evenly suspendedin a solution of partly denatured 3.5% colla-gen, which serves as a vehicle for deep dermalimplantation. All microspheres have a definedsize of 32 to 40 �m in diameter, are completelypolymerized, and have a smooth, round sur-face. Because of the smooth surface of themicrospheres, each microsphere becomes en-capsulated by the patient’s own collagen fibers,thereby preventing dislocation.

Artecoll consists of 20 volume% polymethyl-methacrylate microspheres evenly suspendedin 80 volume% U.S. bovine collagen per sy-ringe. After deep dermal injection of Artecoll,the collagen carrier is degraded by the bodywithin 1 to 3 months and completely replacedby the body’s own collagen at a similar rate,ensuring a steady augmentation result. Be-cause the microspheres are nonbiodegradableand too large to migrate or to be phagocytosedby macrophages, the tissue augmentation isexpected to be permanent, consisting of 80volume% autologous connective tissue.

Artecoll is approved and available in manycountries in the world. Since its introduction in1994, an estimated 200,000 patients have been

From the Division of Plastic Surgery, University of California. Received for publication May 19, 2003; revised November 5, 2003.Presented in part at the 52nd Annual Meeting of the California Society of Plastic Surgeons, in Rancho Mirage, California, May 25, 2002.Dr. Cohen and Dr. Holmes are consultants to Artes Medical, San Diego, California.

DOI: 10.1097/01.PRS.0000133169.16467.5F

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treated with a reported complication rate of0.01 percent.4 On February 28, 2003, the U.S.Food and Drug Administration’s General andPlastic Surgery Devices Advisory Panel recom-mended that Artecoll be approved, with condi-tions, for marketing in the United States. Arte-coll is expected to become the first long-lastinginjectable wrinkle filler to gain Food and DrugAdministration approval since collagen was in-troduced in 1981. After approval, Artecoll willbe marketed as “Artefill” in the United States,Canada, and Mexico.

MATERIALS AND METHODS

As an implant material, Artecoll is a class IIIdevice requiring Food and Drug Administra-tion approval via the premarket approvalroute. This clinical trial was conducted in ac-cordance with the Investigational Device Ex-emption regulations to obtain safety and effi-cacy data for inclusion in the premarketapproval application to the Food and DrugAdministration. The Investigational Device Ex-emption application for the Artecoll clinicaltrial received final approval by the Food andDrug Administration in August of 1999, andthe trial was completed in September of 2001.The purpose of this study was to compare thesafety and efficacy of Artecoll injections in theglabellar frown lines, nasolabial folds, radialupper lip lines, and corner-of-the-mouth (mar-ionette) lines to the safety and efficacy of col-lagen (Zyderm II or Zyplast; Inamed Corpora-tion, Santa Barbara, Calif.).

The primary objectives of the study were tocompare the cosmetic correction provided byArtecoll at the end of 6 months to that ofZyderm/Zyplast over the same time period andto explore the safety of Artecoll at 6 and 12months as an injectable implant for correctionof contour deformities of the dermis of theface. The secondary objectives of the studywere to characterize the physician’s assessmentof success with respect to how closely the treat-ment met the physician’s expectations for cor-rection and to characterize the subject’s assess-ment of satisfaction with respect to thesubject’s personal expectations. Though physi-cians were not masked as to the identity of thetreatment, subjects were not told which treat-ment they had received until after they hadcompleted the 6-month evaluation.

The study was performed at eight centers(four plastic surgery centers and four derma-tology centers) with institutional review board

approval and informed consent from all sub-jects. The study was controlled and random-ized, with potential subjects agreeing to be as-signed to either the Artecoll or the controlgroup. The subjects and evaluators weremasked and unaware of which injection mate-rial was received (double-blinded). To be in-cluded in the study, a subject had to fulfill thefollowing inclusion criteria: age 18 years orolder, realistic expectation of benefits, willingand able to give informed consent, presentingfor treatment in at least one of the four injec-tion sites, and willing and able to comply withfollow-up requirements. Exclusion criteria in-cluded pregnancy, treatment with botulinumtoxin type A or collagen or any other wrinkleaugmentation material within 6 months of thetrial, anticipation of cosmetic surgery beforecompleting the study, chemotherapy or corti-costeroid treatment within 3 months of begin-ning the study, ultraviolet light therapy duringthe course of the study, anticoagulant therapy,autoimmune disorder or history thereof, atro-phic skin disease, and extremely thin and/orflaccid skin. Additional exclusion criteria in-cluded known susceptibility to keloids, knownlidocaine hypersensitivity, history of dietarybeef allergy or undergoing desensitization,known allergy to collagen, severe allergies (his-tory of anaphylaxis), cellulitis or infection atprior implant site, serum immunoglobulin Glevels outside the normal range, and positiveskin test to collagen or two equivocal tests.

Treatment and follow-up consisted of firstscreening the interested candidates and enroll-ing and randomizing them if they met thestudy criteria. A blood sample was then drawnfor serum immunoglobulin G testing, followedby administration of the collagen skin test ap-propriate to the randomization assignment. Ifthe subject met all criteria, treatment was ini-tiated. Subjects were permitted to return for asmany as two re-treatments over a maximumperiod of 1 month, with no limits on the vol-ume of Artecoll or collagen injected. Follow-upappointments were then scheduled at 1, 3, 6,and 12 months, based on the final treatmentdate. Safety was assessed by recording all ad-verse events and by measuring serum immuno-globulin G levels at the 1-month visit, as well asat subsequent visits if it was elevated at theprevious visit. Efficacy was measured by threemasked observers using a Facial Fold Assess-ment Scale to rate wrinkles on the subject’sphotographs. Investigator assessment of suc-

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cess was recorded at 1, 3, and 6 months usingthe following scale: 1 � completely successful,2 � very successful, 3 � moderately successful,4 � somewhat successful, and 5 � not at allsuccessful. Subject assessment of satisfactionwas recorded at 1-, 3-, and 6-month intervalsusing the following scale: 1 � very satisfied, 2 �satisfied, 3 � somewhat satisfied, 4 � dissatis-fied, and 5 � very dissatisfied.

Facial Fold Assessment Scale

The Facial Fold Assessment Scale used tograde wrinkles and furrows is a photographi-cally based classification of mimetic wrinkles. Ithad been previously validated by “live” ratings,photographic ratings, and profilometric mea-surement of wrinkle depth.5 The scale is aneasy, consistent, and reliable tool for the assess-ment of wrinkle depth. Wrinkle depth isgraded from 0 (least wrinkle depth) to 5 (mostwrinkle depth). The six-point scale was used inthe present study by three masked observers toobjectively rate wrinkle severity before treat-ment and at 1, 3, and 6 months after treatmentwith Artecoll or collagen. Each rater comparedstandardized photographs taken at each studyinterval to reference photographs to assign agrade of 0 to 5 to each of the study wrinkles.5Rating was conducted in a randomized mannerand raters were not informed of the treatmentgroup or evaluation period (pretreatment orfollow-up) for any photograph. Each of thethree raters independently evaluated eachphotograph. Efficacy-dependent variables wereexpressed as the improvement of Facial FoldAssessment Scale ratings from baseline, aver-aged across the two facial sides in the case ofbilateral treatment. A single overall improve-ment score was also computed for each subjectand was also calculated by averaging the im-provement across facial areas.

Injection Technique

Before injection, topical EMLA cream (lido-caine 2.5% and prilocaine 2.5%; AstraZeneca,Wilmington, Del.) and, for the upper lip, localanesthesia were employed when indicated bythe investigator. The dermal layer utilized forArtecoll implantation is shown in Figure 1. Themethod of implanting Artecoll is more tech-nique-sensitive than that for injecting collagen.The “tunneling technique” (i.e., moving theneedle in a linear fashion back and forth justbeneath the wrinkle) was utilized. Since theviscosity of Artecoll is three times higher than

that of Zyplast, a higher constant pressure wasapplied throughout the injection procedure. A27-gauge needle half an inch in length wasutilized. The thickness of the needle and skinwas used to help determine the depth of injec-tion. The thickness of facial skin varies from 0.2mm (eyelids) to 0.4 mm (nasolabial folds) to0.8 mm (glabellar frown lines).6 The thicknessof the skin in a deep crease is diminished toabout one quarter of its normal thickness. Atthe start of the procedure, the needle wastested by squeezing a small quantity of Artecollout of the tip. Artecoll was then implanteddeeply intradermally (e.g., into the reticulardermis just above the junction between thedermis and subcutaneous fat). If Artecoll wasinjected into the papillary dermis, causing ablanching effect, the injection was stopped andthe needle was placed at a deeper level. At theend of implantation, the implant was evenlymassaged with the fingernail and slight pres-sure was applied to any detected lump. Sub-jects were advised that there would be someswelling for the first 12 to 24 hours and thatareas of light pink coloration along the injec-tion sites might be present for 2 to 5 days. Theywere also advised to minimize mimetic activityfor 1 to 2 days.

FIG. 1. The dermal plane of Artecoll implantation.(Above) The dermal thickness is diminished under a wrinkle.(Below) Artecoll is injected into the deep dermis to “fill” thewrinkle.

966 PLASTIC AND RECONSTRUCTIVE SURGERY, September 15, 2004

Statistical Analysis

Adverse events were described by counts ofevents and counts of subjects experiencing ad-verse events. Counts of elevated immunoglob-ulin G levels were also provided. Tests for treat-ment group differences in number oftreatments and quantity of product were madeusing independent t tests. Nonparametric testswere used for ratings variables. Groups werecompared with Mann-Whitney U tests for im-provements in observer-rated and investigator-rated Facial Fold Assessment Scale scores andfor investigator success ratings and subject sat-isfaction ratings. Within-group tests for im-provements in the Artecoll treatment groupwere made using Wilcoxon matched-pairssigned rank data to accommodate the 12-month observations. Rater reliability for ob-server Facial Fold Assessment Scale ratings wasevaluated using intraclass correlation.

RESULTS

There were 251 subjects entered into thestudy. One hundred twenty-eight subjects re-ceived Artecoll (11 men and 117 women),while 123 subjects (11 men and 112 women)received the collagen control (Table I). Themean age was 53.2 years (range, 28 to 82 years)for the Artecoll subjects and 51.2 years (range,29 to 78 years) for the control subjects (TableI). Of these 251 subjects, 247 had at least onefollow-up visit (98.4 percent) and 233 (92.8percent) had a 6-month follow-up visit. Inthe Artecoll group, 12-month follow-up wasobtained for 111 subjects (86.7 percent).Since Artecoll treatment was offered to allsubjects in the collagen group at the 6-monthfollow-up, no 12-month follow-up could beobtained for the collagen group. Of the 116collagen subjects who completed the6-month follow-up evaluation, 106 (91 per-cent) were treated with Artecoll.

Artecoll was injected into the glabellarfrowns of 81 subjects, the nasolabial folds of108 subjects, the upper lip lines of 69 subjects,and the mouth corners of 86 subjects; collagenwas injected into the glabellar frowns of 86subjects, the nasolabial folds of 104 subjects,the upper lip lines of 59 subjects, and themouth corners of 87 subjects (Table II). Intotal, 1334 wrinkles were injected: 320 glabellarfrowns, 420 nasolabial folds, 253 lip lines, and341 mouth corners were treated in the 251subjects (Table II).

The number of treatments to each of thefacial areas (i.e., glabellar frowns, nasolabialfolds, radial upper lip lines, and corner-of-the-mouth lines) was not significantly different (p� 0.316 to 0.974) between the Artecoll andcontrol groups (Fig. 2). Almost twice as muchcollagen as Artecoll was used at each of thefour injection sites (Fig. 3), a statistically signif-icant difference (p � 0.001 in each case).

Results of Primary Objectives

Although adverse reactions were uncommonin both groups, more redness and swelling andmore lumpiness at the injection site werenoted in the collagen group. There were a totalof 27 adverse events in the Artecoll group com-pared with 38 in the collagen control group.These numbers were not statistically signifi-cant. One subject underwent “incidental” re-moval and/or drainage in the Artecoll grouprelated to excision of an actinic keratosis in thevicinity of the previous Artecoll injection, andtwo subjects in the collagen group requiredremoval and/or drainage for abscesses (TableIII).

Serum immunoglobulin G levels were ele-vated in one subject undergoing Artecoll im-plantation after 1 month. Levels were elevatedin one subject at 1, 3, and 6 months aftercollagen injection (Table IV).

TABLE ISubject Data

Artecoll Control Total

SexMale 11 11 22Female 117 112 229Total 128 123 251

AgeMean 53.2 51.2 52.2Range 28–82 29–78 28–82SD 10.3 11.3 10.8

TABLE IITreatment Data

Artecoll Control Total

No. of subjects treatedGlabella 81 86 167Nasolabial fold 108 104 212Lip lines 69 59 128Mouth corners 86 87 173

No. of wrinkles treatedGlabella 155 165 320Nasolabial fold 214 206 420Lip lines 137 116 253Mouth corners 171 170 341


Table V summarizes improvement over timein the masked observers’ Facial Fold Assess-ment Scale ratings. Observations 1 month afterinjection showed no statistically significant dif-ference between the two groups for nasolabialfolds, upper lip lines, or mouth corners, whilethe control treatment was more effective (p �0.004) than Artecoll for glabellar folds. By 3months, the masked observers’ ratings showeda statistically significantly greater improvementin the nasolabial folds (p � 0.001) and thecorner-of-the-mouth wrinkles (p � 0.001) inthe Artecoll group when compared with thecollagen control group. Averaged across facialareas, the overall result was also significant (p� 0.001). At 6 months after injection, the Ar-tecoll was statistically better (p � 0.001) thanthe collagen injection in the nasolabial foldand overall (p � 0.001). Facial Fold AssessmentScale reliability among the three masked ratersranged from 0.835 for the glabellar frowns to0.900 for the corner-of-the-mouth lines.

Results of Secondary Objectives

Table VI summarizes improvement in inves-tigators’ Facial Fold Assessment Scale ratingsover time. Unlike masked observers who rated

from photographs, investigators were notmasked and rated their live experience withsubjects against the reference photographs ofthe assessment scale. At 1 month, significantlygreater improvement in glabellar folds wasseen with control collagen than with Artecoll(p � 0.034), while significantly greater im-provement in mouth corners was seen withArtecoll than with control collagen (p �0.041). By 3 months, all facial areas except forthe glabellar folds (p � 0.317) showed signifi-cantly greater improvement with Artecoll thanwith control collagen (p � 0.001 in each case).The overall average was also significantlygreater for Artecoll (p � 0.001). By 6 months,all four facial areas and the overall averageshowed significantly greater improvement withArtecoll than with control collagen (p �0.001).

Investigator success ratings over time aresummarized in Figure 4. The ratings for thetwo groups were similar at 1 month. However,by 3 months and 6 months, significantly moresuccess was noted in the Artecoll group than inthe control group (p � 0.007 to p � 0.001). By6 months, Artecoll ratings were generally in thevery successful range while collagen ratingswere generally in the somewhat successfulrange.

A similar presentation for subject ratings ofsatisfaction is shown in Figure 5. No significantdifferences between treatment groups werenoted at 1 month. By 3 months, the subjects inthe Artecoll group reported significantlygreater satisfaction than subjects in the controlgroup did (p � 0.038 to p � 0.001). At 6months, the subjects in the Artecoll group con-tinued to report significantly greater satisfac-tion than did the control group subjects (p �0.001 in each case). By 6 months, the meansfor the Artecoll group were generally in thesatisfied range while the means for the controlgroup were generally in the dissatisfied range.

12-Month Artecoll Efficacy Analysis

Data on improvement at 12 months in FacialFold Assessment Scale ratings were availablefor the Artecoll group only, per protocol, dueto cross-over of collagen subjects to the Artecolltreatment at 6 months. Ratings from masked ob-servers and from investigators were included.

Single-group tests were computed formasked observer ratings to determine whetherefficacy could be detected 12 months aftertreatment. The results showed significant im-

FIG. 2. During the 4 weeks after initial treatment, addi-tional treatments were permitted. The number of treatments(mean � SE) did not differ significantly between Artecoll andcontrol collagen (p � 0.974, 0.316, 0.705, and 0.608, for theglabellar lines, nasolabial fold, upper lip lines, and mouthcorners, respectively).

FIG. 3. The quantity of Artecoll injected (mean � SE) wassignificantly lower than the amount of control collagen in-jected for each facial area (p � 0.001 in each case).


provement in Facial Fold Assessment ratingsfor the each of the four facial areas and theoverall average (p � 0.047 to p � 0.001).

Similar tests were computed for investigatorFacial Fold Assessment ratings. These showedsignificant results in all four of the treatmentareas and overall (p � 0.001 in each case).These ratings for masked observers and inves-tigators demonstrated effectiveness 12 monthsafter Artecoll treatment.

Investigators’ ratings of success and subjects’ratings of satisfaction in the Artecoll group at12 months are presented in Figures 4 and 5,respectively. The success and satisfaction rat-ings remained high for the Artecoll group at12 months.

DISCUSSION

The results of this study show Artecoll to bea safe and effective soft-tissue filler. AlthoughArtecoll had fewer adverse events reportedthroughout the 12-month safety study periodcompared with collagen (Zyderm/Zyplast) in a6-month study period, these results were notstatistically significant. Artecoll was more effec-tive than collagen for correction of nasolabialfolds in masked observers’ ratings at the6-month effectiveness study period. No statisti-cally significant difference was noted betweenmasked observer ratings for Artecoll and colla-gen in the other injection sites; however, thequantity of Artecoll used was nearly half that ofcollagen. Investigators’ success ratings for Ar-tecoll were superior to those for collagen at 6months for each of the four injection sites.Subjects’ satisfaction ratings for the Artecollgroup were also higher than for collagen ineach of the injection sites at 6 months afterimplantation.

Zyderm was introduced as a dermal fillerinto the clinical arena in 1982.7 It was initiallyvery well received, but enthusiasm cooled be-cause of its short duration of action. It is thegeneral impression of many clinicians that vir-tually all biological materials eventually are ab-

TABLE IVAbnormal Immunoglobulin G Levels in Artecoll and

Control Groups

Treatment/Level

Follow-Up

1 Month 3 Months 6 Months

ArtecollAbove 1 0 0Below 0 0 0

ControlAbove 1 1 1Below 6 3 1

TABLE IIIAdverse Events from Artecoll and Control Collagen Injections

Event

No. of Events

Artecoll Control

ReportedRemoval orDrainage* Reported

Removal orDrainage*

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 hours after injection 2 2Lumpiness at injection site �1 month after injection 8 (1‡) (1†) 1§ 4Blurred 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†Adverse events 26 1 36 2Total

Total no. of subjects 21 1 16 2Total no. of subjects evaluated 128 128 123 123% of subjects 16.4 0.8 13.0 1.6

* Adverse events with removal or drainage are included in total reported.† Not related to implant.‡ Used contrary to protocol lip augmentation.§ Pathology showed no foreign-body reaction. Diagnosis (seborrheic keratosis) not related to implant.


sorbed. To provide permanent tissue augmen-tation, polymethylmethacrylate, a substancewidely used as a permanent implant, was com-bined with a temporary collagen carrier to de-liver smooth, round polymethylmethacrylate

microspheres into the deeper skin layers.8

Once in position, the bovine collagen carrier isreplaced by autologous connective tissue whichindividually encapsulates each of the micro-spheres, creating a bulk augmentation that is

TABLE VIImprovement in Investigator Ratings Using the Facial Fold Assessment Scale

Artecoll Control

pNo. Mean SD SE No. Mean SD SE

1 MonthGlabellar 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 MonthsGlabellar 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 MonthsGlabellar 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 MonthsGlabellar 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

TABLE VImprovement in Masked Observers Ratings Using the Facial Fold Assessment Scale

Artecoll Control

pNo. Mean SD SE No. Mean SD SE

1 MonthGlabellar 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 MonthsGlabellar 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 MonthsGlabellar 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 MonthsGlabellar 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


approximately 20 percent synthetic and 80 per-cent the patient’s own collagen.

A preliminary product used in humans bythe same inventor, before Artecoll, was calledArteplast.9 The original suspension consistedof 30- to 42-�m-diameter polymethylmethacry-late microspheres in gelatin. The first clinicaltrials were conducted under the supervision ofthe Ethical Commission of Frankfurt Universityin 1989. One hundred eighty-seven volunteersreceived Arteplast subdermally. In this group,plus in the 400 subjects who received Arteplastup until its replacement by Artecoll in 1994, atotal of 15 subjects (2.5 percent) developedforeign-body granulomas from 6 to 18 monthsafter injection.4 The majority of these granulo-mas were treated with intralesional steroid in-jection and rarely with surgical excision. In1994, a new purification and washing tech-nique was introduced.4 The sieving process was

changed from a nylon fabric mesh to a metalmesh, and a complex washing and ultrasoundprocedure was devised that removed virtuallyall nanoparticles and electrical surface charges,which were thought to be the cause of foreign-body reactions and granuloma formation. An-other change made at the same time was theuse of collagen as a carrier to replace the gel-atin carrier, which is resorbed too quickly andthereby permits clumping of the particles.

The improved product, named Artecoll, wasbrought onto the market by Rofil Medical In-ternational, Breda, Holland, in 1994, and it hassince been used in an estimated 200,000 pa-tients with a reported granulomatous reactionrate of less than 0.01 percent.4

In evaluating the literature on safety of per-manent injectable fillers, it is critical for theclinician to differentiate between Arteplast andArtecoll. Arteplast and Artecoll have been con-

FIG. 4. The investigators’ success ratings (mean � SE) for Artecoll and controlcollagen were similar at 1 month (p � not significant in each case except for mouthcorners, p � 0.011) and significantly higher for Artecoll than for control collagen atboth 3 and 6 months (p � 0.001 in each case except 3-month glabellar, where p � 0.007).Artecoll success ratings remained high at 12 months.

FIG. 5. The subjects’ satisfaction ratings (mean � SE) for Artecoll and controlcollagen were similar at 1 month (p � not significant in each case) and significantlyhigher for Artecoll at 3 and 6 months (p � 0.001 in each case except for 3-monthglabellar, where p � 0.038). Satisfaction ratings for Artecoll remained high at 12months.


fused with each other in the past, making ac-curate communication about the safety andefficacy of Artecoll difficult.10 Electron micros-copy views of the polymethylmethacrylate mi-crospheres contained in Artecoll clearly dem-onstrate the absence of microparticles in theArtecoll microspheres (Fig. 6).

Biocompatibility

The chemical inertness and biocompatibilityof polymethylmethacrylate has been well ac-cepted since Judet11 introduced the first hipprosthesis made from polymethylmethacrylatein 1947. Animal experiments have docu-mented that an important key to biocompat-ibility in the skin is the round shape andsmooth surface and the size of the polymethyl-methacrylate microspheres.12,13 In comparison,other synthetic fillers, such as Teflon and sili-cone particles, have irregular surfaces andcause a chronic granulomatous reaction.14 Mi-croscopically, the predominant cells seen inthe reaction to Teflon or silicone particles are

foreign-body giant cells. In contrast, in the rarecase of foreign-body reaction to Artecoll, histo-logically, the true granulomas show broadbands of collagen fibers between micro-spheres, which are pushed apart, with rare lym-phocytes, macrophages, and giant cells.15

These granulomas almost always respond tointralesional injection with corticosteroid.4,16

Most materials that are used as biologicalfillers to increase the thickness of the dermis ina wrinkle line are phagocytosed within a fewmonths. Therefore, a lasting effect can beachieved only by using either an autogenousmaterial that becomes vascularized and sur-vives as a graft or nonresorbable synthetic sub-stances. There are six million polymethyl-methacrylate microspheres in each 1 cc ofArtecoll. Beneath the wrinkle crease, the mi-crospheres stimulate fibroblasts to encapsulateeach individual microsphere. Collagen is usedas a carrier substance that prevents clumpingduring injection and favors tissue ingrowth.The 20 volume% polymethylmethacrylate mi-crospheres provide the scaffold for the 80 vol-ume% autologous connective tissue deposi-tion. The Artecoll serves as a filler that seems to“splint” the wrinkle crease, preventing furtherfolding and allowing the dermis to regeneratein the wrinkle fold.

Treatment Areas

The glabellar lines posed little problem withinjection since the dermis is thick and the un-derlying connective tissue provides good sup-port for the implant (Fig. 7). Slight overcorrec-tion may be necessary and deeper lines mayrequire repeated injections. It is difficult toexplain the lack of statistical difference be-tween collagen and Artecoll in the glabellarfrown region using masked observer ratings.Initial overcorrection was common for colla-gen treatment. However, there was a generalreluctance among U.S. clinical trial investiga-tors to inject as much Artecoll as collagen ineach of the four study areas due to its perma-nent effect, which may account for the absenceof clear-cut statistical significance, with the ex-ception of nasolabial folds. Nevertheless, sub-ject satisfaction ratings and investigator successratings were higher for Artecoll at the 6-monthpoint in each of the four study areas.

The results of nasolabial fold augmentationwith Artecoll were excellent (Figs. 8 and 9).Nasolabial creases are best supported by two tothree bands of Artecoll implanted parallel and

FIG. 6. Comparison of scanning electron microscopy im-ages of polymethylmethacrylate bone cement (above) andArtecoll polymethylmethacrylate 32- to 40-�m-diameter mi-crospheres (below). Note the absence of nanoparticles on thesurface of Artecoll microspheres as a result of the washingprocedures.


medial to the fold. During the first several daysafter implantation, Artecoll can be moved lat-erally by facial muscle movement. Care must betaken not to place the Artecoll too superfi-cially. Otherwise, in patients with thin skin theimplant may appear erythematous for severalweeks and the implant may be visualized assmall white granules. A second session is oftennecessary, especially in the inferior aspect ofthe nasolabial crease.

Radial lip lines extend upward or downwardfrom tiny notches in the vermilion-cutaneousborder. In younger patients with nice projec-tion of the white roll, each wrinkle can betreated individually. In patients with four ormore vertical lines and in whom the projectionof the white roll is diminished, Artecoll can beinjected transversely along the entire white rollas well as beneath the individual vertical lines(Fig. 10). There is a natural pocket betweenthe white roll and the orbicularis oris musclethat is easily filled centripetally from the cor-ners of the mouth. Injection into the upperand lower lips may be painful, and field ornerve blocks with local anesthesia may be help-ful. Artecoll is not intended for injection intothe vermilion of the lip.

Wrinkles at the corners of the mouth andmarionette lines may be difficult to treat, butthey often yield excellent results. First, thelower white roll itself is treated horizontallyabout 1 cm in length from the corner. Next,five to 10 vertical and horizontal threads of

FIG. 7. Glabellar lines before (above) and 6 months after(below) treatment with Artecoll.

FIG. 8. Nasolabial fold before (left) and 12 months after (right) treatment withArtecoll.


Artecoll should be implanted using a criss-crossing technique (Fig. 11). This supports theregion and slightly lifts the corners of themouth. The skin is thin in this area and super-ficial injection may lead to telangiectasias. Pref-erably, Artecoll should be implanted in manydifferent tunnels in two or more sessions. In-jection of Artecoll into the orbicularis oris mus-cle is to be avoided as it may result in theformation of nodules that can be palpated in

the wet mucosa. The marionette lines that ex-tend vertically from the corners of the mouthdown to the mandibular border can be im-proved by linear threading combined withdeep intradermal criss-cross injection ofArtecoll.

CONCLUSIONS

The ability to measure the effect of cosmetictreatments, such as wrinkle fillers, has suffered

FIG. 9. Nasolabial folds before (left), 6 months after (center), and 1 year after (right) treatment with Artecoll.

FIG. 10. Upper lip lines, marionette lines, and nasolabial folds before (left), 6 months after (center), and 12 months after (right)treatment with Artecoll.


from the lack of a validated objective ratingscale. The authors hope that the successfulutilization of a photographic facial fold assess-ment scale for this Food and Drug Administra-tion study will encourage development andadoption of similar scales for cosmetic treat-ment evaluations.

This study has demonstrated the safety ofArtecoll relative to collagen control, as mea-sured by relative rates of adverse events. It hasdemonstrated the effectiveness of Artecoll rel-ative to collagen control for the treatment ofnasolabial folds, as measured by the objectiverating scale using masked raters. The effective-ness of Artecoll was demonstrated for all areastreated, using the important outcome mea-sures of investigator success rating and subjectsatisfaction.

Steven R. Cohen, M.D.8010 Frost Street, Suite 412San Diego, Calif. [email protected]

ACKNOWLEDGMENTS

This study was sponsored by Artes Medical, Inc., San Di-ego, Calif. It was approved by an institutional review boardand subjects gave informed consent at all eight study centers.

The authors acknowledge the excellent patient care andstudy data collection of the other 10 clinical investigators whotook part in this clinical trial: Carl F. Berner, M.D., Seattle,Wash.; Mariano Busso, M.D., Miami, Fla.; Douglas Hamilton,M.D., Beverly Hills, Calif.; James J. Romano, M.D., San Fran-cisco, Calif.; Millard P. Thaler, M.D., and Zeena Ubogy, M.D.,Mesa, Ariz.; Peter P. Rullan, M.D., and Cole B. Willoughby,M.D., Chula Vista, Calif.; and Mathew C. Gleason, M.D., and

Thomas R. Vecchione, M.D., San Diego, Calif. The authorsare indebted to Paul Clopton, M.S., Research Service, Vet-erans Affairs Medical Center, San Diego, Calif., for his in-valuable statistical work, and PaxMed International, San Di-ego, Calif., for its diligent and thorough management of thisstudy.

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cosmetic artecoll: a long-lasting injectable wrinkle

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